latest research on gastric cancer

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• Published: 27 May 2023

Gastric cancer treatment: recent progress and future perspectives

• Wen-Long Guan 1 , 2   na1 ,
• Ye He 1 , 2   na1 &
• Rui-Hua Xu 1 , 2  

Journal of Hematology & Oncology volume  16 , Article number:  57 ( 2023 ) Cite this article

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Gastric cancer (GC) is one of the most common malignancies worldwide. Most patients are diagnosed at advanced stages due to the subtle symptoms of earlier disease and the low rate of regular screening. Systemic therapies for GC, including chemotherapy, targeted therapy and immunotherapy, have evolved significantly in the past few years. For resectable GC, perioperative chemotherapy has become the standard treatment. Ongoing investigations are exploring the potential benefits of targeted therapy or immunotherapy in the perioperative or adjuvant setting. For metastatic disease, there have been notable advancements in immunotherapy and biomarker-directed therapies recently. Classification based on molecular biomarkers, such as programmed cell death ligand 1 (PD-L1), microsatellite instability (MSI), and human epidermal growth factor receptor 2 (HER2), provides an opportunity to differentiate patients who may benefit from immunotherapy or targeted therapy. Molecular diagnostic techniques have facilitated the characterization of GC genetic profiles and the identification of new potential molecular targets. This review systematically summarizes the main research progress in systemic treatment for GC, discusses current individualized strategies and presents future perspectives.

Gastric cancer (GC) is the fifth most common malignant tumor and the fourth leading cause of cancer-associated death worldwide [ 1 , 2 ]. The incidence varies geographically across the globe, with the highest incidence in Eastern Asia (Japan and Mongolia) and Eastern Europe, whereas incidence rates in Northern Europe and Northern America are generally low, comparable to African regions [ 2 ]. Notably, the incidence of gastric cancer among young adults (aged < 50 years) in recent years has been progressively rising in both low-risk and high-risk countries. Aside from Helicobacter Pylori infection, the occurrence of GC has been linked to genetic risk factors as well as lifestyle factors, such as alcohol consumption and smoking [ 3 , 4 , 5 , 6 ].

Despite the high incidence of GC, most patients are unfortunately diagnosed at advanced stages with dismal prognoses due to the lack of distinguishing clinical indications [ 7 , 8 ]. Systemic chemotherapy is the mainstay treatment for metastatic GC (mGC), with a median overall survival (OS) of ~ 12 months for patients treated with conventional chemotherapy [ 9 ]. Intratumoral and intertumoral heterogeneity are the prominent features of GC that partly contribute to its poor prognosis. However, histological classifications alone are insufficient to effectively stratify patients for individualized treatment and improve patients’ clinical outcomes [ 10 ]. Therefore, cutting-edge diagnostic techniques and drugs are of fundamental importance for better characterizing molecular profiles and identifying potential novel therapeutic targets for GC patients [ 11 , 12 , 13 ].

Trastuzumab, a monoclonal antibody targeting Human Epidermal Receptor 2 (HER2), was the first approved targeted therapy for GC. However, after the ToGA study, progress in the development of treatments for gastric cancer stalled for nearly a decade [ 14 ]. Emerging advances in immunotherapy, particularly in anti-HER2 therapy, and various biomarker-directed therapies in GC have recently broken this trend. For example, anti-programmed cell death 1 (PD-1) antibodies have demonstrated impressive efficacy and prolonged survival in untreated MSI-H/dMMR mGC patients [ 15 ]. Substantial breakthroughs in the treatment of gastric cancer have been achieved with novel anti-HER2 therapeutic agents, such as T-DXd and disitamab vedotin (RC48) [ 16 ]. In addition, in light of the success of immunotherapy and targeted therapy as first-line treatments for advanced gastric cancer, ongoing research is investigating their potential to advance the treatment of patients with locally advanced stage GC.

The treatment landscape of gastric cancer has evolved significantly in the past few years, with the emergence of new immunotherapy and targeted therapies for patients at various stages of the disease (Fig.  1 ). In this review, we systematically summarize the pivotal clinical trials in GC treatment and provide an update on the management of localized and metastatic gastric cancer. We also discuss the developments in immunotherapy and targeted therapy and highlight current individualized treatments and future perspectives.

Updated immunotherapy and targeted therapy for gastric cancer. This algorithm provides guidance for selecting currently available immunotherapy and targeted therapy based on different biomarkers

Management for localized GC

Radical surgery is the primary treatment for resectable gastric cancer. Several therapeutic approaches have been established to lower the risk of recurrence and improve long-term survival, including perioperative chemotherapy, adjuvant chemotherapy, and adjuvant chemoradiotherapy (Table 1 ). They are listed as the recommended treatments for resectable localized GC in current guidelines[ 5 , 17 , 18 ]. Further, the addition of targeted therapy and/or immune checkpoint inhibitors (ICIs) is currently being studied in the neoadjuvant/adjuvant setting.

• Perioperative chemotherapy

Perioperative chemotherapy has become the standard treatment for resectable localized GC. Several clinical trials have demonstrated that perioperative chemotherapy could improve the prognosis of patients with resectable GC compared to surgery alone.

The MAGIC trial marked a significant advancement in the field of perioperative chemotherapy for resectable GC. In this phase 3 study, 503 patients were enrolled with resectable gastric, gastroesophageal junction (GEJ), or lower esophageal adenocarcinoma. Patients in the experimental group received three preoperative and three postoperative cycles of epirubicin, cisplatin, and fluorouracil (ECF) [ 19 ]. The results showed that the perioperative ECF regimen could decrease tumor stage and significantly improve progression-free survival (PFS, HR 0.66; 95% CI 0.53–0.81, P < 0.001) and overall survival (OS, HR 0.75; 95% CI 0.60–0.93, P  = 0.009). Another phase III trial conducted in 28 French centers compared radical surgery with or without perioperative cisplatin and fluorouracil (CF) chemotherapy and showed that perioperative chemotherapy led to a higher 5-year overall survival rate versus surgery alone (38% versus 24%, respectively; HR 0.69; 95% CI 0.50–0.95, P  = 0.02) [ 20 ]. Recently, the randomized phase II/III FLOT4-AIO study compared perioperative FLOT regimen (fluorouracil, leucovorin, oxaliplatin, and docetaxel) with previous standard ECF/ECX (epirubicin, cisplatin, and fluorouracil/capecitabine) regimen in gastric or GEJ cancer patients who had cT2 or higher and nodal positive (cN +) disease [ 21 ]. The results suggested that the FLOT regimen could improve overall survival (50 months versus 35 months), confirming the role of the FLOT regimen as the new standard perioperative treatment for resectable gastric cancer [ 5 , 18 ].

Since most of the clinical trials mentioned above were conducted in western countries, these perioperative regimens (ECF, CF, and FLOT) are less frequently used in Asia. In the phase III PRODIGY trial, 530 Korean patients with cT2-3N + or cT4N any gastric or GEJ cancer were randomly randomized to the neoadjuvant or adjuvant group. Patients in the neoadjuvant arm underwent preoperative DOS (docetaxel, oxaliplatin, and S-1) followed by surgery and S-1 adjuvant chemotherapy, while those in the adjuvant arm received upfront radical surgery followed by S-1 chemotherapy [ 22 ]. The perioperative chemotherapy group had significantly higher rates of R0 resection and pathological complete response (pCR) (95% and 10.4%, respectively). Moreover, PFS was improved in the perioperative arm compared to the adjuvant arm (HR 0.70; 95% CI 0.52–0.95; P  = 0.023). The major criticism of this study was that the adjuvant S-1 monotherapy was insufficient for stage III patients, considering another phase III study had demonstrated the superiority of docetaxel plus S-1 to S-1 for 3-year relapse-free survival (RFS) in stage III gastric cancer [ 23 ]. Recently, the phase III RESOLVE trial conducted in China investigated the role of perioperative S-1 plus oxaliplatin (SOX) chemotherapy versus upfront surgery followed by adjuvant chemotherapy [ 24 ]. This study recruited over 1,000 patients with cT4aN + or cT4bN any gastric or GEJ adenocarcinoma, of whom over 60% had gastric cancer. Patients in the intervention group received perioperative SOX (three preoperative cycles and five postoperative cycles followed by three cycles of S-1 monotherapy). The two adjuvant groups received surgery followed by SOX or CAPOX (capecitabine and oxaliplatin) chemotherapy. These results suggested that the perioperative SOX chemotherapy could improve the 3-year disease-free survival (DFS) rate compared to adjuvant CAPOX therapy (59.4% vs. 51.1%, respectively, P  = 0.028).

Based on the evidence shown above, perioperative chemotherapy has become the standard treatment in many countries. The FLOT regimen is the most commonly used in Western countries according to the evidence from the FLOT4-AIO study[ 21 ], while the SOX regimen is more recommended in China, based on the results of the RESOLVE study[ 24 ]. However, perioperative chemotherapy is less recommended in Japan, since evidence of the superiority of neoadjuvant chemotherapy is still lacking among Japanese patients[ 25 ].

Adjuvant chemotherapy

Adjuvant chemotherapy is recommended for patients who undergo primary surgery and have stage II or stage III disease due to improvement in survival demonstrated by several clinical trials, particularly in Asian patients. The multi-center phase III CLASSIC trial undertaken in South Korea, China, and Taiwan compared upfront D2 surgery followed by CAPOX adjuvant chemotherapy versus D2 gastrectomy alone in patients with stage II-IIIB gastric cancer [ 26 , 27 ]. Adjuvant CAPOX chemotherapy significantly improved both 5-year DFS (68% vs. 53%; HR 0.58; 95% CI, 0.47 to 0.72; P < 0.0001) and OS (78% vs. 69%; HR 0.66; 95% CI, 0.51 to 0.85; P  = 0.0015) compared with surgery alone. Another similar phase III ACTS-GC trial from Japan randomly assigned 1,059 stage II or III GC patients to undergo D2 surgery followed by S-1 monotherapy or D2 surgery alone and showed that adjuvant S-1 monotherapy for one year led to a better 3-year OS than surgery alone (80.1% vs. 70.1%; HR 0.68; 95% CI, 0.52 to 0.87; P  = 0.003). The survival benefit persisted after five years of follow-up [ 28 ]. Moreover, the phase III JACCRO GC-07 trial investigated the superiority of adjuvant docetaxel plus S-1 over S-1 monotherapy for pathological stage III gastric cancer [ 23 ]. The addition of docetaxel to S-1 after surgery showed a better 3-year RFS (66% vs. 50%; HR 0.632; 99.99% CI, 0.400 to 0.998; P  < 0.001) in the second interim analysis, and the study was terminated as recommended by the independent data and safety monitoring committee. The RESOLVE trial also investigated the non-inferiority of adjuvant SOX chemotherapy compared with the CAPOX regimen. The 3-year DFS was statistically comparable between the two groups (56.5% vs. 51.1%; HR 0.86; 95% CI, 0.68 to 1.07; P  = 0.17) [ 24 ]. Based on the results of the phase III trials presented above, several cytotoxic regimens could be used as adjuvant treatments for stage II-III GC after radical surgery, including S-1, CAPOX, SOX, and DS. The choice of regimens depends on many factors, including the pathological staging, patient performance status, and toxicity profile. In general, S-1 monotherapy is more recommended for stage II disease or for patients with poor performance status. Combination therapies such as CAPOX, SOX, or DS are often recommended for pathological stage III disease[ 17 , 25 ].

GC with microsatellite instability-high (MSI-H) or mismatch-repair deficiency (dMMR) is a distinct subtype [ 11 ]. Recently, an individual-patient-data meta-analysis including data from four large phase III studies (CLASSIC, ARTIST, MAGIC, and ITACA-S trial) explored the role of adjuvant chemotherapy in the MSI-H subtype [ 29 ]. It showed that for resectable MSI-H/dMMR GC patients, the prognosis of patients who received surgery alone was better than those who underwent surgery followed by adjuvant chemotherapy, even though the sample size of MSI-H/dMMR in this meta-analysis was very modest (N = 121). Based on this result, adjuvant chemotherapy is not recommended for resectable MSI-H/dMMR GC patients in the latest ESMO guideline [ 5 ]. Additionally, the updated CSCO guidelines suggest that either observation or adjuvant chemotherapy could be considered after a thorough discussion with the patients regarding the possible risks and benefits [ 17 ].

Adjuvant chemoradiotherapy

Unlike chemotherapy, the role of radiotherapy for resectable GC in the adjuvant setting is controversial. Adjuvant chemoradiotherapy (CRT) was once adopted in North America, according to the results of the phase III INT-0116 trial [ 30 ]. In this study, 556 patients with resectable GC or GEJ adenocarcinoma were randomly assigned to the upfront surgery plus adjuvant CRT group or the surgery group. Patients in the experimental arm received adjuvant fluorouracil chemotherapy plus 4500 cGy of radiation (5 × 5). Overall, CRT did prolong the OS compared to surgery alone (36 vs. 27 months, respectively; P  = 0.005). However, most patients in this study received D0 or D1 lymphadenectomy and only 10% had D2 lymphadenectomy. The extent of dissection might affect the outcome of the surgery-only group. The phase III ARTIST trial from Korea evaluated the role of postoperative CRT based on the D2 dissection backbone [ 31 ]. Four hundred fifty-eight patients who received D2 lymphadenectomy and R0 resection were enrolled and randomly assigned to the adjuvant chemotherapy arm (capecitabine plus cisplatin, XP) or the adjuvant CRT arm (XP-XRT-XP). Unfortunately, the addition of radiotherapy postoperatively did not improve their DFS ( P  = 0.0862). However, in the subgroup analysis, DFS was significantly prolonged in the CRT arm in the patients with lymph node-positive (N +) disease (3-year DFS rate: 77.5% vs.72.3%, HR 0.69, 95% CI 0.474–0.995, P  = 0.0365). Based on these findings, the subsequent ARTIST II trial further explored the role of adjuvant CRT in patients with lymph node-positive GC [ 32 ]. Five hundred forty-six patients after D2 dissection were randomly assigned to adjuvant S-1, adjuvant SOX, and adjuvant SOX plus radiotherapy (SOXRT) in a 1:1:1 ratio. However, there was no significant difference in DFS between the adjuvant SOX and SOXRT treatments (3-year DFS rate: 72.8% vs.74.3%; HR 0.97, 95% CI 0.66–1.42, P  = 0.879). Therefore, according to current results from these clinical trials, adjuvant CRT is not recommended in patients who received D2 lymphadenectomy and R0 resection.

Novel perioperative therapies

Perioperative targeted therapy.

Anti-HER2 and anti-vascular endothelial growth factor (VEGF) therapies have been recommended as the standard treatments for advanced GC in the first- and second-line setting, respectively. However, the role of targeted therapy in the perioperative or adjuvant setting is still unclear and is currently under investigation.

Anti-HER2 therapy

According to the ToGA study, adding trastuzumab to chemotherapy improved the OS in patients with metastatic HER2-positive GC [ 14 ]. However, the role of anti-HER2 therapy in resectable GC was unclear. In the multicenter phase II HER-FLOT study, patients with HER2-positive esophagogastric adenocarcinoma received perioperative FLOT chemotherapy for four cycles preoperatively and four cycles postoperatively, followed by 9 cycles of trastuzumab monotherapy [ 33 ]. The pCR rate was 21.4%, and the median DFS was 42.5 months. The phase II randomized PETRARCA study investigated the efficacy of adding trastuzumab and pertuzumab to perioperative FLOT chemotherapy in patients with ≥ cT2 or cN + resectable GC [ 34 ]. The pCR rate was significantly improved with trastuzumab and pertuzumab (35% vs. 12%, P  = 0.02), and the R0 resection rate and surgical morbidity were comparable between both groups. However, adding targeted therapy to perioperative chemotherapy did not improve DFS or OS and caused more severe adverse events (≥ grade 3), especially diarrhea (41% vs. 5%) and leukopenia (23% vs. 13%). Based on these results, the trial did not proceed to phase III. Another phase II NEOHX study recruited 36 HER2-positive GC patients who received perioperative CAPOX plus trastuzumab treatment, followed by 12 cycles of trastuzumab maintenance therapy [ 35 ]. The pCR rate, 18-month DFS rate, and 5-year OS rate were 9.6%, 71%, and 58%, respectively. The randomized phase II INNOVATION trial assigned patients to 3 groups: perioperative chemotherapy, chemotherapy plus trastuzumab, and chemotherapy plus trastuzumab and pertuzumab [ 36 ]. According to the investigators' choice, the chemotherapy could be FLOT, CAPOX, FOLFOX, or XP. The primary endpoint was major pathological response (MPR) rate, and the result is pending. In general, adding anti-HER2 therapy to chemotherapy showed certain efficacy in the perioperative setting, but the associated survival benefit should be further investigated in a larger randomized trial.

Anti-VEGF therapy

As for anti-VEGF therapy, the randomized, open-label, phase II/III ST03 trial recruited 1,063 resectable esophagogastric adenocarcinoma patients and randomly assigned them to perioperative chemotherapy (ECX) group or perioperative chemotherapy plus bevacizumab group [ 37 ]. The result showed that adding bevacizumab did not improve the 3-year OS (48.1% vs. 50.3% for chemotherapy alone; HR 1.08; 95% CI, 0.91 to 1.29; P  = 0.36). Besides, adding bevacizumab was associated with higher rates of postoperative anastomotic leak (24% vs. 10%). Ramucirumab, a VEGF receptor 2 inhibitor, has become one of the standard choices in the second-line treatment of GC [ 5 , 17 , 18 ]. The RAMSES/FLOT7 evaluated the efficacy of adding ramucirumab to perioperative FLOT for resectable GC [ 38 ]. The R0 resection rate in the intervention group was improved compared to the chemotherapy group (96% vs. 82%, P  = 0.0093). The median DFS was prolonged in the FLOT plus ramucirumab group (32 months vs. 21 months), while the OS was similar in both groups (46 months vs. 45 months).

Perioperative immunotherapy

Based on several phase III clinical trials, programmed death 1 (PD-1) inhibitors were approved for first- and third-line treatment of unresectable/metastatic GC in different countries [ 5 , 17 , 18 ]. However, the role of ICI in resectable GC remains unclear and is being investigated in various clinical trials. In the randomized phase II DANTE trial, patients with resectable GC were assigned to the experimental arm with the PD-L1 inhibitor atezolizumab plus FLOT chemotherapy and the control arm with standard FLOT chemotherapy [ 39 ]. The R0 resection rate, surgical morbidity and mortality were comparable in both groups. Atezolizumab combined with chemotherapy was associated with tumor downstage and pathological regression, which were more pronounced in patients with a higher PD-L1 combined positive score (CPS).

Several single-arm phase II clinical trials explored the efficacy of perioperative ICIs combined with different treatments (chemotherapy, targeted therapy, or radiotherapy) in resectable GC [ 40 , 41 , 42 , 43 , 44 ]. The pCR rates ranged from 10 to 41%. In the phase III ATTRACTION-5 trial (NCT03006705), the use of nivolumab in the adjuvant setting was investigated. Patients who have undergone D2 surgery will receive either S-1 for one year or CAPOX for six months, with nivolumab added to the adjuvant therapy in the intervention arm. The primary endpoint of the study is relapse-free survival (RFS). The result was announced recently. Unfortunately, the addition of nivolumab did not extend the RFS compared with adjuvant chemotherapy alone. Additionally, the role of pembrolizumab in combination with perioperative chemotherapy for resectable GC is being examined in the phase III clinical trial, KEYNOTE-585 [ 45 ]. The chemotherapy regimens under investigation are XP, FP, or FLOT, and the primary endpoints of the study are OS, event-free survival (EFS), and pCR rate. The potential survival benefits and efficacy of ICI are also being evaluated in the double-blind, randomized phase III MATTERHORN study, which is based on the FLOT backbone [ 46 ]. Patients with resectable GC will receive either perioperative FLOT or FLOT plus durvalumab (a PD-L1 antibody). The primary endpoint of the study is EFS, with secondary endpoints including OS and pCR rate.

For the dMMR/MSI-H subgroup, as discussed above, the value of chemotherapy was controversial. Considering dMMR/MSI-H is a predictive biomarker for immunotherapy in advanced GC, treatment with immune checkpoint inhibitors in the perioperative setting has the potential to improve the response rate and survival. The phase II GERCOR NEONIPIGA study evaluated the response rate and safety of the combination of neoadjuvant nivolumab and low-dose ipilimumab followed by adjuvant nivolumab in patients with dMMR/MSI-H locally advanced G/GEJ adenocarcinoma. Among 29 patients who underwent surgery, 17 (58.6%; 90% CI, 41.8–74.1) achieved pCR[ 47 ]. Similarly, the pCR rate of tremelimumab plus durvalumab was 60% in the neoadjuvant setting (cohort 1) in the phase II INFINITY study[ 48 ]. Based on these encouraging results, it is possible for patients who achieved pCR after neoadjuvant immunotherapy to avoid surgery. Cohort 2 of the INFINITY study has started enrollment to investigate the activity of tremelimumab plus durvalumab as the definitive treatment for dMMR/MSI-H locally advanced GC.

Management for unresectable/metastatic GC

Chemotherapy.

Cytotoxic agents, including fluoropyrimidine, platinum, taxanes and irinotecan, are the main treatment in advanced gastric cancer. Generally, fluoropyrimidine (fluorouracil, capecitabine, and S-1) combined with platinum is used as the backbone therapy in the first line. Oxaliplatin is considered to be as effective as cisplatin. In the phase III SOX-GC trial, the SOX regimen showed improved survival compared to the SP regimen in diffuse or mixed-type GC[ 49 ]. For patients who are not fit for intensive chemotherapy (older age or poor performance status), the phase III GO2 trial showed that a modified dose of two-drug chemotherapy (60% of the full dose) provided a better tolerance but did not compromise the clinical outcome[ 50 ]. Paclitaxel, docetaxel, and irinotecan are commonly used in the second line of chemotherapy. In the ABSOLUTE phase III clinical trial conducted in Japan, weekly use of albumin-bound paclitaxel (nab-paclitaxel) was not inferior to weekly solvent-based paclitaxel in terms of overall survival[ 51 ]. In third-line treatment, trifluridine-tipiracil (TAS-102), an oral cytotoxic agent, has been proven in the phase III TAGS trial to improve overall survival compared with placebo (5.7 vs.3.6 months, HR 0.69, 95% CI 0.56–0.85)[ 52 ].

Immune Checkpoint Inhibitors (ICIs) in unresectable/metastatic GC

Immune checkpoint inhibitors (ICIs) (monotherapy or combined with other treatments) have shown anti-tumor effects across a spectrum of solid tumors, including gastrointestinal tumors. Here, we present an overview of current evidence of ICI treatment in GC (Table 2 ) and discuss different predictive biomarkers for ICIs.

KEYNOTE-062 was the first global, randomized phase III trial to compare the efficacy and safety of immuno-monotherapy (pembrolizumab) or immunotherapy plus chemotherapy versus standard chemotherapy in HER2-negative advanced GC in the first-line setting [ 53 ]. According to the last update in ASCO 2022, it was suggested that pembrolizumab monotherapy was non-inferior to chemotherapy alone (cisplatin and fluorouracil/capecitabine) in patients with PD-L1 CPS ≥ 1 (median OS 10.6 vs. 11.1 months, HR 0.90, 95% CI 0.75–1.08) but was superior in the CPS ≥ 10 population (median OS 17.4 vs. 10.8 months; HR, 0.62; 95% CI, 0.45–0.86) [ 54 ]. However, the combination of pembrolizumab and chemotherapy did not bring OS benefit compared to chemotherapy alone in either CPS ≥ 1 (12.5 vs. 11.1 months; HR, 0.85; 95% CI, 0.71–1.02) or CPS ≥ 10 (12.3 vs. 10.8 months; HR, 0.76; 95% CI, 0.56–1.03) subgroup [ 54 ]. In another double-blind, placebo-controlled phase III KEYNOTE-859 study, the addition of pembrolizumab to chemotherapy (FP or CAPOX) demonstrated slight survival benefit compared with chemotherapy alone (OS 12.9 vs. 11.5 months, HR, 0.78; 95% CI, 0.70–0.87. PFS 6.9 vs. 5.6 months, HR, 0.76; 95% CI, 0.67–0.85). The results were generally consistent in different PD-L1 CPS subgroups[ 55 ].

CheckMate-649 is another global, randomized, phase III trial investigating the effects of ICIs (nivolumab plus ipilimumab, a CTLA-4 inhibitor) or ICI (nivolumab) plus chemotherapy versus chemotherapy (CAPOX or FOLFOX) alone in metastatic HER2-negative GC patients [ 56 ]. One thousand five hundred eighty-one patients were assigned to nivolumab plus chemotherapy arm or chemotherapy arm. The addition of nivolumab to chemotherapy improved the OS (14.4 vs. 11.1 months; HR 0.71; 98.4% CI, 0.59 to 0.86; P < 0.0001) and PFS (7.7 vs. 6.05 months; HR 0.68; 98% CI, 0.56 to 0.81; P  < 0.0001) for the patients with PD-L1 CPS ≥ 5; therefore both primary endpoints were met. For all-randomized patients, nivolumab combined with chemotherapy also improved OS (13.8 vs. 11.6 months; HR 0.80; 99.3% CI, 0.68 to 0.94; P  = 0.0002). Moreover, all CPS subgroups exhibited an increased objective response rate in the nivo-chemotherapy arm. However, the chemo-free treatment with nivolumab and ipilimumab did not show OS improvement compared to chemotherapy alone [ 57 ]. Based on these findings, nivolumab combined with chemotherapy was listed as one of the recommended first-line treatments in the NCCN, ESMO, and CSCO guidelines [ 5 , 17 , 18 ].

ATTRACTION-04 was a randomized, double-blind, placebo-controlled, multicenter phase II/III trial that evaluated the effects of nivolumab plus chemotherapy (SOX or CAPOX) compared with chemotherapy alone in the first-line treatment for HER2-negative advanced GC in the Asian population, regardless of PD-L1 expression [ 58 ]. The combination therapy significantly improved the PFS (HR 0·68; 98·51% CI 0·51–0·90; P  = 0·0007) but not the OS (both groups achieved > 17 months of median OS). One of the possible reasons for the different results of OS between ATTRACTION-04 and CheckMate-649 could be the subsequent anticancer therapies, whereby the proportion of patients who received subsequent anticancer treatments or ICIs therapy was much higher in ATTRACTION-04 (66% vs. 39% in CheckMate-649).

The efficacy of immunotherapy plus chemotherapy was further confirmed in the Asian phase III ORIENT-16 trial, which compared sintilimab plus chemotherapy (CAPOX) to chemotherapy alone as the first-line treatment [ 59 ]. The pre-specified interim result was reported at ESMO 2021. Sintilimab plus chemotherapy showed a survival benefit versus chemotherapy alone in patients with CPS ≥ 5 (18.4 vs. 12.9 months; HR 0.660; 95% CI 0.505–0.864) and all randomized patients (15.2 vs. 12.3 months; HR 0.766; 95% CI 0.626–0.936). Another PD-1 antibody, tislelizumab, is currently being investigated in the phase III RATIONALE-305 trial [ 60 ]. Advanced GC patients are randomized to receive tislelizumab plus chemotherapy (CAPOX/FP regimen) or chemotherapy alone. The primary endpoints are PFS and OS. Results from the interim analysis of the PD-L1 + (i.e., PD-L1 TAP score ≥ 5%) population were represented at 2023 ASCO-GI, showing that tislelizumab plus chemotherapy led to significant OS (17.2 vs. 12.6 months; HR 0·74; 95% CI 0·59–0·94) and PFS (7.2 vs. 5.9 months; HR 0·67; 95% CI 0·55–0·83) improvement compared to chemotherapy alone[ 61 ]. The ITT population outcomes will be reported after the final analysis.

In summary, in first-line treatment for HER2-negative advanced GC, the addition of anti-PD-1 therapy could improve clinical outcomes in patients with high PD-L1 expression, according to the results from CheckMate-649, ORIENT-16, and RATIONALE-305. For patients with low PD-L1 expression or unknown PD-L1 status, the survival benefit of adding PD-1 antibodies is still controversial (discussed below), and the risk–benefit balance of ICIs treatment should be considered, and decisions should be discussed case by case.

The role of maintenance therapy with ICIs after first-line chemotherapy was evaluated in the phase III JAVELIN Gastric 100 trial [ 62 ]. Patients with HER2-negative advanced GC without progression after at least 12 weeks of first-line chemotherapy (oxaliplatin plus fluoropyrimidine) were randomly assigned to avelumab (a PD-L1 inhibitor) maintenance or continued chemotherapy. Avelumab maintenance did not show OS benefit compared to chemotherapy (24-month OS rate: 22.1% versus 15.5%; HR 0.91; 95% CI, 0.74–1.11;  P  = 0.1779).

Second line and beyond

The randomized, open-label, phase III KEYNOTE-061 trial compared pembrolizumab monotherapy with paclitaxel in patients with advanced GC or GEJ cancer in the second-line setting [ 53 ]. Though the primary endpoints (the OS and PFS in patients with PD-L1 CPS ≥ 1) were not met, it was suggested that the efficacy of pembrolizumab monotherapy was associated with the PD-L1 CPS level. Patients with CPS ≥ 10 had a better outcome in the pembrolizumab group than in the chemotherapy group.

KEYNOTE-059 was a phase II study that explored the effect of pembrolizumab in patients with advanced GC after progression from ≥ 2 lines of treatment [ 63 ]. Among the 259 patients enrolled, the ORR and median duration of response (DoR) was 11.6% and 8.4 months, respectively. Moreover, pembrolizumab showed higher efficacy in the subgroup with PD-L1-positive cancer (CPS ≥ 1) compared to PD-L1-negative cancers (ORR 15.5% vs. 6.4%; DoR 16.3 vs. 6.9 months, respectively). The phase III ATTRACTION-2 study compared nivolumab monotherapy versus placebo in advanced GC patients after two lines of therapy, regardless of the PD-L1 expression [ 64 ], and survival benefit was observed in the nivolumab group (OS 5.3 vs. 4.1 months; HR 0·63, 95% CI 0·51–0·78; P  < 0·0001). Based on the results of this study, nivolumab is recommended as monotherapy in third-line treatment for GC in the CSCO guideline but not in the ESMO or NCCN guidelines due to the patients enrolled being exclusively Asian. The role of avelumab in the third-line treatment for advanced GC was investigated in the phase III JAVELIN Gastric 300 trial [ 65 ]. Though avelumab showed a more manageable safety than the physician's choice of chemotherapy, it did not improve OS (primary endpoint, 4.6 vs. 5.0 months; HR 1.1, 95% CI 0·9–1.4; P  = 0.81), PFS, or ORR.

Molecular Biomarkers of Immunotherapy in GC

HER2-positive GC, defined as immunohistochemical (IHC) expression 3+ or 2 + combined with positive fluorescent in situ hybridization (FISH) verification, accounts for approximately 15–20% of gastric or gastroesophageal cancer. The phase III ToGA study has established trastuzumab combined with chemotherapy as the standard first-line treatment for HER2-positive advanced GC [ 14 ]. In preclinical models, HER2 signaling could regulate the recruitment and activation of tumor-infiltrating immune cells [ 66 ]. Besides, trastuzumab has been shown to upregulate the expression of PD-1 and PD-L1 [ 67 , 68 ], and anti-PD-1 antibodies could significantly increase the therapeutic activity of HER2 inhibitors [ 69 ]. Several phase I/II studies demonstrated the promising efficacy of the addition of ICIs to trastuzumab and chemotherapy in HER2-positive GC. In the phase Ib Ni-HIGH study conducted in Japan, patients with HER2-positive advanced GC received nivolumab, trastuzumab, and chemotherapy (CAPOX or SOX regimen) in the first-line setting, and the ORR was 75%, as reported at ASCO 2020 [ 70 ]. The multi-institutional phase Ib/II PANTHERA trial explored the efficacy and safety of the combination of pembrolizumab, trastuzumab and chemotherapy as first-line therapy for HER2-positive advanced GC [ 71 ]. The updated data at ASCO-GI 2021 showed that the ORR was 76.7% (CR 16.3%, PR 60.5%), the PFS was 8.6 months (95% CI 7.2–16.5 months), and the OS was 19.3 months (95% CI 16.5-NR). The striking efficacy was also reported in another phase II study, in which patients with HER2-positive GC received pembrolizumab, trastuzumab and chemotherapy (oxaliplatin/cisplatin + capecitabine/5-FU) [ 72 ]. Overall, the ORR was 91% and DCR was 100%. The median PFS and OS was 13·0 months and 27·3 months, respectively, which was much better than the OS reported in the ToGA study. Recently, the randomized, double-blind, placebo-controlled phase III KEYNOTE-811 trial reported the results of its first interim analysis [ 73 ], in which patients with metastatic HER2-positive GC or GEJ cancer received pembrolizumab or placebo plus trastuzumab and chemotherapy. The results showed that adding pembrolizumab to trastuzumab and chemotherapy could markedly increase the ORR (74.4% vs. 51.9%; the estimated difference between the two groups was 22.7%; 95% CI, 11.2–33.7%; P  = 0.00006). Based on this result, the FDA approved pembrolizumab combined with trastuzumab and chemotherapy as the first-line treatment for advanced HER2-positive gastric or GEJ adenocarcinoma. The results of the primary endpoints (PFS and OS) are still immature.

MSI-H tumor is one of the four subtypes of GC according to The Cancer Genome Atlas (TCGA) Research Network [ 11 ]. The incidence of MSI-H status in GC was reported to range from 8 to 25%, which was much lower in metastatic disease [ 74 ]. Mismatch repair (MMR) proteins are supposed to fix the errors that occur during DNA replication. When MMR proteins are deficient, the defects of DNA replication will lead to the accumulation of mutations and the expression of neoantigens, which may act as potential targets of immune cells [ 75 ]. Hence, it is reasonable that tumors with MSI-H/dMMR status may attract more immune cell infiltration and enhance the effect of immune checkpoint inhibitors. A post hoc analysis of KEYNOTE-059 (third-line treatment), KEYNOTE-061 (second-line treatment), and KEYNOTE-062 (first-line treatment) was conducted to evaluate the efficacy of pembrolizumab versus chemotherapy in the patients with MSI-H advanced G/GEJ adenocarcinoma [ 15 ]. Overall, 7 of 174 patients (4.0%) in KEYNOTE-059, 27 of 514 (5.3%) in KEYNOTE-061, and 50 of 682 (7.3%) in KEYNOTE-062 with MSI-H status were enrolled. By the time of analysis, the OS of the patients with MSI-H was not reached for pembrolizumab monotherapy in KEYNOTE-059, 061 and 062, or for pembrolizumab combined with chemotherapy in KEYNOTE-062, compared with an OS of around 8 months for chemotherapy alone. Besides, the ORR was much higher in the immunotherapy groups. In another meta-analysis including four phase III trials (KEYNOTE-062, CheckMate-649, JAVELIN Gastric 100, and KEYNOTE-061), 2545 patients with known MSI status were enrolled, and the proportion of MSI-H was 4.8% [ 76 ]. In the MSI-H group, the HR for OS benefit with immunotherapy was 0.34 (95% CI 0.21–0.54), compared to 0.85 (95% CI 0.71–1.00) for the MSS group. Among the patients with MSI-H status, the HR for PFS was 0.57 (95% CI 0.33–0.97; P  = 0.04), and the odds ratio (OR) for ORR was 1.76 (95% CI 1.10–2.83; P  = 0.02). Altogether, these findings suggested that MSI-H status was a predictive biomarker for immune checkpoint inhibitor treatments, regardless of the line of therapy.

Epstein-Barr virus-associated GC (EBVaGC) is another distinct molecular subtype of the TCGA classification [ 11 ], accounting for about 9% of GC in the TCGA cohort and approximately 5% in China [ 77 , 78 ]. EBV has been linked to CD8 + T cell infiltration and increased expression of PD-L1 and PD-L2 [ 11 , 79 ], making it a potential biomarker for ICI treatment. While a Korean study with a small sample size (n = 6) once reported a 100% response rate in EBV-positive advanced GC [ 80 ], several other studies did not demonstrate a high response rate [ 81 , 82 , 83 ]. Differences in response rates across studies may be attributed to confounding factors such as tumor mutational burden (TMB) and PD-L1 expression. Therefore, the role of EBV positivity in immunotherapy for GC remains unclear and requires further investigation.

As discussed earlier, the level of PL-L1 expression, especially the CPS score, has been considered a predictive biomarker for response to ICIs. However, the reliable cut-off value to predict the benefit of immunotherapy is needed to be determined. The cut-off points often used in clinical trials are 1, 5 and 10. In the KEYNOTE-059 trial, CPS ≥ 1 was used to separate the patients that could benefit from third-line pembrolizumab treatment [ 63 ]. However, this benefit was not seen compared to chemotherapy in the KEYNOTE-061/062 trials [ 53 , 84 ]. In KEYNOTE-061/062, CPS ≥ 10 effectively differentiated the response to pembrolizumab. Patients with CPS ≥ 10 had better OS benefits than those with CPS ≥ 1. A comprehensive analysis of patients with CPS ≥ 10 in KEYNOTE-059, 061 and 062 also showed consistent improvement toward better outcomes with pembrolizumab in different lines of treatment in this subgroup [ 85 ]. In the CheckMate-649 and ORIENT-16 studies, CPS ≥ 5 was used as the cut-off value for the primary endpoint OS. Though the OS benefit of nivolumab plus chemotherapy was also observed in all randomized patients in CheckMate-649, the subgroup analysis suggested that the benefit was insignificant in the CPS < 5 or < 1 group [ 86 ]. A recent study reconstructed unreported Kaplan–Meier plots of PD-L1 CPS subgroups of three phase III trials (CheckMate-649, KEYNOTE-062, and KEYNOTE-590) and investigated the outcome of low CPS subgroup [ 87 ]. The result suggested that patients with low PD-L1 expression (CPS 1–4 and CPS 1–9) did not benefit from adding ICIs to chemotherapy. In summary, although the predictive role of PD-L1 CPS for immunotherapy efficacy has been demonstrated in multiple clinical trials, there is still a need to determine the optimal cut-off value for CPS and to develop further classifications for patients with low CPS scores. Recently, the result of the phase III RATIONALE-305 trial suggested that the TAP score > 5% also had predictive value for ICI treatment in gastric cancer[ 61 ], and further exploration is needed.

Tumor mutation burden (TMB)

It is hypothesized that a high TMB status results in the high expression of neoantigens, which are immunogenic and can induce the response of the immune system and potentially increase the efficacy of ICI treatment. In a phase Ib/II study that explored the efficacy of the PD-1 antibody toripalimab in patients with advanced GC, patients with TMB-high (TMB-H, TMB ≥ 12 mut/Mb) showed a higher ORR and better OS compared with patients with TMB-L status (ORR 33.3% vs. 7.1%, P  = 0.017; OS 14.6 vs. 4.0 months, P  = 0.038)[ 88 ]. In the subgroup analysis of the KEYNOTE-061 study, the TMB status (≥ 10 or < 10 mut/Mb) was associated with response rate, PFS, and OS in patients treated with pembrolizumab. In the TMB-H subgroup, pembrolizumab demonstrated a better OS compared with paclitaxel, and this benefit remained even when MSI-H patients were excluded[ 89 ]. Though FDA granted approval for the use of pembrolizumab in patients with TMB-H (i.e., TMB ≥ 10 mutations/Mb) advanced solid tumors that progressed after standard treatments, according to the subgroup analysis of KEYNOTE-158 study[ 90 ], the evidence is still not enough for the use of ICIs in TMB-H gastric cancer, and phase III studies to illustrate the predictive value of TMB are needed.

Molecular targeted therapy in unresectable/metastatic GC

Molecular targeted therapy remains an essential treatment option for patients with advanced GC, aimed to inhibit tumor proliferation and increase survival rates. Targeted therapies, including anti-HER2, anti-angiogenesis, and other biomarker-directed therapies, have demonstrated promising efficacy in treating GC, with significant benefits observed in biomarker-enriched patients (Table 3 ). Therefore, next-generation sequencing or ctDNA detection is crucial for mGC patients to establish a comprehensive molecular profile, including the status of HER2, fibroblast growth factor receptor (FGFR), Claudin18.2 (CLDN18.2), PD-L1 and EGFR.

HER2, also known as ERBB2, is a member of the ERBB protein families that includes the epidermal growth factor receptor (EGFR or HER1), HER3, and HER4 [ 91 ]. HER2 overexpression or amplification has been found in a range of 7.3% to 20.2% in advanced gastric and gastroesophageal junction adenocarcinomas, with the overexpression rate varying globally [ 92 ]. In addition, intestinal-type gastric cancers and those arising from the proximal stomach or gastroesophageal junction are more likely to exhibit HER2 positivity. [ 11 , 93 ].

Trastuzumab is a humanized monoclonal antibody that targets HER2 extracellular domain 4, then inhibits downstream signal activation and cancer cell proliferation. Trastuzumab plus chemotherapy has been established as the standard first-line treatment for HER2-positive advanced GC. The landmark ToGA trial revealed that trastuzumab plus chemotherapy significantly improved the overall survival of patients with advanced GC [ 14 ], especially for patients with HER2 positivity, who were identified as having HER2 immunohistochemistry (IHC) scores of 2 + and fluorescence in situ hybridization (FISH)-positive or HER2 IHC 3 + based on a post-hoc exploratory analysis [ 92 ]. The EVIDENCE trial has demonstrated that combining first-line trastuzumab with chemotherapy was associated with improved clinical outcomes in Chinese patients with HER2-positive metastatic GC, providing real-world evidence. [ 94 ].

However, subsequent attempts of HER2-targeted therapy in advanced GC were not as successful as expected. Even though pertuzumab [ 95 , 96 ], trastuzumab emtansine (T-DM1) [ 97 ], and lapatinib [ 98 , 99 ] were all investigated in several first-line and second-line trials, no survival improvement was observed in any of these trials. Additionally, trastuzumab beyond progression also failed to show a survival benefit in pre-treated HER2-positive GC patients in the T-ACT trial [ 100 ].

Potential resistance mechanisms of HER2-targeted therapy

Primary or acquired resistance is a major impediment to the management of mGC patients, while mechanisms underlying the poor efficacy of HER2-directed therapy in GC are not fully understood. Multiple potential resistance mechanisms have been researched, as listed below, and further studies are warranted to improve treatment resistance in GC patients treated with HER2-targeted therapy in clinical settings.

HER2 heterogeneity

Intratumoral HER2 heterogeneity is observed in 23% to 79% of GC patients and is associated with patients’ survival [ 101 , 102 , 103 ]. Specifically, Shusuke et al. reported prolonged survival in homo-HER2 positive GC patients, defined as all tumor cells overexpressing HER2 in biopsy specimens [ 101 ]. Tumor cells with HER2 overexpression or amplification are killed during HER2-targeted therapy, while residual drug-resistant colonies keep proliferating and eventually take control, leading to tumor recurrence. As a result, resistance to HER2-targeted therapy has been associated with the heterogeneity of HER2 expression [ 101 , 104 , 105 ]. Discordance between next-generation sequencing and FISH/IHC may also indicate intratumoral heterogeneity and result in an unfavorable treatment outcome. In addition, there still exist discrepancies in HER2 status between primary tumor and metastatic sites, which increases the risk of HER2-targeted therapy failure due to false-positive HER2 detection [ 106 , 107 ].

Loss of HER2 expression

For mGC patients experiencing progression on trastuzumab, 29–69% of them may experience loss of HER2 expression, which is an important factor responsible for resistance [ 108 , 109 , 110 ]. Given the risk of HER2 expression loss during treatment, patients should re-evaluate HER2 status upon progression after anti-HER2 therapy to determine the most optimal treatment.

Gene amplification

Receptor tyrosine kinase (RTK) amplification was commonly detected in MET-amplified metastatic GC, with 40% to 50% of cases exhibiting co-amplification of either HER2 or EGFR. These patients did not usually respond to HER2-targeted therapy, but MET and HER2 combination inhibition could sometimes bring extra clinical benefit [ 111 ]. CCNE1, which encodes the cell cycle regulator cyclin E1, is another oncogene co-amplified with HER2 in metastatic GC. CCNE1 co-amplification has been found to be more strongly related to HER2-positive AGC than to HER2-positive breast cancer [ 112 ]. In a phase II study of lapatinib with capecitabine and oxaliplatin in HER2-positive AGC patients, CCNE1 amplification was demonstrated to play a role in resistance to HER2-targeted therapy [ 113 ]. A high level of copy number variation for CCNE1 has also been associated with worse survival in patients with HER2-positive metastatic GC treated with trastuzumab [ 114 ]. Other studies have also reported that deletion of ErbB2 16 exon and co-mutation and/or amplification of KRAS, HER3, EGFR, PI3K or PTEN could contribute to the resistance of anti-HER2 therapy [ 109 , 113 , 115 , 116 ].

Alterations in intracellular signaling

HER2-targeted therapy suppresses downstream signaling pathways by blocking the binding of HER2 receptors and ligands, which inhibits the migration and proliferation of tumor cells and leads to apoptosis. RTK/RAS/PI3K signaling alterations have been shown to be involved in the development of resistance to trastuzumab. [ 109 ]. Furthermore, activation of the bypass pathway might also result in resistance. Sampera et al. discovered that SRC-mediated persistent activation of the MAPK-ERK and PI3K-mTOR pathways was connected to the treatment resistance in HER2-positive GC cell lines [ 117 ]. NRF2 has also been associated with HER2 resistance by activating the PI3K-mTOR signaling pathway [ 118 ].

Newer HER2-targeted agents

To overcome intrinsic and acquired resistance to trastuzumab, various clinical trials have explored newer agents and combinations. The following innovative HER2-targeted agents for advanced metastatic GC are currently under investigation (Table 4 ): monoclonal antibodies (mAbs) (e.g., margetuximab), bispecific antibodies (BsAbs) (e.g., ZW25, KN026), antibody–drug conjugates (ADCs) (e.g., T-DXd, Disitamab vedotin, ARX788), tyrosine kinase inhibitors (TKIs) (e.g., tucatinib), and other novel therapeutic approaches.

Monoclonal antibodies

Margetuximab

Margetuximab is an Fc-engineered anti-HER2 mAb that targets the same epitope as trastuzumab but with a higher affinity for single-nucleotide polymorphisms of the activating Fc receptor (CD16A) [ 119 , 120 ]. Margetuximab can recruit CD16A-expressing natural killer cells, macrophages and monocytes and further promote antibody-dependent cell-mediated cytotoxicity (ADCC) [ 119 ]. The first phase I study of margetuximab in humans illustrated that margetuximab was well-tolerated with promising efficacy in relapsed HER2-overexpressing carcinoma [ 121 ]. Later in the phase Ib/II CP-MGAH22-05 study, patients with previously treated HER2-positive GC responded effectively to a chemotherapy-free treatment consisting of margetuximab plus pembrolizumab. Patients with HER2 IHC3 + and PD-L1 positive (CPS ≥ 1, by IHC) had an ORR of 44% and a DCR of 72% [ 122 ]. More recently, the phase II/III MAHOGANY trial has reported the efficacy of margetuximab plus anti-PD-1 antibody retifanlimab (Cohort A) for the first-line treatment of patients with G/GEJ adenocarcinoma, with an ORR and a DCR of 53% and 73% [ 123 ]. The ORR reported in this trial was superior to the ORR observed with other history chemotherapy-free treatments; nonetheless, given that chemotherapy-based regimens remain the predominant treatment for GC, the MAHOGANY trial has been halted for commercial reasons.

Bispecific antibodies (BsAbs)

Zanidatamab (ZW25)

Zanidatamab (ZW25) is a novel HER2-targeted bispecific antibody that binds to HER2 extracellular domain (ECD) II and IV. According to a phase I study, ZW25 was well tolerated with durable response in heavily pretreated GEA patients (including prior HER2-targeted therapy) [ 86 ]. Later in a phase II trial involving patients with advanced/metastatic HER2-positive GEA, zanidatamab plus chemotherapy (CAPOX or FP) showed a confirmed ORR of 75%, mDOR of 16.4 months and mPFS of 12.0 months in the first-line setting [ 124 ]. Based on these findings, a global phase III study (HERIZON-GEA-01) has been designed to assess the efficacy and safety profiles of zanidatamab plus chemotherapy with or without tislelizumab versus standard of care (trastuzumab plus chemotherapy) for patients with metastatic HER2-positive GEAs in first-line settings [ 125 ].

KN026 mimics the dual effects of trastuzumab and pertuzumab by simultaneously binding to HER2 ECD II and IV [ 126 ]. In a phase II clinical study, KN026 showed favorable results in patients with HER2-overexpressing G/GEJ adenocarcinoma (IHC3 + or IHC 2 + ISH +) with an ORR of 56% [ 127 ]. The ongoing phase II/III trial (KN026-001) is planned to evaluate the survival benefit of KN026 plus chemotherapy in patients with HER2-positive unresectable or advanced G/GEJ adenocarcinoma upon progression after trastuzumab-containing treatment (NCT05427383). Most recently, the preliminary data presented at ESMO 2022 illustrated that KN026 plus KN046, a recombinant humanized PD-L1/CTLA-4 bispecific antibody, had remarkable efficacy and tolerable safety in HER2-positive G/GEJ patients without prior systemic treatment [ 128 ]. In this phase II study, the ORR was 77.8%, and the DCR was 92.6%, indicating the need for a future randomized clinical trial to confirm the efficacy of KN026 plus KN046 treatment versus standard of care.

Other BsAbs

PRS-343 is a BsAb that targets HER2 and the costimulatory immunoreceptor 4-1BB on immune cells. In patients with advanced HER2-positive solid tumors, including GC, PRS-343 showed anticancer efficacy both alone and in combination with the anti-PD-L1 antibody atezolizumab in a phase I clinical study [ 129 ]. A phase II study (NCT05190445) is ongoing to investigate the efficacy of PRS-343 in combination with ramucirumab and paclitaxel in patients who have already received treatment for HER2-high (IHC 3+ or IHC 2+ with HER2/neu gene amplification) G/GEJ adenocarcinoma and in combination with tucatinib in HER2-low (IHC 1+ or IHC 2+ without HER2/neu gene amplification) G/GEJ adenocarcinoma.

Antibody–drug conjugates (ADCs)

Trastuzumab deruxtecan (T-DXd)

Trastuzumab deruxtecan (T-DXd) is an antibody–drug conjugate (ADC) composed of an anti-HER2 antibody connected to a cytotoxic topoisomerase I inhibitor via a cleavable tetrapeptide-based linker [ 130 ]. Different from T-DM1, T-DXd has a bystander effect on nearby cells, including those not expressing HER2, thus greatly enhancing the antitumor effect [ 131 ]. This action method is inspiring, particularly for advanced GC patients with diverse intratumoral HER2 expression. In the Asia DESTINY-Gastric01 trial, T-DXd significantly improved overall survival in patients with HER2 + advanced GC compared with chemotherapy in the later-line settings [ 132 ]. Interestingly, the efficacy and safety of T-DXd were also evaluated in exploratory cohorts of patients with HER2-low G/GEJ cancers in the DESTINY-Gastric01 trial (cohort 1, IHC 2 + /ISH–; cohort 2, IHC 1 +). The confirmed ORR was 26.3% in Cohort 1 and 9.5% in Cohort 2. The median OS was 7.8 months in cohort 1 and 8.5 months in cohort 2[ 133 ]. These results provide initial evidence that T-DXd has clinical benefits in patients with heavily pretreated HER2-low G/GEJ cancers.

Similarly, T-Dxd in the DESTINY-Gastric02 trial also achieved encouraging results in 2L western GC patients with a cORR of 41.8% and a median PFS of 5.6 months [ 134 ]. Other trials, such as phase III 2L DESTINY-Gastric04 and phase III 1L DESTINY-Gastric03, are also in progress (NCT04379596, NCT04704934).

Disitamab vedotin (RC48)

Disitamab vedotin (RC48) is a novel HER2-ADC drug independently developed in China, which is composed of three parts: anti-HER2 extracellular domain antibody, MC-Val-Cit-PAB linker, and cytotoxin monomethyl auristatin E (MMAE) [ 135 ]. This novel antibody has a stronger affinity to HER2 than the standard of care. Unlike T-DM1, disitamab vedotin has a bypass-killing effect on nearby tumor cells regardless of HER2 status, which could help overcome spatial heterogeneity and enhance anti-tumor effects. RC48 was well tolerated and showed promising antitumor activity in patients with HER2-positive advanced GC in a phase I trial [ 136 ]. The phase II RC48-C008 trial revealed a significant benefit of RC48 with HER2-overexpressing GC patients who had undergone at least two prior lines of therapy, in which the ORR was 24.8%, mPFS was 4.1 months and mOS was 7.9 months [ 137 ]. Of note, the ORR of RC48 in patients with HER2 IHC2 + /FISH- was 16.7%, slightly lower than in HER2-positive patients. These findings indicated that RC48 exerted considerable anti-tumor effectiveness and tolerable safety in patients with HER2-positive GC, as well as in those with HER2 low expression GC. In June 2021, disitamab vedotin was approved in China for the treatment of patients with HER2-overexpressing advanced or metastatic G/GEJ adenocarcinoma who received at least two systemic chemotherapy regimens. The ongoing phase III RC48-C007 (NCT04714190) trial aims to evaluate the efficacy and safety of RC48 as a third-line treatment and beyond in patients with advanced HER2-positive GC.

ARX788 is another investigational anti-HER2 antibody–drug conjugate consisting of HER2-targeted monoclonal antibody (mAb) coupled with a highly effective tubulin inhibitor (AS269). ARX788 was well tolerated and had a promising anti-tumor effect in HER2-positive GC patients previously treated with trastuzumab-based regimens in a phase I multicenter dosage expansion trial [ 138 ]. The ORR was confirmed to be 37.9%, and the DCR was 55.2%. With a median follow-up period of 10 months, the mPFS and OS were 4.1 and 10.7 months, respectively. On March 18, 2021, the FDA granted ARX788 as an orphan drug for treating HER2-positive GC. A randomized controlled, multicenter, open-label phase II/III study is underway to assess the efficacy of ARX788 as second-line treatment for HER2-positive advanced G/GEJ adenocarcinoma (Chinadrugtrials.org.cn: CTR20211583).

Tyrosine kinase inhibitors

Tucatinib, a highly selective HER2-directed tyrosine kinase inhibitor (TKI), was approved by FDA for HER2-positive metastatic breast cancer in 2020 and is under exploration in GC. In preclinical studies, tucatinib plus trastuzumab demonstrated superior activity compared to a single agent in GEC xenograft models [ 139 ]. Recently, the phase II/III MOUNTAINEER-02 (NCT04499924) was initiated to evaluate the efficacy of tucatinib, trastuzumab combined with ramucirumab, and paclitaxel in previously treated HER2 + advanced G/GEJ adenocarcinoma [ 140 ].

Other novel therapeutic approaches are being under investigation, including anti-HER2 CAR-T-cell therapy (NCT04511871, NCT04650451), CAR-natural killer cell (NK) therapy [ 141 ], and CAR-macrophage (CAR-M) therapy (NCT04660929), B-cell and monocyte-based immunotherapeutic vaccines (BVAC-B), BAY2701439 and CAM-H2 targeted HER2 radiotherapy (NCT04147819, NCT04467515). These widespread attempts at HER2-targeted CAR cell therapy in solid tumors may hopefully lead to the development of new drug candidates in patients with HER2-positive GC.

Antiangiogenic therapy

Blocking angiogenesis is a key strategy in GC therapy, including anti-VEGF monoclonal antibodies, VEGF-binding proteins, and VEGF receptor TKIs (Table 5 ) [ 142 ]. Ramucirumab, a typical antiangiogenic monoclonal antibody, targets VEGFR-2 and is approved by the FDA for treating advanced GC [ 143 ]. In the second-line REGARD trial, ramucirumab demonstrated significant improvement in patient OS and PFS versus best supportive care in metastatic GC [ 144 ]. In the RAINBOW trial, when coupled with paclitaxel, ramucirumab significantly prolonged overall survival compared to paclitaxel alone [ 145 ]. Similarly, results from RAINBOW-Asia bridging study also supported the application of ramucirumab plus paclitaxel as second-line therapy in a predominantly Chinese population with advanced gastric or GEJ adenocarcinoma [ 146 ]. However, neither ramucirumab nor bevacizumab brought extra survival benefits when added to platinum or fluoropyrimidine chemotherapy in GC patients in the first-line settings [ 147 , 148 ].

Regorafenib is an oral multi-kinase inhibitor targeting angiogenic, stromal and oncogenic receptor tyrosine kinases (RTK). Results from a phase III trial (INTEGRATE IIa) presented at ASCO GI 2023 demonstrated that regorafenib significantly improved OS (4.5 months vs. 4.0 months; HR = 0.52; P  = 0.011) in patients with advanced gastro-oesophageal cancer (AGOC) in later-line settings [ 149 ]. Meanwhile, other studies exploring the efficacy of anti-VEGF and anti-PD1 combination in GC populations are also under investigation. The combination of regorafenib and nivolumab had a manageable safety profile and effective antitumor activity in a phase I trial for the GC subgroup [ 150 ]. INTEGRATE IIb ((NCT0487936)), an international randomized phase 3 trial, is ongoing to compare regorafenib plus nivolumab to standard chemotherapy in pre-treated patients with AGOC. Besides, lenvatinib plus pembrolizumab showed promising anti-tumor activity with an ORR of 69% in the first-line and second-line treatment of advanced GC [ 151 ].

Apatinib is a small molecule VEGFR inhibitor with China Food and Drug Administration (CFDA) approval for the treatment of advanced or metastatic chemotherapy-refractory GC. Apatinib improved median PFS and OS versus placebo in Chinese patients with advanced gastric or gastroesophageal junction adenocarcinoma in the third line and beyond[ 152 ]. Most of the patients in this trial did not receive prior antiangiogenic therapies since they were not standard treatments in China at that time, so clinical evidence is still lacking for the use of apatinib in patients who previously received ramucirumab. Unfortunately, no significant improvements were observed in overall survival (OS) in western populations in the phase III ANGEL clinical trial [ 153 ].

Fruquintinib is a highly selective VEGFR family kinase inhibitor that targets VEGFR1, 2 and 3 and is independently developed in China. Fruquintinib was approved in China by the NMPA in September 2018 and commercially launched in late November 2018 as a third-line treatment for patients with metastatic colorectal cancer. In a phase Ib/II study, adding fruquintinib to paclitaxel as second-line treatment for mGC patients at recommended phase 2 dose (RP2D) showed an mPFS of 4 months and mOS of 8.5 months. In the 4 mg dose cohort of 27 patients with evaluable tumor response, the ORR was 25.9% and the DCR was 66.7%[ 154 ]. A randomized phase III FRUTIGA study has investigated fruquintinib plus paclitaxel versus paclitaxel alone in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who had progressed after first-line standard chemotherapy (NCT03223376). Initial results from FRUTIGA showed that fruquintinib combined with paclitaxel showed significant improvements in PFS, ORR and DCR. Full detailed results are still being analyzed and will be revealed soon.

Other biomarker-targeted therapy

Novel diagnostic techniques have contributed to characterizing the genetic profile of GC and identifying new potential molecular targets. Recently, researchers have looked into Claudin-18.2-targeted therapy, fibroblast growth receptor (FGFR) pathway inhibitors, and EGFR inhibitors as effective targeted therapies to treat advanced GC (Table 5 ). Although emerging innovative drugs have made remarkable progress in GC treatments, extensive clinical explorations are needed to advance precision medicine.

CLAUDIN 18.2-targeted therapy

Claudin 18.2 (CLDN18.2), a component of intercellular junctions [ 155 ], is exclusively detected in gastric mucosa and absent from other healthy tissues. Upon malignant transformation, CLDN18.2 expression can be retained in various tumor tissues, including G/GEJ cancer and especially diffuse-type GC [ 156 ]. The prevalence of CLDN18.2 overexpression in GC varies wildly among studies ranging from 14.1% to 72% [ 157 , 158 , 159 ].

Zolbetuximab is a chimeric IgG1 monoclonal antibody that binds to CLDN18.2 and induces antibody-dependent and complement-dependent cytotoxicity [ 160 ]. To date, zolbetuximab has shown great potential to become a valuable target in GC. In the phase II MONO study, single-agent zolbetuximab achieved an ORR of 9% and a disease control rate of 23% in 43 patients with previously treated oesophageal or G/GEJ cancers [ 161 ]. A randomized phase II study (FAST) indicated that zolbetuximab plus first-line chemotherapy significantly improved PFS and OS in patients with CLDN18.2-positive G/GEJ cancer [ 159 ]. Subgroup analysis indicated a correlation between moderate-to-strong CLDN18.2 expression and a better overall survival rate. In the phase III SPOTLIGHT trial, zolbetuximab plus mFOLFOX6 significantly improved mPFS (10.61 vs 8.67 months, HR 0.751, P  = 0.0066) and mOS (18.23 vs 15.54 months, HR 0.750, P  = 0.0053) in patients with CLDN18.2-positive and HER-2-negative advanced G/GEJ cancer[ 162 ].

GLOW (NCT03653507) is another phase III trial investigating zolbetuximab plus CAPOX as first-line treatment in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or GEJ cancer. In this study, zolbetuximab plus CAPOX showed a significant improvement in mPFS (8.21 vs 6.80 months, HR 0.687, P  = 0.0007) and mOS (14.39 vs 12.16 months, HR 0.771, P  = 0.0118) compared to placebo plus CAPOX[ 163 ]. Additionally, zolbetuximab is also being studied in combination with immunotherapy in patients with CLDN18.2-positive advanced gastric or GEJ cancer in the ILUSTRO study (NCT03505320).

Another promising therapeutic approach targeting CLDN18.2 employs CLDN18.2-specific chimeric antigen receptor (CAR) T cells. CLDN18.2-specific CAR T cells achieved partial or complete tumor regression in CLDN18.2-positive PDX models [ 164 ]. A phase I study of CLDN18.2-specific CAR T cells in gastrointestinal cancers conducted by Prof. Shen Lin's team demonstrated that in GC patients, the ORR and DCR were 57.1% and 75.0%, respectively, and the 6-month overall survival rate was 81.2% [ 165 ]. Claudin 18.2 served as a new target for the later-line treatment of GC, with considerable ORR improvement achieved in Claudin 18.2 CAR-T therapy, which has become a hallmark event for cellular immunotherapy in solid tumors. Currently, several new drugs focusing on Claudin 18.2, such as Claudin 18.2 bispecific antibodies (Claudin 18.2/CD3, Claudin 18.2/PD-L1) and ADC analogs, are being developed. Although these drugs have not been approved for clinical applications, some of them showed promising preclinical data and are being widely studied in different clinical trials. Since Claudin 18.2 is also expressed on the normal gastric mucosal epithelial surface, the risk of adverse reactions and whether ADC drugs may aggravate normal mucosal damage should also be a concern.

FGFR-targeted therapy

FGFR1 mutations, FGFR2 amplifications, and FGFR3 rearrangements are the most common FGFR alterations in GC [ 166 ]. Different types of FGFR targeting agents were explored or developed in GC, including multikinase inhibitors, pan-FGFR inhibitors, FGFR1-3 inhibitors, selective FGFR inhibitors and ADC. Nevertheless, most multikinase inhibitor studies were preclinical or single case reports in GC without robust clinical evidence [ 167 ]. Futibatinib, an irreversible and highly selective FGFR1–4 inhibitor that permanently disables FGFR2, has been tested in a phase II trial involving patients with advanced-stage solid tumors harboring FGFR alterations, including those with FGFR2-amplified G/GEJ cancers [ 168 ]. Although the ORR was reported to be 22.2% in the GC cohort [ 169 ], more data are needed to support the efficacy of multiple FGFR inhibitors in different FGFR gene alterations in GC.

Currently, bemarituzumab has shown some promising results in the treatment of mGC [ 170 ]. It is a first-in-class afucosylated monoclonal antibody against the FGFR2b splice variant frequently overexpressed in FGFR2- amplified G/GEJ cancers. In a phase I trial, 17.9% of patients with FGFR2 amplifications had a confirmed response to bemarituzumab [ 171 ]. Based on the safety and activity profile of bemarituzumab monotherapy in GC, the phase II FIGHT trial was designed to evaluate the efficacy of bemarituzumab plus mFOLFOX6 regimen in previously untreated, FGFR2b-overexpressing advanced-stage G/GEJ cancers [ 172 ]. The trial showed a 2-month improvement in PFS, and the OS was not reached (NR) in the experimental arm (bemarituzumab + mFOLFOX6). However, the experimental arm had a higher incidence of adverse events than the control chemotherapy arm, particularly in regard to ocular toxicity.

EGFR-targeted therapy

Approximately 5–10% of patients with G/GEJ cancers have EGFR amplifications or EGFR overexpression, both of which are associated with poor prognosis [ 173 ]. Previous large randomized clinical trials have failed to demonstrate any significant survival benefit with EGFR-targeted agents [ 92 , 174 ], perhaps because most of the studies were performed in unselected patient populations regardless of EGFR status. Besides, biomarker analysis of the EXPAND and COG trials suggests activity in patients with tumors expressing high levels of EGFR, thus supporting the significance of patient selection for future trials [ 175 , 176 ]. In a prospective cohort, patients with metastatic gastroesophageal adenocarcinoma were screened for EGFR amplification and subsequently treated with anti-EGFR therapy (cetuximab). The ORR was 58% (4 of 7 patients), and the DCR was 100% (7 of 7 patients), implying that EGFR inhibition should be further studied in selected patients [ 177 ]. Many of the ongoing EGFR inhibitor studies should test EGFR alterations in the GC patients prior to enrollment to overcome resistance to EGFR-targeted therapies.

MET/HGF pathway inhibitors

c-Mesenchymal-Epithelial Transition (c-MET) is a tyrosine kinase receptor from MET families, and hepatocyte growth factor (HGF) is the common ligand to c-MET [ 178 ]. MET/HGF pathway activation is associated with tumor invasiveness and poor disease prognosis. The anti-MET monoclonal antibody, onartuzumab, has been studied in a phase III trial of onartuzumab plus mFOLFOX6 vs placebo plus mFOLFOX6 in patients with metastatic HER2-negative G/GEJ cancers. However, the addition of onartuzumab to mFOLFOX6 did not improve clinical outcomes in the ITT population or in the MET-positive population [ 179 ]. Rilotumumab is a humanized monoclonal antibody targeting HGF. Two phase III trials (RILOMET-1 and RILOMET-2) investigated rilotumumab plus chemotherapy in advanced MET-positive G/GEJ cancers. Unfortunately, both studies were terminated due to increased number of deaths in the rilotumumab group[ 180 , 181 ]. Additionally, several selective/non-selective c-MET TKIs, such as tinvatinib, AMG 337 and foretinib, have also been tested in MET-positive GC, but no significant benefit was seen in clinical trials[ 182 , 182 , 184 ].

Challenges and future perspectives

Even though substantial advances have been made in the treatment of GC, further research and development are still necessary. Improving early detection, reducing recurrence and optimizing treatment strategies are the primary challenges and prospects for GC management. To increase GC early detection and promote patients’ overall survival, endoscopic screening programs should be implemented in high-risk regions, and more precise early detection technologies are of great value. In a previous study, we demonstrated an artificial intelligence (AI) diagnostic platform, GRAIDS, to detect upper gastrointestinal cancers using real-world endoscopic imaging data from six Chinese hospitals with varying experience in the endoscopic diagnosis of upper gastrointestinal cancer [ 185 ]. GRAIDS provided both real-time and retrospective assistance for enhancing the effectiveness of upper gastrointestinal cancer screening and diagnosis, with high diagnostic accuracy and sensitivity in detecting upper gastrointestinal cancers. In the near future, the AI system will help many physicians in community-based hospitals identify upper gastrointestinal cancers more efficiently and accurately [ 186 ].

In addition, recurrence of GC remains common despite the multimodality treatment, so many studies in progress aim to identify individuals at risk of recurrence after treatment. Circulating tumor DNA (ctDNA) can be detected in the circulation of cancer patients and has the potential to predict minimal residual disease [ 187 ]. Liquid biopsies can detect a broader spectrum of abnormalities in a heterogeneous tumor compared to conventional tissue biopsies. According to a study investigating perioperative therapies in patients in the CRITICS trial with resectable GC, the presence of ctDNA could predict recurrence when analyzed within nine weeks after preoperative treatment and after surgery in patients eligible for multimodal treatment [ 187 ]. These findings highlight the significance of ctDNA as a biomarker for predicting patient outcomes following perioperative cancer treatment and surgical resection in patients with GC. In another 1630-patient cohort of ctDNA results, genomic alterations were correlated with clinicopathologic characteristics and outcomes and provided prognostic and predictive information [ 188 ]. As for advanced GC, ctDNA also serves as a potential biomarker of immunotherapy response, and its potential role in predicting irAEs is worth further investigation [ 189 ]. Further research aimed at prospectively collecting ctDNA is needed to confirm these findings. The existence of persistent ctDNA following curative-intent treatment of GC may indicate minimal residual disease, and trials are underway to determine whether additional adjuvant therapy can result in the clearance of ctDNA.

Intratumoral, intrapatient, and interpatient heterogeneity in GC is the major barrier to drug development for systemic therapies. Most GC patients are not susceptible to immune checkpoint inhibitor monotherapies. Thus, one of the major challenges in systemic treatments for GC is overcoming resistance to ICI therapy. One strategy is to develop novel ICIs with better efficacy. Recently, many novel immune checkpoint modulators have been widely investigated, including LAG-3, VISTA, TIM-3, TIGIT, CD38, CD39, and CD73[ 190 ]. Another key strategy is combining ICI and other therapies, such as other ICI, targeted therapies, other immune-modulating agents, chemotherapy (as discussed above), and radiotherapy [ 191 ]. As mentioned above, in the CheckMate-649 study, the combination of anti-PD-1 and anti-CTLA-4 agents (nivolumab plus ipilimumab) failed to improve treatment outcomes compared to traditional chemotherapy [ 57 ]. In the EPOC1706 study, lenvatinib, an anti-angiogenic multiple receptor tyrosine kinase inhibitor, combined with pembrolizumab showed an exciting activity with an ORR of 69% in the first-line and second-line treatment of advanced GC[ 151 ]. ICI combined with other anti-immunosuppressive factor agents, such as anti-transforming growth factor-β (TGF-β), is also being investigated in clinical trials (NCT04856774). To fully understand the mechanism of resistance to immunotherapy, factors such as epigenetics, metabolism, immune suppression, and microbiota must be considered. Therefore, the development of combined therapies should be based on understanding the underlying mechanisms of immune modulation and resistance, rather than simply combining available therapies in a haphazard manner.

Rapid developments are ongoing in the clinical use of ADCs and are now considered one of the current hot spots for antitumor drug development. In particular, ADCs have emerged as a new era of targeted therapy in the field of GC treatment. The latest generation of ADCs has expanded the treatment population to include novel targets and demonstrated superior clinical outcomes compared to traditional chemotherapy drugs. Nevertheless, certain aspects of ADCs remain to be addressed. Firstly, it is necessary to explore ways to advance ADCs as first-line therapy to benefit a larger number of patients. Secondly, to make better use of medical resources, a more differentiated target layout needs to be established, moving beyond the focus on distinct targets such as HER2. To address these challenges, optimization of the toxin, linker and toxicity of ADCs is essential, along with the development of ADC-combination therapies to improve efficacy. We anticipate the discovery of more potential ADC drugs and expect a breakthrough in first-line treatment.

Currently, many clinical trials have complex treatment regimens, including mono-immunotherapy, double-checkpoint inhibitors, anti-angiogenic drugs, and biomarker-directed therapies [ 190 , 192 ]. However, the challenge of determining the optimal treatment strategy and the appropriate timing of molecular biomarker screening has yet to be resolved. We expect that extensive translational research, preclinical investigations, and multi-omics-based clinical trials will lead to breakthroughs in the diagnosis and treatment of GC. Therefore, we eagerly anticipate future studies that have the potential to improve clinical practice in the coming years.

Availability of data and materials

Not applicable.

Abbreviations

Antibody–drug conjugates

Antibody-dependent cell-mediated cytotoxicity

Advanced gastro-oesophageal cancer

Artificial intelligence

American Society of Clinical Oncology

Bispecific antibodies

Best supportive care

Capecitabine and oxaliplatin

Chimeric antigen receptor

Cisplatin and fluorouracil

China Food and Drug Administration

Confidence interval

Claudin18.2

Combined positive score

Chemoradiotherapy

Chinese Society for Clinical Oncology

Circulating tumor DNA

Cytotoxic T lymphocyte antigen-4

Disease control rate

Disease-free survival

Mismatch-repair deficiency

Duration of response

Docetaxel, oxaliplatin, and S-1

Epstein-Barr virus

Epstein-Barr virus-associated gastric cancer

Extracellular domain

Epirubicin, cisplatin, and fluorouracil

Event-free survival

Epidermal growth factor receptor

Epirubicin and oxaliplatin

Erythroblastic leukemia viral oncogene homolog

Extracellular regulated protein kinase

European Society for Medical Oncology

Food and Drug Administration

Fibroblast growth factor receptor

Fluorescent in situ hybridization

Fluorouracil, leucovorin, oxaliplatin, and docetaxel

Fluorouracil, leucovorin, and oxaliplatin

Fluorouracil and cisplatin

• Gastric cancer

Gastroesophageal junction adenocarcinoma

Gastroesophageal junction

Human epidermal growth factor receptor 2

Hazard ratio

Immune checkpoint inhibitor

Immunohistochemistry

Kirsten rats sarcomaviral oncogene homolog

Lymphocyte-activation gene 3

Mitogen-activated protein kinase

Mesenchymal epithelial transition

Cytotoxin monomethyl auristatin E

Microsatellite instability

Mammalian target of rapamycin

National Comprehensive Cancer Network

Not evaluable

Natural killer

Objective response rate

Overall survival

Pathological complete response

Programmed cell death 1

Programmed cell death ligand 1

Progression-free survival

Phosphatidylinositol-3-kinase

Phosphatase and tensin homolog

Relapse-free survival

Recommended phase 2 dose

Receptor tyrosine kinase

S-1 and oxaliplatin

S-1, oxaliplatin and radiotherapy

S-1 and cisplatin

Tumor area positivity

The Cancer Genome Atlas

Trastuzumab emtansine

Trastuzumab deruxtecan

Transforming growth factor-β

T cell immunoreceptor with Ig and ITIM domain

T cell immunoglobulin and mucin domain 3

Tumor mutational burden

Vascular endothelial growth factor

V-domain Ig suppressor of T cell activation

Capecitabine and cisplatin

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 82203678 to Y.H.), the Science and Technology Program of Guangdong (Grant No. 2019B020227002 to R.-H.X.), the CAMS Innovation Fund for Medical Sciences (Grant No. 2019-I2M-5-036 to R.-H.X.).

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Wen-Long Guan and Ye He have contributed equally.

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Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of China

Wen-Long Guan, Ye He & Rui-Hua Xu

Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, People’s Republic of China

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Rui-Hua Xu designed this review. Rui-Hua Xu, Wen-Long Guan, and Ye He drafted the manuscript and prepared the figures. Rui-Hua Xu, Wen-Long Guan, and Ye He collected the related references and participated in the discussion. All authors contributed to this manuscript and revised the manuscript. All authors read and approved the final manuscript.

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Guan, WL., He, Y. & Xu, RH. Gastric cancer treatment: recent progress and future perspectives. J Hematol Oncol 16 , 57 (2023). https://doi.org/10.1186/s13045-023-01451-3

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DOI : https://doi.org/10.1186/s13045-023-01451-3

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MINI REVIEW article

Current therapies and progress in the treatment of advanced gastric cancer.

• Department of Gastroenterology, The People’s Hospital Of Changxing Country, Zhejiang, China

Gastric cancer (GC) remains one of the most life-threatening disease worldwide with poor prognosis because of the absence of effective treatment and the delay in diagnosis. Due to the delay of diagnosis, a large proportion of GC patients are diagnosed as advanced GC, with extreme short lifespan. In the past few years, some pivotal progress and novel therapies was proposed, and conducted into clinical researches and practice. In this study, we summarized the development of several novel immunotherapy or targeted treatment modalities for advanced GC, including immune checkpoint inhibitors, anti-angiogenic therapy and cancer vaccines. Additionally, the advantage and potential weakness in each of these therapeutic methods are also listed. Finally, we discussed the promising research direction of advanced GC treatment, and the limitation in basic and clinical research of advanced GC, including the combination of immunotherapy and targeted therapy.

1 Introduction

Gastric cancer (GC) is the fourth leading cause of cancer-related deaths worldwide and the fifth most frequently diagnosed malignancy ( 1 ). South American and Asian nations account for the majority of new diagnoses of stomach cancer each year ( 2 ). Patients with advanced GC have a poor prognosis and a short lifespan of roughly one year because of the absence of effective medications and the delay in detection ( 3 ). Radiation therapy, chemotherapy, and targeted therapy are the treatments that are most frequently utilized, while primary criteria used to establish a treatment plan are the illness stage, the existence of biomarkers, and the recommended regimen of the treating physician ( 2 ). For the treatment of advanced gastric cancer, medications such regorafenib, imatinib, entrectinib and Larotrectinib are frequently utilized ( 3 – 5 ). Traditional treatments, however, in many cases cause multi-drug resistance and tumor relapse ( 6 ). The most recent 8th edition of the American Joint Committee on Cancer (AJCC) cancer staging system (cTNM), which was released in 2017, has significantly improved decisions on the treatment of GC ( 7 ). Despite the fact that the many classification systems and terminology used for this disease around the world can make it difficult to diagnose GC based on subtypes, it is obvious that it still remains a fatal disease that is not meaningfully controlled by current treatment options or earlier detection strategies ( 2 ). Due to its tremendous potential, immunotherapy has recently emerged as a revolutionary therapy for treating advanced GC and has attracted the interest of researchers everywhere.

Studies have indicated that the development of immune check point inhibitors (ICIs), such as antibodies against the cytotoxic T-lymphocyte antigen CTLA-4 ( 8 ), targeted immunotherapies in the pathways of programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) antibodies, have transformed the treatment paradigms of a variety of solid tumors by efficiently killing cancer cells through activation of the immune response ( 8 ).

ICIs have already shown efficacy and safety in clinical trials for several cancers. In order to treat advanced gastric tumors, a number of ICIs, including pembrolizumab, avelumab, sintilimab, tislelizumab, and ipilimumab, have been given clinical approval ( 3 , 9 – 11 ). The outcomes of recent trials testing these novel drugs raise the question of how to identify the people who might benefit the most. Therefore, advances in our understanding of the biology and mechanisms behind various clinical characteristics of the disease will make new drug development possible ( 8 ). Although chemotherapy is still the mainstay of treatment for patients with advanced gastric cancer, progress in its molecular characterization and the creation of tailored medicines may represent a promising strategy ( 12 ). In this study, we sought to examine the perspective and development of several immunotherapy treatment modalities for GC. Additionally, we discussed the difficulties that immunotherapies now face as well as potential solutions to these problems, such the combination of immunotherapy and targeted therapy.

2 Molecular profile

The organization of GC is gradually evolving away from histological classification and toward more complicated molecular categorization ( 8 , 13 , 14 ). Lauren classification (1960s) and the WHO classification (2010) are most commonly used in GC classification ( 15 ). Lauren Classification system divided GC into three main subgroups using the structural cellular components of the disease: well differentiated (non-cardia/intestinal), poorly differentiated (cardia/diffuse), and mixed type disease ( Figure 1 ). A fourth new subtype, solid GC, is also included ( 2 , 16 ). While, tubular, papillary, poorly cohesive and mucinous are subtypes in WHO classification ( 15 ). The distribution of subtypes varies greatly by region, and more significantly, the clinicopathological features of gastric cancer are evolving, with a declining prevalence of distal, well differentiated type tumors and a rising proportion of poorly differentiated/diffuse histology ( 17 ). However, these classified subtypes have shown minimal relevance in clinical practice because they lack predictive value and have minimum therapeutic implications.

Figure 1 Molecular Classification of Gastric Cancer.

Scientists have only recently started to fully understand the true heterogeneity of gastric cancer (GC), and they have been the pioneers in presenting its molecular characterization ( 18 ). They found that amplifications in the genes encoding for receptor tyrosine kinase proteins (RTKs) including VEGFA, ERBB2 (also known as HER2), EGFR, cell-cycle mediators, JAK2, FGFR2, ERBB3, and KRAS or NRAS are present in about 40% of these tumors ( 19 ). By demonstrating these targetable molecular traits, the majority of phase II and III clinical trials for GC during the subsequent decade considered treatments by targeting these molecular abnormalities ( 20 ). In 2014, using six molecular platforms (whole-exome sequencing, messenger RNA sequencing, array-based somatic copy number analysis, microRNA sequencing, array-based DNA methylation profiling and reverse-phase protein array), clustering analysis of data from 295 GC patient samples from around the world was carried out as part of The Cancer Genome Atlas (TCGA) program ( 17 ). The analysis identified four subtypes: microsatellite instability (MSI), chromosomal instability (CIN), Epstein-Barr virus (EBV) and genomically stable (GS) ( 21 ). Although GC is classified molecularly, these findings have not yet been applied in therapeutic settings ( 8 ). Moreover, an analysis of over 1000 gastric cancer samples revealed that non-Asian tumors had higher expression of T cell markers (CD45R0, CD3 and CD8), including CTLA-4 signaling, and lower expression of the immunosuppressive T regulatory cell marker FOXP3 compared to Asian tumors. This data suggests that disparities in immunological profiles merit additional exploration, as does a comparison of ICI response between Asian and non-Asian populations ( 9 ).

3 Immunotherapy treatments for advanced GC

3.1 immune checkpoint inhibitors (icis).

Over the past few years, a better understanding of the molecular mechanism of gastric cancer has greatly facilitated the development of novel therapies ( 22 ). Immunomodulating drugs are actively reshaping the medical field in a variety of cancer types and represent a potential path for GC ( 23 ) ( Figure 2 ). Tumor cells may exploit immunological checkpoints in an inadvertent manner to avoid host immunosurveillance and immune destruction ( 24 ). Immune checkpoints may be counteractively used by tumor cells to evade host immunosurveillance and escape immune destruction. Because of that, inhibition of checkpoints by ICIs helps restore host immunity against tumor cells ( 25 , 26 ). ICIs could successfully disrupt immune checkpoint interactions, resulting to tumor cell death by activation of the host immune system ( 27 ).

Figure 2 Components of effective immunotherapy in gastric cancer.

Individual patients with advanced-stage cancer have shown durable responses to ICI treatment. As a result, these agents represent the most promising new therapy alternatives for GC patients ( 24 ). Anti-PD-L1 (avelumab), anti-PD-1 (nivolumab, pembrolizumab) and as well as anti-CTLA-4 (ipilimumab, tremelimumab), have shown enhanced results in cancer patients. Recent analyses have also proven the efficacy of these medicines in GC patients ( 8 ). Ipilimumab was the first ICI approved in the world (2011) to treat melanoma. Immunotherapies have since transformed advanced gastric cancer therapy techniques. There are mainly three types of ICIs, anti-PD1/PD- L1 and anti-CTLA4 antibodies. Inhibitors targeting these immune checkpoints have been generated and studied in pre-clinical and clinical trials ( 3 ). These achievements in immunotherapy have marked a new era for advanced gastric cancer treatment ( 3 , 28 ). Indeed, treatment with ICIs has elicited sustained responses in individual patients with advanced- stage cancer. Thus, these agents constitute the most promising new therapeutic options for patients with GC ( 24 , 29 ).

3.2 PD-1 inhibitor

The primary functions of immune checkpoint inhibitor (known as PD-1) is regulating the alterations caused to the cellular system, this is a promising cancer therapeutic target in different cancers including gastric cancer. Typically, immune checkpoint inhibitors target key regulatory molecules associated with escaping or protective processes for tumor cells from immune attack. Thus, PD-1 is a prominent concern in the regulation of cytotoxic activity of anti-tumor T cells. A wide range of studies based on extensive randomized controlled trials have concluded that gastric cancer and associated cancer types can achieve disease control and improve overall survival from treatment with PD-1 inhibitors treatment ( 30 ). Nivolumab, a PD-1 inhibitor, is a monoclonal antibody that was approved by the FDA in 2014 for the treatment of advanced gastric cancer ( 31 ). Through phase III clinical studies, which were carried out in more than 40 Asian nations, the benefits of nivolumab against advanced GC were investigated ( 3 ). According to preliminary findings, nivolumab might considerably improve patient survival compared to placebo. Nivolumab therapy in patients with GC showed 12-month overall survival rates of 26.2% compared to 10.9% with placebo treatment, suggesting a hopeful cure for this population with a dismal prognosis ( 31 ). In particular, nivolumab has received approval for use in clinical settings as a cutting-edge strategy to treat advanced and recurring GC ( 2 ).

Another effective PD-1 inhibitor is pembrolizumab. Pembrolizumab was most recently given expedited clearance by the Food and Drug Administration (FDA) in conjunction with trastuzumab, first-line chemotherapy for patients with HER2 positive advance GC, based on the interim findings of KEYNOTE-811 ( 9 ). To compare the effectiveness of pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy a total of 763 patients were randomly assigned. Pembrolizumab was shown to be noninferior to chemotherapy in patients with untreated, advanced GC, with less adverse effects in this phase 3 randomized clinical trial. However, pembrolizumab or pembrolizumab with chemotherapy did not outperform treatment in terms of overall survival (OS) or progression-free survival (PFS) ( 32 ).

3.3 PD-L1 inhibitors

PD-L1 is a cancer cell surface marker that is overexpressed on multiple cancer cells and escapes immune system identification by suppressing T-cell inhibition ( 33 ). Prevention of GC with the PD-L1 inhibitor Pembrolizumab (Keytruda) has been authorized for third-line usage in gastric cancer based on the results of the phase II KEYNOTE-059 trial, which boosted the rate of responses to 11.6% compared to 2.3% in the control arm ( 2 ). Avelumab, durvalumab, and atezolizumab are a few of the well-known PD-L1 inhibitors ( 3 ). A phase III trial of the anti-PD-L1 mAb avelumab in people with advanced gastric cancer showed that it was well tolerated. Patients from Japan who took avelumab showed significant rates of overall response and survival. Additionally, avelumab’s effectiveness against advanced gastric cancer is increased when used in conjunction with other treatments ( 12 ). The mechanism by which PD-L1 inhibitors contribute to advanced gastric cancer may be that PD-L1 inhibition activates DC cells, T lymphocytes, and natural killer cells, resulting in gastric tumor elimination ( 3 ). It appeared that high levels of PD-L1 (an adaptive immune resistance-type mechanism) were related with CD8+ T-cell infiltration in GC, pointing to the potential effectiveness of anti-PD-1/PD-L ( 8 )However, further research is required to fully comprehend the prognostic significance of immune cell activity and PD-L1 expression. Interesting new findings demonstrated that patients with greater CD8+ T-cell density have higher PD-L1 expression and poorer outcomes in a small cohort of resected GCs ( 23 ).

3.4 CTLA-4 Inhibitors

CTLA-4 is an essential component of the human immune system. Because CTLA-4 is identical to CD28, it can control or even block CD28 signaling ( 3 ). CTLA-4 is a well-studied immunological checkpoint in GC. However, the predictive impact of CTLA-4 expression in GC is unclear ( 34 ).

CTLA-4 inhibitors tremelimumab and ipilimumab have been evaluated in clinical trials of advanced gastric cancer ( 3 ). Combination therapy of ipilimumab and nivolumab has been approved to treat advanced gastric cancer. However, the efficacy of CTLA-4 inhibitor as a monotherapy in advanced gastric cancer remains to be further investigated ( 3 ).

4 Anti-angiogenic therapy

Angiogenesis is a well-known phenomenon defined as the process of new blood vessels formation. It is a complex and dynamic process, which contributes crucially to tumor growth, invasion, and metastasis. This process is regulated by various pro- and anti-angiogenic molecules involved in the progression and development of cancer. Researchers have demonstrated the molecular processes associated with tumor angiogenesis. Most prominent biomolecules elucidated by advances in molecular and cellular biology in angiogenesis, include growth factors, chemokines, and adhesion factors. Based on these molecules, targeted therapeutic research has driven treatment with anti-angiogenic agents to become a promising therapeutic strategy against different cancer types including gastric cancer. Some of the most common and prominent anti-angiogenic agents are tyrosine kinase inhibitors and monoclonal antibodies, which can target vascular endothelial growth factor pathway ( 35 ). Angiogenesis is a promising therapeutic target which plays a key role in cancer cell proliferation and metastasis. Several studies indicated that pharmacologic blockade of angiogenesis may be a promising therapeutic approach. In the several clinical trials different anti-angiogenic therapies for gastric cancer, including anti-VEGF or anti-VEGF receptor (VEGFR)-2 monoclonal antibodies, VEGF-Trap and VEGFR tyrosine kinase inhibitors, the anti-VEGFR-2 antibody ramucirumab was demonstrated to prolong overall survival both as a single agent and in combination with paclitaxel as a second-line chemotherapy ( 36 – 39 ). The next step in anti-angiogenic therapy is to evaluate anti-angiogenic therapy in combination with immune checkpoint inhibitors, assess the safety and efficacy of combination therapy with chemotherapeutic agents as an earlier treatment option or in the perioperative setting, and establish a clinically meaningful biomarker. Ramucirumab’s early results in combination with anti-PD-1/PD-L1 therapy are promising for the continued development of gastric cancer treatments to increase patient survival ( 39 , 40 ).

5 Conclusion

Development of immunotherapy in advanced gastric cancer has demonstrated great advantages over traditional therapies. However, there still exists various challenges that have severely limited the clinical application of immunotherapy in advanced gastric cancer, for instance, the side effects and toxicity of ICIs, cancer vaccines and CAR-T therapies.

Author contributions

SM: Conceptualization, Investigation, Methodology, Validation, Writing – original draft. HL: Data curation, Formal Analysis, Investigation, Resources, Visualization, Writing – review & editing. SW: Conceptualization, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This paper was funded by the natural science fund project of Huzhou City, Zhejiang province, China to HL.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: advanced gastric cancer, immunotherapy, anti-angiogenic therapy, immune checkpoint inhibitors, treatment

Citation: Li H, Shen M and Wang S (2024) Current therapies and progress in the treatment of advanced gastric cancer. Front. Oncol. 14:1327055. doi: 10.3389/fonc.2024.1327055

Received: 25 October 2023; Accepted: 05 February 2024; Published: 26 February 2024.

Reviewed by:

Copyright © 2024 Li, Shen and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Shihao Wang, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

• Open access
• Published: 03 September 2024

The prognostic role of palliative gastrectomy in advanced gastric cancer: a systematic review and meta-analysis

• Desheng Luo 1 ,
• Hongtao Xu 1 ,
• Chuan Jiang 1 ,
• Jingjing Zheng 1 ,
• Laizhen Tou 1 ,
• Haifeng Que 1 &
• Zheng Sun 1  

BMC Cancer volume  24 , Article number:  1096 ( 2024 ) Cite this article

Metrics details

The effectiveness of palliative gastrectomy for advanced GC remains a topic of debate. This study sought to establish whether palliative gastrectomy has an impact on prolonging survival.

We carried out systematic searches in PubMed, Cochrane Library, Web of Science, and the EMBASE databases from database inception to July 2023 to gather studies that examined the connection between palliative gastrectomy and the prognosis of advanced GC. The study employed overall survival as the primary outcome, with the hazard ratio serving as the selected parameter to gauge the association. Subgroup analyses were performed to delve into potential differences within the included studies, categorizing them by study region and sample size in order to examine possible sources of heterogeneity. The stability of individual studies was assessed through sensitivity analysis. The analysis included 20 articles, encompassing a total of 23,061 patients.

According to the meta-analysis results, patients who underwent palliative gastrectomy exhibited a noteworthy enhancement in overall survival (HR: 1.49; 95% CI: 1.12–1.99; P  = 0.006) in comparison to those who did not receive this procedure. There was no association between the type of surgery and the length of hospital stay, as revealed by the analysis (HR = -0.02; 95% CI: -0.84–0.81; P  = 0.970).

Conclusions

Based on this meta-analysis, patients with advanced gastric cancer who underwent palliative gastrectomy may experience an extended survival duration without a significant prolongation of their hospitalization.

Peer Review reports

Even with substantial advancements in diagnosis, experimental research, and therapeutic approaches, GC remains responsible for more than 6.8% of global cancer-related mortality and retains its position as the fifth key cause of cancer-related mortality, following female breast [ 1 , 2 ]. Yet, recent years have seen significant progress in new treatment modalities and chemotherapy, leading to improved overall survival rates among GC patients with untreatable factors, as compared to those undergoing solely supportive treatment [ 3 , 4 , 5 ]. Timely diagnosis leads to improved long-term outcomes in cases of early GC, but when it comes to advanced GC with incurable factors, the outlook is less hopeful [ 6 , 7 ]. Peritoneal dissemination, distant lymph node metastases, liver dissemination, lung metastases, and the presence of a significantly large primary tumor are the factors that classify patients with advanced gastric cancer as incurable [ 8 ]. Thus, palliative approaches remain essential for gastric cancer patients, particularly those in advanced stages [ 9 ].

In accordance with the guidelines from the National Comprehensive Cancer Network (NCCN), the use of gastric resections is advised primarily for symptom palliation, such as the management of uncontrollable bleeding orobstruction, in patients with incurable disease [ 10 ]. The guidelines established by the Japanese Gastric Cancer Association (JGCA) propose that patients diagnosed with metastases, yet not experiencing significant symptoms, may be eligible for treatment involving gastrectomy [ 11 ]. While surgical resection is generally deemed the most appropriate approach for treating GC, there remains ongoing debate concerning its application in cases of GC with incurable factors. Moreover, the guidelines established by the JGCA propose that patients diagnosed with oligometastatic disease may be eligible for weakly recommended surgical treatment following chemotherapy. Through palliative gastric resection, symptoms such as bleeding and obstruction can be alleviated and oral food intake can be restored [ 12 , 13 ]. According to several research studies, gastric resection has been associated with potential advantages in terms of survival, symptom relief, and the enhancement of quality of life [ 13 , 14 , 15 , 16 , 17 ]. Conversely, a number of additional studies have noted that survival following palliative gastrectomy was linked to notable morbidity, extended hospitalizations, and diminished quality of life [ 18 , 19 ]. It was recommended to consider gastrectomy only in cases characterized by severe complications, such as organ perforation or tumor bleeding [ 20 , 21 ]. This study focuses specifically on palliative gastrectomy, which involves the surgical removal of part or all of the stomach for symptom relief in incurable cases, as opposed to other palliative surgeries that may not involve gastric resection.

Several review studies have explored palliative gastrectomy in patients with advanced, incurable GC. It is not difficult to find that the industry is increasingly clear about the therapeutic intent of palliative gastrectomy in patients with advanced, incurable GC and the positive impact on their survival outcomes. [ 22 , 23 ] Given the timeliness of previous published studies and significant quality issues in some of the included trials, meta-analyses incorporating the latest findings are necessary to further identify the most appropriate surgical treatment strategies and patient populations. Therefore, we conducted this meta-analysis to assess the clinical relevance of palliative gastrectomy on overall survival for patients diagnosed with incurable advanced gastric cancer, paying particular attention to the criteria for patient selection and the choice of treatment strategy.

This study is registered on the PROSPERO with the registration number: CRD42023454278.

Systematic search strategy

A comprehensive and sensitive search strategy was created to include literature published from database inception to July 2023, ensuring a comprehensive coverage of relevant material. Electronic databases such as PubMed, Cochrane Library, Web of Science, and the EMBASE were employed in the comprehensive search process. Keywords such as “palliative gastrectomy,” “stomach neoplasm” and “gastric cancer,” were integrated into the search strategy. The search strategy was adapted for each database’s specific syntax and indexing terms while maintaining the core concepts of palliative gastrectomy and advanced gastric cancer. Two independent reviewers (Luo and Xu) were responsible for the article search process. In instances of discordance, they engaged in comprehensive discussions to achieve a consensus resolution. Titles and abstracts from studies considered potentially relevant were collected and incorporated into management software (EndNote ® ).

Inclusion and exclusion criteria

Inclusion criteria: (1) Population: In this analysis, all the studies were comparative studies, specifically addressing patients with incurable advanced gastric cancer (GC). The core focus of these studies was the comparison between patients who received palliative gastrectomy and those who did not. In this context, advanced GC was explicitly defined using the TNM classification criteria, which encompassed T1–4N3M0, T4N1–3 M0, and any T or N with an M1 tumor designation [ 24 , 25 ] The present study considered articles that included patients diagnosed with GC with metastasis, even if they did not utilize the TNM staging system. To ensure only incurable cases were included, we carefully reviewed the full texts of studies to confirm that patients had M1 or locally advanced disease deemed unresectable. Studies that did not clearly differentiate between potentially curable and incurable cases were excluded. (2) Intervention: effect of palliative surgery on prognosis in patients with advanced GC. We defined palliative gastrectomy as surgical removal of part or all of the stomach in patients with known incurable disease. Studies that did not clearly distinguish between curative-intent and palliative gastrectomies were excluded. (3) Outcome: overall survival, survival curves, median survival time and hazard ratio (HR), were included in the study to provide a comprehensive assessment of the data. (4) Study design: retrospective, cross-sectional, case-controlled, prospective studies, and randomized controlled trials (RCTs). Exclusion criteria: (1) In this study, only published studies that had undergone peer review and were available in journals were included. The exclusion criteria encompassed the exclusion of conference abstracts, reviews, protocols, letters, comments, articles lacking full-text, and any data that could not be obtained from the authors. (2) In instances where multiple investigations were conducted simultaneously by the same team, this study made the selection to include either the most recent publication or the article with the most extensive dataset. Additionally, any pertinent supplemental data were incorporated as needed.

Data extraction and quality assessment of the included literature

Two researchers conducted the data collection and analysis, utilizing predefined tables with categories that encompassed authorship, publication date, geographical origin, study period, sample size, median survival duration, overall survival, and hospitalization duration. In instances where HR for overall survival were absent in the articles, the analysis utilized Engauge Digitizer 4.1 software to extract and compute HRs from the survival curves. Data extraction was undertaken by the first reviewer (Jiang), and the accuracy of the extracted data was verified through a thorough review performed by the second reviewer (Zheng).

The assessment of study quality in this meta-analysis was performed based on the Newcastle-Ottawa Quality Assessment Scale (NOS), ensuring rigorous evaluation of the included studies. For cohort studies, the NOS evaluated the quality of each study with regard to three domains: participant selection, comparability of groups, and the outcome of interest. The scoring system utilized in the NOS spans from 0 to 9, with studies that received scores surpassing 6 being deemed of high quality [ 26 ].

Study outcomes

The primary outcomes were median survival in the two groups and the potential association of palliative gastrectomy for gastric cancer with overall survival. Secondary outcomes included length of hospitalization; post-operative complications and in-hospital mortality. Length of hospitalization analysis excluded patients with hospital mortality. Post-operative complications, as outlined in this study, comprised incidents that could be either surgically related or non-surgically related in origin. Hospital mortality, as defined in this study, encompassed deaths occurring either during the hospital stay or within 30 days following admission.

Statistical analysis

The Tierney et al. method was utilized to calculate HRs and their corresponding 95%CIs based on the available data, in order to investigate potential associations with overall survival in the two study groups [ 27 ]. Length of hospitalization was compared based on the difference in mean and standard deviation of post-treatment length of stay between the control and intervention groups. The random-effect model was employed in this study to calculate the aggregated results for various study characteristics. The estimation of hospital stay for continuous outcomes involved the calculation of the standardized mean difference (SMD) along with a 95% confidence interval (CI). The overall effect size was determined using Cohen’s categories, which included the delineation of effect sizes into three categories: small (0.2–0.5), moderate (0.5–0.8), and large (> 0.8).

The assessment of statistical heterogeneity among the studies involved the use of Cochran’s Q test and the I 2 statistic for quantitative evaluation, along with forest plots for visual examination. Heterogeneity was categorized as follows: 0–40%, considered not important; 30–60%, characterized as low heterogeneity; 50–90%, denoted moderate heterogeneity; and 75–100%, indicative of high heterogeneity. In cases where statistical heterogeneity was observed, subgroup analysis was performed to investigate the origin of heterogeneity. This analysis was based on two factors: the study area (China or non-China) and the sample size of studies (< 100 vs. ≥100). To gauge the possibility of publication bias, the research conducted visual screening of the Begg’s funnel plot and performed Begg’s test as an analytical tool to evaluate the presence or absence of publication bias. To enhance the reliability of our findings, a sensitivity analysis was carried out. The study implemented sensitivity analysis to assess the potential effect of individual studies on the overall results. This was accomplished by sequentially excluding one study at a time from the pooled analysis. The significance level for effect sizes in this research was defined at a P value of 0.05.

The statistical analysis in this study was carried out using Stata SE version 15.1 (Stata Corp, College Station, TX, USA). Reporting in this study was guided by the PRISMA Checklist.

The included literature and methodological quality

From the initial literature search, a total of 3,571 articles were collected, with 605 originating from PubMed, 2,104 from Web of Science, 643 from Embase, and 219 from the Cochrane Library. After removing duplicate studies and filtering out non-relevant articles via the evaluation of article titles and abstracts, 116 studies that held promise for relevance underwent an in-depth review. In accordance with the pre-defined inclusion and exclusion criteria, this study encompassed a total of 20 studies, which collectively involved 23,061 patients diagnosed with advanced gastric cancer [ 15 , 20 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ] Fig.  1 provides a visual representation of the literature search flow. The studies included in this analysis were published over a span of 18 years, from 2003 to 2021. All the articles considered in this study were observational trials, with a patient population of 5,431 individuals who underwent palliative gastrectomy and 17,630 individuals who did not undergo palliative surgery. The details regarding the characteristics of the studies and the results of the methodological quality assessment are presented in Table  1 .

Flow diagram of study selection

The primary outcomes

Median survival.

Nine of the included articles presented data related to median survival times. The calculated weighted average of the median survival time in the palliative gastrectomy group was 13.91 months (95% CI: 10.84–16.99), as illustrated in Fig.  2 A; and within the non-gastrectomy group, the weighted mean of the median survival time was calculated to be 7.42 months (95% CI: 4.63–10.21), as depicted in Fig.  2 B.

Forest plots show the association between palliative gastrectomy ( A ) non-gastrectomy ( B ) and overall survival

Overall survival

The 20 studies explored the association between palliative gastrectomy and OS outcomes. The prevailing results across the studies consistently pointed to the benefit of palliative gastrectomy in enhancing long-term survival for patients afflicted with incurable gastric cancer. The statistical significance of between-study heterogeneity was investigated, and the HR for overall survival was determined to be 1.49 (95% CI: 1.12–1.99; p  = 0.006). The presence of significant heterogeneity ( P  < 0.001, I2 = 94.4%) was observed, and this is visually represented in Fig.  3 .

Forest plots show the association between palliative gastrectomy and overall survival outcomes

The secondary outcomes

Length of hospital stay.

A total of six studies participated in the length of hospital stay analysis of the relationship between palliative gastrectomy and non-resection procedure. The results showed that the length of hospital stay was not related to the type of surgery (HR =-0.02, 95% CI: -0.84–0.81, P  = 0.970), and the heterogeneity across the studies was significant ( P  < 0.001, I2 = 97.3%; Fig.  4 ).

Forest plots show the length of hospital stay between palliative gastrectomy and non-resection procedure

Post-operative complications

Nine studies reported data on the incidence of postoperative complications in patients undergoing palliative surgery and non-gastrectomy. Palliative gastrectomy was linked to a rise in overall complications when compared to non-gastrectomy surgery (OR = 1.96; 95% CI: 1.02–3.75; p  = 0.042). Furthermore, there was significant heterogeneity observed across the studies ( P  < 0.001, I2 = 76.0%; as depicted in Fig.  5 ).

Forest plots show the post-operative complications in patients undergoing palliative gastrectomy and non-resection procedure

In-hospital mortality

Data on in-hospital mortality, specifically comparing patients who underwent palliative surgery to those who did not, were reported in five studies. The analysis indicated that palliative surgery did not result in a statistically significant increase in in-hospital mortality when compared to non-gastrectomy surgery (OR = 1.29; 95% CI: 0.77–2.16; p  = 0.337). Remarkably, there was no significant heterogeneity observed among the included studies ( P  = 0.907, I2 = 0.0%), as depicted in Fig.  6 .

Forest plots show the in-hospital mortality comparing patients undergoing palliative surgery compared to non-gastrectomy

Meta regression analysis

Taking the effect size as the dependent variable, and year of publication, time period, country, number of people, and intervention method of the control group as the independent variables, Meta-regression analysis was conducted, and it was found that these variables did not significantly affect the effect size, and the specific results are shown in Table  2 .

Subgroup analysis

To investigate the likely causes of heterogeneity in the combined HR for overall survival, we carried out subgroup analyses by dividing eligible studies into subgroups based on study area (China vs. non-China) and sample size (< 100 vs. ≥100). The heterogeneity among the studies ceased to exist when they were categorized into two subgroups based on sample size. With regard to sample size, palliative gastrectomy was significantly correlated with longer OS (HR: 1.86; 95%CI:1.40–2.48; I2 = 0.0%; P  < 0.001) in<100 compared with ≥ 100 (HR:1.49; 95%CI: 1.05–1.95; I2 = 95.0%; P  = 0.022) (Fig.  7 A). The subgroup analysis based on study area did not result in a significant modification of the prognostic impact of palliative gastrectomy on overall survival. However, it’s noteworthy that significant heterogeneity persisted across the studies, as shown in Fig.  7 B.

Forest plots show the association between palliative gastrectomy and overall survival stratified by the sample size ( A ) and studied area ( B )

Sensitivity analysis and publication bias

Sensitivity analyses were then performed as part of the study. The sensitivity analyses involved the stepwise removal of a single study from the meta-analysis in order to reveal the influence of each individual dataset on the aggregated HR. The results from the sensitivity analyses conducted in this study demonstrated that the exclusion of any individual study had no notable effect on the meta-analytic outcomes. This underscores the robust nature of the results, as visually represented in Fig.  8 . The results from the Begg’s funnel plot demonstrated considerable asymmetry for all the included studies, which is visually represented in Fig.  9 . It’s noteworthy that, despite the visual asymmetry in the Begg’s funnel plot, the quantitative assessment using Begg’s test indicated the absence of statistically significant publication bias in the studies reporting overall survival ( P  = 0.347).

Sensitivity analysis examining the influence of individual studies on pooled results

The Begg’s funnel plot for all included studies

Over the course of the last 30 years, there have been transformations in the metastasis, recurrence, and survival characteristics of gastric cancer patients, accompanied by a decrease in the worldwide incidence of the disease. This trend has been accelerated by the implementation of strategies to combat Helicobacter pylori [ 47 ], advancements in standardized surgical techniques and supplementary tools, and enhancements in the overall quality of life across various societies, among other factors [ 48 ]. Nevertheless, patients diagnosed with GC are often already in an advanced stage. Recent advancements in chemotherapy protocols have led to enhanced survival rates among gastric cancer patients with incurable factors. Despite this, there is still a debate surrounding the suitability of palliative resection for patients diagnosed with advanced GC [ 49 ]. Hence, our study stands as the pioneering effort to conduct a meta-analysis on palliative resection in patients diagnosed with incurable advanced gastric cancer. The data revealed a discernible trend that implied palliative gastrectomy could be associated with enhanced survival in patients with advanced GC in an incurable state. Patients who undergo palliative gastrectomy experience hospital stays of similar duration to those who opt for non-resection procedures.

Almost all the articles in this study employed median survival time as the measure for evaluating the effect. Consequently, the overall survival rates derived from each article were considered suitable for examination within the scope of this study. In spite of notable heterogeneity, the results of this study still pointed towards an improvement in overall survival rates associated with palliative gastrectomy, reflecting an HR of 1.49 (95% CI 1.12–1.99).

The comprehensive meta-analysis by Cowling et al. provides important context for interpreting our results [ 50 ]. While they found improved 1-year survival with palliative gastrectomy, the benefits became less clear over time. This underscores the importance of considering both short-term and long-term outcomes when evaluating the role of palliative gastrectomy. Their observation of increased complications with palliative resections aligns with our findings of higher complication rates, emphasizing the need to carefully weigh potential benefits against risks. Three of other relevant systematic review and meta-analysis offers additional support for our findings [ 22 , 23 , 51 ]. Among these researches, Zheng et al.‘s observation that palliative gastrectomy plus chemotherapy improved overall survival compared to non-resection surgery plus chemotherapy is consistent with our results. However, their study also highlighted the potential benefits of specific surgical approaches, such as D1 + and D2 lymphadenectomy, which were not specifically addressed in our analysis. This suggests an area for future research to refine patient selection and surgical techniques for optimal outcomes. Morever, while affirming that palliative gastrectomy prolongs survival period, Sun et al. highlighted its superior performance in patients with stage M1 GCs [ 23 ].

While our results support the potential benefit of palliative gastrectomy, they also highlight the persistent challenges in this field. As noted by Lasithiotakis et al., the heterogeneity of patients with advanced gastric cancer makes it difficult to draw definitive conclusions about the universal applicability of palliative gastrectomy [ 52 ]. Our subgroup analyses, particularly the differences observed between studies from China and other regions, underscore the need for careful consideration of patient and tumor characteristics when deciding on treatment approaches.

The value of palliative gastrectomy for incurable patients depends on whether it improves survival and quality of life. In clinical practice, the benefits of surgery must be weighed against the risks and costs before a treatment decision is made. It’s important to note that the decision for palliative gastrectomy was typically made either upfront based on preoperative staging or intraoperatively upon discovering unresectable disease. The specific decision-making process varied among studies and was not always clearly reported. Quality of life is an important factor in assessing the effect of resection, but it is rarely mentioned in the articles included in the analysis. As we have limited data from retrospective trials and therefore cannot determine quality of life and costs, current evidence cannot elucidate potential clinical benefit or harm. However, Chang [ 30 ] used length of hospital stay as a parameter to evaluate quality of life. Our pooled results on length of hospital stay suggest that palliative gastrectomy may not reduce quality of life. Despite this, the question of whether palliative gastrectomy has an impact on quality of life continues to be a matter of contention, highlighting the requirement for future research.

In multiple Asian nations, early diagnosis and prevention strategies are rigorously executed [ 53 ], yielding a greater proportion of early-stage tumor diagnoses and improved prognostic outcomes for individuals with gastric cancer when compared to their European and Western counterparts. Discrepancies in the outcomes could be attributed to variances in geographical regions. Among the articles included in this study, nine were contributed by China, while the remaining eleven were from sources outside of China. Subgroup analyses were performed by region to investigate whether regional differences had an influence on the analysis. According to our results, the potential benefit of palliative gastrectomy on survival was more prominent in China, while the dataset exhibited noticeable heterogeneity. Before arriving at a definitive conclusion, it is essential to gather additional data from non-Chinese sources for comparison with the existing Chinese data.

It’s important to note that there are certain limitations in our study. First, while our meta-analysis included studies from various institutions, including large database studies like those using SEER data, it’s important to note that many of the included studies were single-institution retrospective analyses. This mix of study types contributes to the heterogeneity observed in our results. It’s important to note that the second limitation of our study lies in the fact that the decision to opt for either palliative gastrectomy or non-resection procedures was based on a case-by-case assessment conducted by the surgical team. The third limitation is related to the fact that we did not have access to data on performance status, quality of life metrics, or detailed information about the chemotherapy regimen. The observed heterogeneity in the included studies was largely attributed to disparities in study design as well as variations in treatment modalities, such as single-agent versus combination chemotherapy regimens and chemotherapy with or without non-resection surgery. Fourth, our analysis of hospital stay length has limitations. Patients who received outpatient treatments like chemotherapy were not captured in this metric. This could potentially skew the results and should be considered when interpreting the findings. Finally, future research endeavors may find it worthwhile to explore the possibility of surgical resection following chemotherapy as a strategy to enhance the survival of patients with advanced GC. Substantial emphasis should be placed on conducting high-quality multicenter clinical RCTs in the future to meticulously examine the influence of gastrectomy on overall survival (OS).

Finally, it should be acknowledged that this study does not encompass data on long-term complications, morbidity, and the quality of life of patients in the aftermath of gastrectomy. It is vital to recognize that, for a subset of patients, these considerations play a pivotal role in their treatment decisions. Hence, future studies on this topic should prioritize a more robust investigation of these elements.

The results of this meta-analysis demonstrate that palliative gastrectomy confers a statistically significant survival advantage for individuals diagnosed with incurable advanced GC, while not imposing a substantial increase in the duration of hospitalization. However, further validation of the survival advantages linked to palliative gastrectomy in advanced GC patients necessitates the execution of prospective trials and RCTs.

Data availability

All data generated or analysed during this study are included in this article.

Abbreviations

National comprehensive cancer network

Japanese gastric cancer association

Randomized controlled trials

Newcastle-Ottawa quality assessment scale

Standardized mean difference

Confidence interval

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Acknowledgements

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This research was funded by Impact and significance of different digestive tract reconstruction methods on pancreatic exocrine function after laparoscopic early proximal gastric cancer resection (Grant number: 2022KY1429). The funders had no role in study design, data collection and analysis, decision to pub-lish, or preparation of the manuscript.

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Desheng Luo, Hongtao Xu, Chuan Jiang, Jingjing Zheng, Dan Wu, Laizhen Tou, Haifeng Que & Zheng Sun

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Conceptualization, LDS, XHT; methodology, LDS, XHT; formal analysis, LDS, WD, TLZ; investigation, JC, ZJJ; data curation, QHF, SZ; writing—original draft preparation, LDS, XHT; writing—review and editing, LDS, XHT. All authors have read and agreed to the published version of the manuscript.

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Luo, D., Xu, H., Jiang, C. et al. The prognostic role of palliative gastrectomy in advanced gastric cancer: a systematic review and meta-analysis. BMC Cancer 24 , 1096 (2024). https://doi.org/10.1186/s12885-024-12860-z

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Gastric Cancer: Advances in Carcinogenesis Research and New Therapeutic Strategies

Lornella seeneevassen.

1 Biological and Medical Sciences Department, University of Bordeaux, INSERM, BaRITOn, U1053, F-33000 Bordeaux, France; [email protected] (L.S.); [email protected] (E.B.); [email protected] (F.M.); [email protected] (P.L.); [email protected] (P.D.)

Emilie Bessède

2 Centre National de Référence des Helicobacters et Campylobacters, Centre Hospitalier Universitaire de Bordeaux, F-33000 Bordeaux, France

Francis Mégraud

Philippe lehours, pierre dubus.

3 Department of Histology and Pathology, Centre Hospitalier Universitaire de Bordeaux, F-33000 Bordeaux, France

Christine Varon

Associated data.

Data is contained within the article.

Gastric cancer’s bad incidence, prognosis, cellular and molecular heterogeneity amongst others make this disease a major health issue worldwide. Understanding this affliction is a priority for proper patients’ management and for the development of efficient therapeutical strategies. This review gives an overview of major scientific advances, made during the past 5-years, to improve the comprehension of gastric adenocarcinoma. A focus was made on the different actors of gastric carcinogenesis, including, Helicobacter pylori cancer stem cells, tumour microenvironment and microbiota. New and recent potential biomarkers were assessed as well as emerging therapeutical strategies involving cancer stem cells targeting as well as immunotherapy. Finally, recent experimental models to study this highly complex disease were discussed, highlighting the importance of gastric cancer understanding in the hard-fought struggle against cancer relapse, metastasis and bad prognosis.

1. Histological and Molecular Classifications

Gastric cancer is the most common stomach malignancy among lymphomas, sarcomas, gastrointestinal stromal and neuroendocrine tumours. This heterogeneous disease has different phenotypes and most cases are gastric adenocarcinomas (GC) [ 1 ]. The two main GC, according to topographic sites, are the cardia and the non-cardia GC. The complexity of GC explains the diverse histological classification systems which exist [ 2 , 3 ].

The most commonly used classification is the Laurén classification which divides GC into intestinal, diffuse and intermediate subtypes, according to their histological phenotypes. Intestinal type GC, characterised by malignant cohesive epithelial cells and intestinal-type glandular differentiation infiltrating the tissue, is the most common type occurring in about 54% cases while diffuse type GC, found in about 32% cases, contains poorly differentiated and poorly cohesive tumour cells [ 2 ]. GC can also be classified since 2010, according to the WHO classification, into tubular, papillary, mucinous, poorly cohesive (including signet ring cell carcinoma) and mixed carcinomas. While the poorly cohesive including signet ring cell carcinomas corresponds to the diffuse subtype of the Laurén classification, the tubular, papillary and mucinous types correspond to the intestinal subtype [ 2 ]. The Carneiro system distinguishes 4 categories of gastric tumours: glandular, isolated cell, solid and mixed, based on their immunophenotype such that it further divides the Laurén intestinal subtype into tumours with intestinal, gastric or mixed differentiation, according to the expression of specific markers (MUC6, MUC5AC mucins and TFF1 peptide gastric markers or MUC2, CDX2, CD10 and pepsinogen-1 intestinal markers, amongst others) [ 3 ]. Finally, the Goseki classification also divides GC into 4 groups according to intracellular mucin production (poor or rich) and level of tubular differentiation (poorly or well differentiated) [ 2 ].

GC vary not only histologically, but also molecularly. The most commonly mutated gene in GC (40% cases) is the tumour suppressor gene TP53 , key regulator of cell genomic stability [ 4 ]. Diffuse type GC are often characterised by somatic or hereditary mutations of CDH1 gene, coding for E-cadherin, a cell junction protein whose invalidation participates to the “independent cell” GC phenotype. Epigenetic alterations such as gene inactivation-associated hyper-methylations in CpG islands can be observed in certain cancer-related genes ( APC , K-RAS , hMLH1 , CDKN2A ). This CpG island methylator phenotype (CIMP) is an early event in GC and can be found in contiguous normal tissue associated with H. pylori infection [ 2 , 5 , 6 ].

Based on these molecular differences, the Cancer Genome Atlas Research Network (TCGA) has proposed a molecular classification dividing GC into 4 groups: Epstein Barr Virus (EBV)-positive (EBV), microsatellite instable (MSI), genomically stable (GS) and chromosomal instability (CIN) [ 7 ]. Array-based somatic copy analysis, whole-exome sequencing, array-based DNA methylation profiling, mRNA and miRNA sequencing, reverse-phase protein assay, microsatellite instability testing and whole-genome sequencing, used on 295 tumour samples in comparison with the germline profile, showed 8.8% EBV, 21.7% MSI, 19.7% GS and 49.8% CIN cases. The last subtype is mainly associated to the intestinal-type histology [ 7 ]. The Asian Cancer Research Group (ACRG) also proposed a 4-group classification based on mRNA expression, somatic copy number and targeted gene sequencing: microsatellite instability (MSI), microsatellite stable and epithelial to mesenchymal transition phenotype (MSS/EMT), microsatellite stable and presence of TP53 (MSS/TP53+) or no TP53 signature (MSS/TP53-) [ 8 ]. These two molecular classifications use advanced molecular techniques which are not feasible in practice for individual therapy decisions. To overcome this challenge, Setia et al. proposed techniques available in routine diagnostic practice like in situ hybridisation and immunohistochemistry and identified 5 GC groups: EBV-positive (5% cases), mismatch repair-deficient (16%), aberrant E-cadherin expression (21%), aberrant p53 expression (51%) and normal p53 expression (7%) [ 9 ]. Furthermore, Li et al. used the TCGA RNA-sequencing data to identify differentially expressed set of genes in diverse tumour types for use as diagnosis biomarkers and drug development [ 10 ].

Finally, recent developments in single cell methods allows more precise deciphering of GC cells heterogeneity, though not applicable as routine diagnosis. Zhang et al. propose a GC transcriptome atlas after analysis of 22,677 cells from 3 non-tumorous samples and 9 tumours [ 11 ]. Comparison of malignant epithelium to no malignant ones put into evidence overexpression of tumour specific genes like REG4 , TFF3 , CLDN4 and CLDN7 . Genes involved in gastric mucus and enzyme secretion like GKN1 , PGC , MUC5AC and LIPF were more expressed in non-tumorous epithelium [ 11 ]. In order to compare the cellular genetic profiles obtained to known histopathological classifications, tumour samples with known histology were added to analysis. Analysed malignant cells clustered 5 main cell groups: C1 having 96.9% cells from diffuse-type sample, C2 composed of 97.1% cells from intestinal-type sample, C3 with mixed-type and intestinal- type cells, C4 containing cells mainly from one of the intestinal-type samples and C5 with cells from EBV+ patients. Interestingly, C4/C5 seem to be correspond to novel subtypes, molecularly different from C1, C2 and C3 which correspond to the Lauren classification subtypes [ 11 ].

These GC classifications ( Figure 1 ) are the key to the comprehension of this disease and its underlying mechanisms, thus opening new pathways for novel targeted therapies since different GC types can be related to different risk factors, prognosis, and treatment management.

Gastric adenocarcinoma histological and molecular classifications.

2. Epidemiology and Risk Factors

Gastric Cancer is the 5th most common and the 3rd deadliest cancer worldwide, according to the latest report of the International Agency for research on Cancer [ 12 ]. Its geographic incidence remains heterogenous with most cases occurring in Eastern Asia (619,226 in 2018), and men being twice as much affected as women. Interestingly, a decrease in GC incidence has been noted in Western Europe and North America over the past decade [ 13 ].

Different risk factors are known to affect gastric cancer incidence, among which Helicobacter pylori ( H. pylori ) infection is the essential one. H. pylori infection involves almost 50% of the world’s population and induces chronic inflammation of the gastric mucosa, 5 to 15% of which evolve in gastric and duodenal ulcers and less than 1% in GC. The Correa cascade shows how intestinal type GC begins with H. pylori -induced chronic gastritis followed by gastric atrophy, intestinal metaplasia, and dysplasia [ 14 ]. Intestinal GC subtype is mainly caused by environmental factors while diffuse GC subtype also includes hereditary and genetic factors. About 10% intestinal GC cases are associated to infection with EBV and interestingly, EBV-positive GC are mostly associated to MSI molecular type and are related to less worst survival prognosis than diffuse/mixed GC subtypes [ 15 , 16 ].

The overall decrease in GC incidence can mostly be attributed to the decrease in intestinal type GC due to a lower H. pylori prevalence and modified dietary habits [ 13 , 17 ]. The better comprehension of intestinal type GC over the past decade has largely contributed to this, and the Correa cascade has provided a window for its prevention and early detection. Studies show that H. pylori eradication treatments, both as primary and as secondary prevention, reduces the risk of GC development. It also decreases the rate of metachronous GC in patients having early GC and improves the baseline of gastric corpus atrophy grading [ 18 , 19 ].

Conversely, diffuse GC subtype, not only related to H. pylori infection, is not yet well understood, and still has an increasing incidence. Due to its predominant genetic and hereditary origin, diffuse type GC seems to be more frequently described in young patients (<45 years-old) and to correlate with worse disease-free survival while intestinal type GC with chronic gastric inflammation seems to appear mostly after 45 years-old (around 70 years-old) [ 20 ]. GC trends not only show a distinct evolution ratio between the two GC subtypes but also between GC localisation, with an increase in cardia GC incidence compared to distal GC which is mostly related to H. pylori infection [ 13 ].

Despite the high GC incidence, GC survival rates seem to be better in Eastern Asia with a 64.2% 5-year survival [ 12 ] compared to North America (2.7%) or Europe (8.5%). Indeed, risk factors comprehension has helped develop strategies against GC and in Eastern Asia screening programs have been established allowing early detection of GC. More than 50% of cases are diagnosed at an early stage in Japan for example, against 27% in the USA [ 13 ]. Asian GC cases are mostly non-cardia which, again due to H. pylori eradication campaigns and programs, can be detected early. Also, secondary preventive strategies like endoscopic screening and high-risk histology surveillance has been successful and will further contribute to decrease H. pylori -induced GC [ 18 ]. In North America and Europe, non-cardia GC incidence has decreased while cardia GC rates remain stable and is possibly increasing [ 13 ]. In addition, non-cardia GC seems to decrease in older populations (>50 years-old) and increase in younger persons, especially women, which could be linked more to autoimmune gastritis and less to H. pylori -related gastritis [ 15 ]. H. pylori eradication does not affect the cardia GC trend [ 18 ] and it is important to find precursor lesions or biomarkers allowing their early detection and maybe treatment.

Still, GC incidence does not follow H. pylori prevalence, showing the role of other risk factors like the host’s genetics, H. pylori strain characteristics as well as environmental factors like salty diet in this disease. Indeed, Eastern Asian populations harbour highly virulent H. pylori strains possessing variants of bacterial pathogenicity factors associated with GC such as VacA, CagA oncoprotein and other proteins including BabA and SabA outer membrane proteins [ 21 , 22 ]. Chronic inflammation plays an important role in gastric carcinogenesis. A recent European Prospective Investigation into Cancer and Nutrition (EPIC) study focussed on the association between inflammatory potential of diets and the risk of cardia and non-cardia GC: 476,160 subjects from 10 European countries were followed for 14 years and the results showed that the inflammatory potential of diets is associated with an increased risk of GC. Low-grade chronic inflammation induced by food intake may be associated with cardia GC risk, the pattern being less consistent for non-cardia GC [ 23 ].

Furthermore, many cancers including GC and colorectal cancers have been linked to the consumption of red and/or processed meat [ 24 ]. These contain either carcinogens like heterocyclic aromatic amines and polycyclic aromatic hydrocarbons, produced by cooking at high temperature, or N-nitroso-compounds and polycyclic aromatic hydrocarbons in cured or smoked meat. In addition, processed meat contains much salt, one of the risk factors for GC, along with tobacco smoking and low vegetable and fruit intake which are sources of antioxidant vitamins [ 25 ].

Apart from external elements, intrinsic factors such as host susceptibility also affect GC. Almost 40% hereditary diffuse GC are due to the invalidating mutation of CDH1 [ 26 ]. Moreover, whole-exome sequencing analyses show other germline mutations than CDH1 , for example in tumour suppressor genes SDHB , CTNNA1 , STK11 and in genes involved in DNA repair PALB2 , BRCA2 and ATM . In addition, patients suffering from syndromes affecting DNA repair genes, TP53 , APC as well as tumour suppressor genes ( BRCA ) are more likely to develop GC [ 2 , 5 , 6 ].

3. Gastric Carcinogenesis

3.1. a helicobacter disease.

Helicobacter pylori , the major risk factor of GC, colonises the gastric mucosa and induces chronic gastric inflammation. Nevertheless, most infected individuals do not develop GC. Possible reasons might be the heterogeneity of the bacterial genome and its different virulence factors. The cag pathogenicity island ( cag PAI) encodes the major virulent factors of the bacterium, which are CagA oncoprotein and proteins forming a type IV secretion system, normally related to the bacterial conjugation system allowing it to exchange DNA with other bacteria. Other pathogenic factors associated to GC include adhesins (BabA, SabA), outer membrane proteins (OipA, HomB), and VacA cytotoxin which is encoded by a cag -PAI independent locus [ 21 ]. Many studies have described the pro-oncogenic role of these different factors, either by being translocated into the host cells, by translocating other factors into host cells, or by facilitating gastric mucosa colonisation by H. pylori . CagA, the first described bacterial oncoprotein, is injected by the type IV secretion system into the cytoplasm of host gastric epithelial cells where it interacts with different signalling pathways. CagA destabilises cellular junctions and apico-basal cell polarisation, activates pro-inflammatory and oncogenic signalisation pathways leading to disturbance of the gastric epithelium integrity, differentiation and self-renewal [ 21 ]. Still, malignant transformation mechanisms are not fully known.

Horvat et al. showed that H. pylori inhibits p14ARF tumour suppressor in a CagA dependent manner by inducing its degradation [ 27 ]. p14ARF is a critical tumour suppressor having important functions in oncogenic stress regulation. The chromosome region on which is located this gene is often deleted in primary GC and hypermethylation inactivates its expression in more than 30% of GC cases. The use of isogenic H. pylori mutants showed that CagA is responsible for the overexpression of E3 ubiquitin ligase, TRIP12, inducing ubiquitination and degradation of p14ARF protein in H. pylori infected cells and inhibition of autophagy in a p53-independent manner. TRIP12 is also overexpressed in the gastric mucosa of H. pylori -infected patients [ 27 ]. H. pylori also promotes gastric carcinogenesis in a p53-dependent manner. Costa et al. showed that this bacterium can reduce the expression of transcription factor USF1, known for its p53 stabilizing role in response to genotoxic stress [ 28 ]. The consequent p53 proteasomal degradation participates to gastric carcinogenesis promotion. In addition, H. pylori delocalises to foci nearby cell membranes and prevents USF1 /p53 nuclear translocation, altering their transcriptional function, one of which is the protection of gastric cells against H. pylori infection [ 28 ].

H. pylori infection also interferes with other tumour suppression pathways. This bacterium can downregulate the tumour suppressor Receptor for Activated C Kinase 1 (RACK1) which is physiologically involved in the modulation of NF-κB signalling pathway activity. By doing so, H. pylori promotes the upregulation of integrin β-1, leading to the upregulation of the NF-κB signalling pathway involved in H. pylori -induced carcinogenesis. In addition, this study shows that RACK1 is downregulated in GC tissue compared to normal tissue distant to tumour and is correlated to poor prognosis of patients [ 29 ].

Helicobacter pylori can use the host mechanisms to increase its virulence. It can control the activation of c-Abl kinase to maintain CagA virulence factor phosphorylation [ 30 ]. In addition, it has been recently shown that H. pylori not only induces c-Abl kinase activity but also alters the localisation of the activated protein. c-Abl becomes cytoplasmic, promotes cell migration and prevents apoptosis thus participating to H. pylori -related gastric carcinogenesis [ 31 ].

Gastric mucosal barrier disruption by H. pylori infection and inflammation also plays a role in gastric carcinogenesis [ 21 , 32 ]. The gastric mucosa contains epithelial cells with transmembrane and peripheral scaffolding proteins among which Claudins with a role in the regulation of tight junctions’ permeability [ 32 ]. Hagen et al. showed that Claudin-18 is decreased in models of GC infected with H. pylori as it is in GC patients where this loss is associated with an aggressive phenotype and poor prognosis [ 33 ]. Targeted deletion of CLDN18 gene encoding Claudin-18 results in pre-neoplastic stomach lesions in 7-weeks mice. Interestingly, 20 weeks post-infection, H. pylori is not able to colonise Claudin-18 deficient mice but, atrophy of the gastric corpus as well as high level of dysplasia and gastrointestinal neoplasia resembling human intramucosal carcinoma are noted in sham and H. pylori -infected mice [ 33 ].

Cell adhesion molecules modifications induce Epithelial-to-Mesenchymal Transition (EMT) where epithelial cells transdifferentiate and transit from their epithelial phenotype to a mesenchymal phenotype and in so doing, migrate or invade (in case of tumours). H. pylori infection is known to initiate EMT in gastric epithelial cells [ 34 , 35 ]. Invalidation of IQGAP1 , involved in adherent junctions stability and sequestration of β-catenin to the junctions, increases H. pylori -induced EMT in gastric epithelial cell lines in vitro and promotes H. pylori -induced pre-neoplastic lesions in vivo with 6 times more Gastric Intra-epithelial Neoplasia (GIN) in mice mutated for IQGAP1 compared to wild-type mice [ 36 ]. A recent study shows that H. pylori also downregulates other adherence proteins like Afadin, having a role in tight junction stabilisation, and in so doing, induces EMT phenotype in GC cell lines. Afadin regulation is independent of CagA, type-IV secretion system and VacA virulence factors [ 37 ]. Also, H. pylori upregulates the expression and activity of various matrix metalloproteases family proteins (MMPs) in GC cells, exacerbating their invasive properties. The use of several signalling pathways inhibitors has revealed the role of Src, NFκB, ERK and JNK pathways in H. pylori -induced EMT and EGFR-modulated MMPs (MMP9, 3, 10) regulation [ 34 , 35 , 38 ].

CagA+ H. pylori infection dysregulates the Hippo signalling pathway, responsible for the control of stem cell properties and proliferation, in physiology. H. pylori induces Hippo oncogenic effector YAP1 overexpression both in vitro and in vivo in infected patients. Consequently, activation of YAP1/TEAD oncogenic pathway in gastric epithelial cells promotes EMT as well as the acquisition of intestinal metaplasia markers [ 39 , 40 ]. Moreover, the Hippo pathway seems to limit H. pylori -induced preneoplastic changes. The bacterial infection up-regulates oncoprotein YAP1 but also its negative regulator LATS2, a Hippo tumour suppressor kinase, in a coordinated biphasic manner, with an early temporary oncogenic YAP1 activation, followed by LATS2 activation leading to YAP1 phosphorylation and downregulation and thus, oncogenic signal restriction [ 40 ]. YAP1 paralogue TAZ is also activated after H. pylori infection, overexpressed in vivo, and is associated to EMT and to acquisition of tumorigenic and invasive properties in GC cells [ 41 ]. Furthermore, YAP1/TAZ seem to cooperate with β-catenin in Wnt signalling pathway to promote gastro-intestinal neoplasia [ 42 ].

Additionally, gastric carcinogenesis can occur after H. pylori infection through the regulation of connexins (Cxs). This bacterium can upregulate transcription factors like GATA-3 and PBX-1, having a role in the expression of Cx32, which is thus inhibited [ 43 ]. In addition, it can decrease histone acetylation levels which in turn regulates the expression of Cxs. Similarly, H. pylori modulates other connexins such as Cx43, Cx26 and Cx37, expressed in gastric tissue, either by promoter hypermethylation and expression inhibition, protein delocalisation or gene polymorphism induction [ 43 ].

Helicobacter pylori also seems to protect GC cells from anti-tumoral immune response. Programmed death (PD) and programmed death ligand 1 (PD-L1) expression is one of the immune tolerance mechanisms preventing T-cells from attacking one’s own tissues. PD-L1 expression was detected on tumour cells showing that tumour cells seem to exploit this immune-checkpoint pathway to escape cytotoxic T-cells-induced programmed cell death [ 2 ]. H. pylori is able to stimulate PD-L1 expression in gastric epithelial cells. It was recently found that Shh pathway is involved in this CagA dependent process. PD-L1 expression increases in H. pylori -infected organoid cultures and Shh pathway inhibitor GANT61 is able to counteract this response [ 44 ]. In addition, anti-PD-L1 treatment of gastric organoids co-cultured with autologous patient cytotoxic T lymphocytes and dendritic cells provoked organoids death. The use of this PD-L1 mechanism causes epithelial cell survival and protection against immune response, leading to GC progression and interestingly, H. pylori is not the only pathogen using this mechanism. A recent study showed that among EBV-positive tumours, those with high viral load was correlated to higher tumour cells PD-L1 expression and worse patient prognosis compared to those with lower EBV viral load [ 45 ].

H. pylori infection induces the NF-κB pathway which increases Peroxiredoxin 2 (PRDX2) expression in GC [ 46 ]. This antioxidant enzyme plays an important role in the protection of cells from oxidative stress by scavenging H2O2 and ROS from cells and seems to be used by cancer cells as a defence mechanism. PRDX2 expression is high in GC tissues and correlates with low survival of patients [ 46 ].

H. pylori not only alters the hosts’ mechanisms to induce disease, but also undergoes genetic modifications in vitro and in vivo when in contact with the carcinogenic environment. Whole genome sequencing revealed a total of 180 unique single nucleotide polymorphisms (SNPs) in differently virulent H. pylori strains and in strains harvested in low-iron and high-salt carcinogenic conditions compared to reference H. pylori genome [ 47 ]. Common SNPs, including one within fur gene (FurR88H) encoding a ferric uptake regulator, were found in strains cultivated in cancer-like environment. This FurR88H variant seemed to appear after only 5 days exposure to the carcinogenic environment and fur sequencing in clinical isolates showed that 17% of strains coming from patients with premalignant lesions had the FurR88H variant compared to 6% strains from non-atrophic gastritis patients [ 47 ]. Furthermore, a genome-wide association study (GWAS) on 173 H. pylori isolates from European population revealed SNPs and genes, babA and cag pathogenicity island genes, as well as non-synonymous changes in several less well-studied genes, that differed in GC patients compared to those suffering from gastritis. The authors conclude that these bacterial factors differ enough in this pathology for a minor GWAS analysis to detect them [ 48 ].

Nonetheless, host polymorphisms can also render them more sensitive to GC development in presence of H. pylori , for example if there is less production of anti-inflammatory cytokines, activation of pro-inflammatory cyclooxygenases and oxidative damage [ 21 ].

Helicobacter pylori infection indeed affects GC status through a large variety of ways ( Figure 2 ) and understanding the mechanisms will open paths to more targeted and efficient therapies.

Gastric carcinogenesis: a Helicobacter disease.

3.2. A Stem Cell Disease

Despite the major influence of environmental factors, GC remains a heterogenous and multifactorial disease. Tumour cells are different from one another in terms of the mutations they carry, their sensitivity to drugs, their phenotype as well as their tumorigenicity. Indeed, ever since the identification of Cancer Stem Cells (CSCs), cancer cells having stem-like properties, in acute myeloid leukaemia in 1995, several studies have demonstrated the presence of such cells in solid tumours like breast, brain, colon [ 49 , 50 , 51 , 52 ] as well as gastric tumours [ 53 , 54 , 55 ]. GC are diverse entities not only due to the different histological phenotypes between patients but also due to the presence of different cell populations within one tumour mass, among which Gastric Cancer Stem Cells (GCSCs) form a very small proportion, ranging from 0,1 to 3,5% according to Nguyen et al. [ 55 ]. These cells have self-renewal as well as asymmetrical division capabilities allowing them to regenerate themselves and to generate new differentiated cells for proliferation and tumour mass enlargement. These highly tumorigenic cells are also known to resist to conventional chemo- and radiotherapies and to migrate and cause metastasis in patients [ 55 , 56 ]. Studying them is crucial to decipher GC mechanisms and develop more specific and efficient therapies in GC.

Ever since their discovery, many methods have been developed taking advantage of their specific self-renewal, differentiation, and tumour initiation properties. In vitro sphere assays, in which cells are seeded at low density on non-adherent plates in the absence of serum and presence of growth factors, allow only GCSCs to survive and form spheres. In addition, only GCSCs have the capacity to generate new spheres after several passages. In vivo experiments are also used since CSCs can generate heterogenous tumours after subcutaneous xenograft in immunocompromised mice [ 57 ].

In addition, characterisation of GCSCs has allowed the discovery of markers which could be used to isolate them using Fluorescence-Activated Cell Sorting (FACS), for example. CD44, best known as being the hyaluronic acid receptor, is a marker of GCSCs as it is for many other solid tumours [ 50 , 55 ]. Nguyen et al. described CD44 and ALDH activity as being the most important GCSC signature s allowing the detection and the isolation of cells able to generate heterogeneous tumorspheres in vitro and tumours in vivo from non-cardia gastric carcinomas. The authors described ALDH+ cells as being part of the CD44+ cell population and as possessing drug efflux properties increasing their chemoresistance properties [ 55 ]. In addition, many other markers enriched in GCSCs like CD133, CD24, CD166 were described and can be used for GCSC study. These methods have allowed to shed a new light on GC as a stem cell disease and H. pylori , being the major GC risk and having a role in GCSC emergence, many studies associate GCSCs and H. pylori .

Helicobacter pylori induces the emergence of cells with CSC phenotype and properties, through EMT, in infected patients’ gastric mucosa and in cell lines in vitro. Bessède et al. showed that only CD44+ cells seem to display mesenchymal phenotype compared to CD44– cells after H. pylori infection [ 35 ]. H. pylori -induced cell junction alterations also affect CSC properties. Deletion of IQGAP1 junction scaffolding protein increases neoplastic lesion in mice stomach and induces CD44 overexpression, mesenchymal phenotype, and CSC-like properties after H. pylori infection [ 36 ]. H. pylori infection also stimulates Lrig1+ gastric stem cell population, in a CagA-dependent manner, showing another way by which, this bacterium regulates gastric stemness phenotype. Lrig+ cells are enhanced in human GC tissues compared to normal mucosa [ 58 ]. CagA+ H. pylori infection induced-YAP1 and TAZ oncogenic pathway not only promotes EMT as discussed before, but also the acquisition of CSC phenotype as well as tumorigenic and invasive properties in vitro [ 39 , 40 , 41 ]. YAP1, TAZ and their target genes are significantly upregulated in GC and associated to poor prognosis [ 59 ]. Hippo pathway contribution to GCSC phenotype was demonstrated by an enrichment of YAP1 and its partners in CD44+ GC cells, and by the inhibition of GCSC tumorigenic properties in vivo after YAP1/TAZ/TEAD targeting by Verteporfin [ 59 ]. Moreover, activation of Hippo tumour suppressor kinase LATS2 by Leukaemia Inhibitory Factor (LIF), an interleukin-6 family cytokine, decreases GCSC tumorigenic properties and population of GC cell lines and patient-derived xenograft cells (PDX), again showing the implication of this pathway in GCSC phenotype [ 60 ]. High expression of LIF’s receptor (LIFR) in patients is associated to better survival rates and patients having high YAP1/TAZ and target genes expressions which is correlated to bad prognosis, survive better if they also have a high LIFR expression [ 60 ], showing a protecting role of LIF/LIFR signalling in this YAP1/TAZ-pro-GCSC context.

CD44 plays a functional role in H. pylori -induced proliferation of gastric epithelial cells. It acts as a co-receptor of tyrosine kinase c-Met receptor and precipitates with phosphorylated c-Met and CagA. In this context, H. pylori fail s to induce epithelial proliferation in organoids derived from CD44-deficient mice stomachs showing the importance of CD44 in H. pylori -induced gastric carcinogenesis [ 61 ]. CD44+ CSCs presence at the invasive front of GC tumours indicate poor survival of patients compared to patients with no CD44 expression at invasive front and can be used as a prognosis marker [ 56 ].

CD44 exists in multiple isoforms containing at least 20 exons due to alternative mRNA splicing. CD44 variant 8-10 (CD44v8-10) has been identified as being predominantly expressed in gastric cancer cells and less in normal tissues. Exogenous expression of CD44v8-10 increase s the frequency of tumour initiation in immunocompromised mice. Finally, this CD44 variant, and not panCD44, can rescue the tumorigenic phenotype lost after panCD44 silencing [ 62 ].

Furthermore, another CD44 variant, CD44v9 is highly expressed in mouse GCSCs. Analysis of GC samples from 103 patients show a five-year survival rate lower in CD44v9-positive tumours compared to CD44v9-negative ones [ 63 ]. Capping actin protein of muscle Z-line α subunit 1 (CAPZA1) is a protein having an important function in actin polymerisation. Its overexpression in gastric epithelial cells inhibits the formation of autolysosome and results in the accumulation of CagA in host cells, increasing GC risk. In human GC cell line AGS, oxidative stress increases histone H3 acetylation of CAPZA1 promoter, increasing CAPZA1 expression, nuclear accumulation of CD44 transcription factor, β-catenin, and enhancing expression of epithelial splicing regulatory protein 1 responsible for the alternative splicing of CD44 into CD44v9 [ 64 ]. Moreover, CD44 variant 6 (CD44v6) does not seem to play a role in GC progression since CD44v6 overexpression does not affect GC cells growth rate, invasion, migration, or cell-cell aggregation. However, CD44v6 cells survive better than CD44v6- cells in presence of chemotherapy drug cisplatin suggesting a role of CD44v6 in GC chemoresistance [ 65 ].

A recent study analysed the role of Human Epidermal growth factor 2 (HER2), target of trastuzumab in the treatment of HER2+ gastric and breast cancers, on GCSCs and the underlying mechanisms. The authors demonstrated that HER2 overexpressing GC cells had increased stemness and invasiveness and were regulated by the Wnt/β-catenin signalling pathway [ 66 ].

The role of microRNAs (miRNAs) in the gastric carcinogenesis and in GCSCs control is also important. miR-181a_5p and miR-22-3p have been shown to be downregulated in GCSCs while miR-483-5p, miR-4270 and miR-16-5p are overexpressed. A recent study shows that miR-7-5p is also downregulated in GCSCs due to hypermethylation of its promoter region. miR-7-5p silencing increases GCSC invasion properties while its overexpression reduces spheroid formation and invasion by repressing Notch and Shh pathways in vitro and decreases tumour growth in vivo [ 67 ].

Due to their possible role in chemoresistance, relapse and metastasis, GCSCs comprehension ( Figure 3 ) is a key step to understanding GC for biomarkers and therapy development.

Gastric carcinogenesis: a stem cell disease.

3.3. A Microenvironment Disease

The importance of the tumour microenvironment (TME) in tumorigenesis is being more and more explored. A tumour is a dynamic entity with constant communication s between the tumour cells and their rich surrounding environment, source of factors allowing and maintaining cancer cells phenotype and heterogeneity ( Figure 4 ).

Gastric carcinogenesis: a microenvironment disease.

Most immune cells infiltrating tumours are Tumour Infiltrating Lymphocytes (TILs) consisting of CD3+ Tcells (CD8+ Tcytotoxic and CD4+ Thelper cells) as well as FOXP3+ Treg cells. The number of TILs present in tumours reflects the host immune response mechanism. Indeed, Yu et al. demonstrated that high CD8+ and CD3+ T cells infiltration in tumours are associated to better prognosis of patients compared to low infiltration [ 68 ]. Interestingly, CD8+ T cells seem to be less present in diffuse/mixed types GC compared to intestinal type and might be associated to worse outcome [ 69 ].

Tumour associated Neutrophils (TANs) are one of the most important stromal partners having a role in carcinogenesis. TANs are able to increase migration and invasive capacities of GC cells [ 70 ]. Increase in neutrophil blood count, in neutrophil/lymphocyte ratio as well as in TME infiltration with neutrophils reflect poor patient prognosis [ 71 , 72 , 73 ]. Li et al. demonstrate that TANs produce IL-17a which promotes EMT and GC progression by activating the JAK2/STAT3 pathway. IL-17a neutralising antibody was able to reverse TANs effect on GC progression [ 73 ].

Gastric cancer-associated fibroblasts (GCAFs), when activated, are able to enhance migration and invasion properties of gastric cells both in co-culture and in presence of GCAFs-conditioned medium. Activated GCAFs correlate with poor survival of patients and in vitro, paracrine action of factors from GCAFs make gastric cells resistant to 5-fluorouracil (5-FU), one of the conventional chemotherapies used in GC treatment [ 74 ]. A recent study shows the role of GCAFs in stemness, transformation and chemotherapy resistance. Low expression of Secreted Protein Acidic and Rich in Cysteine (SPARC) in GCAFs seems to be associated to low cell differentiation, low 5-year survival rate and 5-FU resistance [ 74 ]. Also, GCAFs produce large amounts of IL-6 which participate to the activation of the JAK/STAT signalling pathway. The use of anti-IL-6 neutralising antibody and inhibitor of JAK2/STAT3 decreases GCAFs effect on GC and GCAFs-induced peritoneal metastasis in vivo showing the role of TME and GCAFs in GC progression through the JAK/STAT pathway [ 75 ]. IL-6 crosstalk between tumour cells and GCAFs not only supports tumour growth, but also promotes CAFs activation through IL-6Rα. Loss of IL-6 and use of inhibitors of STAT3 and MEK/ERK pathways suppress tumorigenesis in 3D organotypic and tumoroid models, showing how STAT3 and MEK/ERK pathways are also solicited in crosstalk between tumour cells and GCAFs for the maintenance of tumour integrity [ 76 ]. Loss of Trefoil Factor 1 (TFF1) is observed in human GCs, linked to STAT3 nuclear localisation and to pro-inflammatory phenotype and gastric lesions in mice. TFF1-knockout mice demonstrate a nuclear localisation of p-STAT Y705 along with an overexpression of STAT3 target genes and on the contrary, the reconstitution of the protein in GC cell lines and organoids from TFF1-knockout mice decreases p-STAT Y705 showing the role of JAK/STAT pathway in GC. TFF1 blocks the dimerization of IL6Rα and GP130 subunits and thus obstructing the binding of IL6 on its receptor and its pro-inflammatory and pro-tumorigenic consequences [ 77 ]. Furthermore, Galectin-1 (Gal-1), a β-galactosidase-binding protein, is highly expressed in GCAFs and is involved in GC progression and metastasis through the activation of signalling cascades like the Hedgehog (Shh) pathway involved in the EMT process. Gal-1 from GCAFs, binds to a carbohydrate structure in β-1 integrin and induces EMT, cell migration and invasion by regulating Glioma-associated oncogene-1 (Gli-1). High expressions of Gal-1 and Gli-1 are correlated to poor prognosis of patients [ 78 ]. GCAFs also induce the expression of Discoidin domain receptor 1 (DDR1) in GC cells leading to increased tumorigenesis both in vitro and in vivo [ 79 ]. Communications between the stroma and cancer cells are not unidirectional. Indeed, cancer cells also produce factors which modulates the stroma. GC cells produce exosomes which induce pericytes proliferation, migration, and expression of CAFs markers showing that cancer cell-derived exosomes are involved in the transition of pericytes into CAFs [ 80 ]. GC cell-derived exosomes are able to induce BMP (Bone Morphogenic Protein) transfer and activate PI3K/AKT and MEK/ERK in pericytes transforming them into GCAFs. The use of BMP signalling pathway inhibitor Noggin reverses the tumour-exosome-induced pericyte-CAF transition and decreases the expression of CAFs markers by pericytes [ 80 ]. Helicobacter pylori c an also participate to stroma-induced gastric carcinogenesis. In presence of the bacterium, gastric fibroblasts are activated into GCAFs with an increased secretion of TGF-β and conditioned medium from H. pylori -activated GCAFs prompt s EMT-like phenotype in rat gastric epithelial cells RGM-1 [ 81 ].

Tumour associated macrophages (TAMs) can be of 2 phenotypes, M1 and M2, M2 being the cancer cell-activated form of TAMs, essential for their role in tumour growth and progression [ 70 ]. GC tissues are found to be composed mostly of M2 TAMs, which when isolated promote migration and invasion of GC cells [ 73 ]. Interestingly, recent single cell tumour microenvironment genomic characterisation demonstrate that GC TAMs genetic signatures do not match those of known M1 or M2 macrophages [ 82 ]. M1 and M2 known distinguishing genetic markers are co-expressed in the same macrophage cluster. Nevertheless, genes distinguishing these different TAM clusters seem to be related to the HSP family, THBS1 , MMPs family, CCL20 , CCL18 and CCL3 chemokines among others, as well as cell cycle-dependent genes. In addition, these TAMs seem to differ from PBMC monocytes but conserve some similarities with normal tissue macrophages [ 82 ]. Moreover, TAMs abundance in GC microenvironment is associated with a decrease in number and a dysfunction of Natural Killer (NK) cells, which can be reversed by TGFβ1 blockade [ 83 ]. In so doing, TAMs promote tumour immune response in GC. Furthermore, TAM programmed cell death protein 1 (PD1) expression increases as GC progresses in mice and this can also be found in primary human cancers [ 84 ]. PD1 immune checkpoint receptor is normally present on activated T cells to induce their immune tolerance. TAM PD1 expression is correlated to less phagocytosis of tumour cells which express PD1 ligand, PD-L1, as immune escape mechanism [ 84 ].

In relation with immunosuppression mechanisms, Regulatory T cells (Tregs) seem to be abundant in gastric TME [ 82 , 85 ]. Sathe et al. single cell analysis of gastric TME puts into light two different Treg classes marked by different expression level of proliferation-associated genes.

Dendritic cells (DCs) can also reflect GC patient prognosis. Liu et al. showed that different subsets of DCs, plasmacytoid DCs (pDCs) and myeloid CD1+ DCs (mDC1s) are increased in GC patients peripheral blood compared to healthy controls [ 86 ]. Also, high level of pDCs seems to correlate with GC stage progression while mDC1 level does not change. Furthermore, different DC subtypes are found according to GC stages. Early GC T stages present high peripheral DC2 number and tumour infiltrating DC1/DC2 ratio, while low level of tumour infiltrating DC2s and high DC1/DC2 ratio are observed at N0 GC stage [ 87 ].

Stromal R-spondin, produced by gastric myofibroblasts normally controls gastric epithelial cell and gland homeostasis by activating the proliferation of Lgr5+ gastric stem cells. H. pylori increases the expression of R-spondin 3 and causes the hyperproliferation and hyperplasia of the gastric gland [ 88 ]. Interestingly, R-spondin 3, required physiologically for the m aintenance of Lgr5+ cell identity, induces differentiation into a secretory phenotype and, according to a recent study, allows these cells to develop defence mechanisms against bacterial infection. In presence of H. pylori , R-spondin 3 enables Lgr5+ cells to secrete anti-microbial protein Interlectin-1 (Itln1) which binds to the bacteria and agglutinates them. R-spondin-Lgr5 signalling in the stomach thus protects the gland base against infectious agents [ 89 ].

Finally, an acetylcholine-Nerve Growth Factor (Ach-NGF) axis can activate GC niche and promote the disease. Nerves within the gastrointestinal niche regulate both normal and neoplastic stem cell dynamics. Dclk1+ tuft cells and nerves, main Ach source in the gastric mucosa, induce a cholinergic stimulation of NGF expression, which, when overexpressed, expand enteric nerves, and promote carcinogenesis though YAP function [ 90 ].

3.4. A Microbiome Disease

Although the stomach was once thought to be a sterile environment, it is now known to house many bacterial species, leading to a complex interplay between H. pylori and other residents of the gastric microbiota. Data now show that the stomach harbours a large and diverse bacterial community with colonisation densities ranging from 10 1 to 10 3 colony forming units/g [ 91 ]. Moreover, recent advances in molecular techniques and computational analysis have provided evidence that the complex microbiota colonising the gastric epithelium in combination with H. pylori might influence gastric homeostasis and disease [ 92 ]. Currently, there are few studies that have examined differences in microbial composition and outcomes of GC. One of the key steps in the histological progression to intestinal type GC is the development of atrophic gastritis, a condition that predisposes the stomach to an increase in gastric pH due to loss of parietal cells and overgrowth of non- Helicobacter microbiota [ 14 ]. This stomach hypochlorhydria facilitates colonization by bacteria and may promote the progression towards gastric cancer, confirming that microbiota can influence gastric carcinogenesis [ 14 ].

In 2011, a study showed that in the INS-GAS mice model of spontaneous gastric cancer, gastric lesions take 13 months longer to develop when the mice are germ-free than when they are Specific Pathogens Free (SPF) [ 93 ]. Furthermore, the authors showed that H. pylori -mono association accelerates gastritis and GIN but causes less-severe gastric lesions and delays the onset of GIN compared to H. pylori infection of INS-GAS mice with complex gastric microbiota. This data proves that microbiota can influence gastric carcinogenesis and has been confirmed with further works showing that gastric colonisation with a restricted commensal microbiota can replicate the promotion of neoplastic lesions by diverse intestinal microbiota [ 94 ].

In addition, in a recent study describing GC patient microbiota and comparing it with that of chronic gastritis patients, it has been shown that GC microbiota is characterised by reduced microbial diversity, decreased abundance of Helicobacter and by the enrichment of other bacterial genera, mostly intestinal commensals. Furthermore, an analysis of the functional features of the microbiota revealed that GC patients’ microbiota is compatible with the presence of a nitrosating microbial community. Thus, patients suffering from gastric carcinoma have a dysbiotic microbial community with genotoxic potential, which differs from the gastritis patients [ 95 ].

Two recent studies have described and analysed the gastric microbiome of different types of patient. A Taiwanese study profiled gastric epithelium-associated bacterial species in patients at different stages of the Correa cascade (gastritis, intestinal metaplasia and gastric cancer) [ 96 ] and found that the overall microbiota composition is similar between patients with gastritis and those with intestinal metaplasia. In GC patients, H. pylori is indeed more frequent and more abundant, corresponding to a cancer-specific signature, but, Clostridium , Fusobacterium and Lactobacillus species are also frequently abundant in those patients, though their role in gastric carcinogenesis is still not proven. Following this work, another study compared the gastric microbiota of patients presenting GC to controls having a functional dyspepsia [ 97 ]. The authors showed that several bacterial taxa are enriched in GC patients, particularly pro-inflammatory oral bacterial species, lactic acid producing bacteria and bacteria producing short fatty acids. These results are for the moment only descriptive and H. pylori still remains the only bacterium directly implicated in gastric carcinogenesis.

Although several works have shown that gastric microbiota can influence gastric carcinogenesis, there is for now no report of a potential microbiota-based therapeutic or prognosis strategy in GC context. Further work in this direction is thus warranted.

4. Biomarkers and Therapeutic Strategies

4.1. biomarkers and targeting.

Gastric cancer treatment still consists of surgery and additional adjuvant or neoadjuvant radio- and chemotherapies. Early tumours can be excised endoscopically, and surgical resection remains the only curative treatment with unfortunately, a high number of relapse cases. Conventional chemotherapies consisting of leucovorin, oxaliplatin, docetaxel and 5-FU are given as perioperative chemotherapy or as palliative chemotherapy for patients having advanced metastatic disease [ 1 , 98 ]. Nevertheless, GC patient 5-year survival rate remains less than 5% for advanced unresectable or metastatic cases (80% of patients at diagnosis, except for Far East countries) [ 1 ].

The need for personalized targeted treatment is urgent and currently, only few targeted therapies exist. Trastuzumab (Herceptin, Roche, Germany) targets HER2+ GC and is used as first-line treatment for patients with tumours overexpressing HER2, accounting for less than 30% GC cases [ 98 ]. Ramucirumab (Cyramza, Lilly, USA) is another targeted treatment for advanced refractory GC cases. This antibody, used alone or in combination with paclitaxel, targets vascular endothelial growth factor receptor 2 (VEGFR2) thus inhibiting angiogenesis and increasing survival. However, these targeted therapies do not cater for all the different GC types having diverse aggressiveness levels and response to treatment [ 4 , 8 , 10 ].

The multiple molecular classification systems that exist indeed influence endoscopic or surgical choices but are not enough to guide precision individual treatment decisions which are urgently needed. External factors like H. pylori infection are being catered for through the multiple eradication strategies which indeed seem to be efficient [ 18 ]. Unfortunately, in patients where the disease has evolved, the establishment of genetic as well as cell phenotypic changes like the acquisition of resistant CSC and invasive properties make the tumours resistant to conventional therapies [ 98 ]. In addition, patients are diagnosed at late stages of the disease, and proper diagnosis markers development could help detect GC at earlier stages, allowing proper patient care.

Carbohydrate antigen 19-9 is a commonly used biomarker in GC allowing recurrence prediction when in combination with other tumour markers [ 99 ]. Molecules directed against Tyrosine Kinase receptors like cetuximab, rilotumumab or dovitinib could be suitable against GC cases overexpressing their respective targets. Clinical trials for antibodies against FGFR2 (for FGFR2 overexpressing GC) and EGFR (Nimotuzumab; for EGFRhigh GC) are ongoing. Similarly, mTOR pathway inhibitor Everolimus is being tested for patients with MSI type GC often having activating mutations in members of this pathway [ 98 , 100 ].

Studies are more and more trying to understand mechanisms underlying gastric carcinogenesis, may it be induced or not by its principal risk factor H. pylori . In so doing, these studies explore molecules which are either over- or under-expressed in GC compared to non-tumorous tissues and these particular signatures could indeed be used in GC diagnosis and prognosis ( Table 1 ).

Summary of molecules that can be used as potential biomarkers and therapeutic targets for GC.

Hepatoma-derived growth factor (HDGF), overexpressed in GC patients and after H. pylori infection, seems to participate in H. pylori -induced neutrophils recruitment, gastritis and gastric carcinogenesis. HDGF level is also high in patients with intestinal metaplasia and is associated with low survival. Targeting HDGF decreases neutrophil infiltration and inflammatory responses induced by H. pylori infection, making HDGF a potential therapeutic target for H. pylori- induced GC treatment [ 101 ].

Several clinical trials involving antibodies targeting the HGF receptor c-Met were also started but did not give encouraging results. However, positive results were reported from a Phase I trial with a MET specific small molecule AMS 337 showing 1 complete response and 4 partial responses out of 10 patients. MET amplification is observed in 4% GC patients only and bad trial results might be related to an incorrect selection of patients prior to trial since usual immunohistochemistry selection is not the most sensitive one [ 100 ]. Unfortunately, resistance to small molecule inhibitors of MET kinase is quite common. In this context, Andres et al. used the designed ankyrin repeat protein (DARPin) technology and generated MET-binding DARPins covering extracellular epitopes of MET, thus creating sets of bi-paratopic fusion proteins which efficiently inhibited MET kinase activity and downstream signalling [ 102 ]. This strategy using proteins having two paratopes caused receptor downregulation and inhibition of MET induced GC cells proliferation and seems to be an interesting strategy for targeting receptors in therapy [ 102 ]. Furthermore, Zhang et al. showed that exosomes could be used to deliver c-Met siRNA to GC cells thus inhibiting migration, invasion and inducing apoptosis in vitro and enhancing sensitivity to cisplatin in vitro as well as in vivo. The exosomes used were isolated from human embryonic kidney epithelial cell line, HEK293T, transfected with si-c-Met [ 103 ].

Bone marrow stromal cell antigen 2 (BST2) or CD317, playing a crucial role in antiretroviral defence in innate immune response, is also overexpressed in GC tissues compared to contiguous non-tumorous tissue and is correlated to tumour stage and lymphatic metastasis [ 104 ]. BST2 siRNA inhibited GC cell proliferation and motility and induced apoptosis. Furthermore, NF-κB pathway seemed to be involved in the pro-tumour function of BST2. BST2 targeting could be another possible strategy for GC treatment [ 104 ].

Moreover, the cell surface protein CEACAM6 has been identified as a potential endoscopic marker of early GC. CagA+ H. pylori induces this protein expression, which is highly present in early GC and pre-malignant lesions. Fluorescently tagged antibody against CEACAM6 was proposed to mark GC tissue for visualisation, using commercially available endoscopic methods, for use in diagnosis [ 105 ].

4.2. GCSC Targeting

Though the major tumour mass is found to be chemo-sensitive and would respond to therapies targeting GC subtypes or immerging immunotherapies, part of the cells comprising the tumour mass, GCSCs, are believed to resist treatments and to be at the origin of cancer relapse and metastasis [ 98 , 106 ]. GC molecular signatures are more and more being explored to propose diagnosis and prognosis markers and to try to target proteins or signalling pathways having a role in the maintenance of these GCSCs.

Several drugs have been evaluated for repositioning as anti-CSC strategy ( Table 2 ). Verapamil, a calcium antagonist allowing the inhibition of calcium-dependent channels and used to treat angina pectoris and cardiac arrythmias, was found to block efflux mechanisms of GCSCs which normally allow these cells to evacuate chemotherapy drugs through calcium-dependent channels. The use of verapamil thus sensitized GCSCs to conventional chemotherapies [ 55 ]. Tretinoin, also known as all-trans retinoic acid (ATRA), used for the treatment of acne and acute promyelocytic leukaemia due to its pro-differentiation properties, was able to force differentiation of GCSCs thus impacting their tumorigenic self-renewal capacity [ 107 ]. Furthermore, metformin, used for the treatment of type 2 diabetes to decrease insulin resistance and hepatic neo-glucogenesis, showed efficient anti-GCSCs effects by targeting the metabolism of these cells [ 108 ]. Drug repositioning was also used as strategy to target signalling pathways exacerbated in CD44+ GCSCs. Buparlisib (BKM120, a pan-class I PI3K inhibitor), first line treatment of metastatic head and neck epidermoid carcinomas, was found to decrease GCSC tumorigenic properties in vitro and to decrease GC metastasis in vivo [ 109 ]. Verteporfin, an FDA-approved drug for age-related macular degeneration, was repositioned in the GCSC context for its capacity to decrease YAP/TEAD transcriptional activity, cell proliferation, CD44 expression and number of tumorsphere-forming CD44+ALDHhigh GCSCs in vitro. Verteporfin also inhibits tumour growth in vivo [ 59 ]. In addition, residual tumour cells were unable to form new tumorspheres in vitro confirming the decrease of the in vivo CSC pool after verteporfin treatment [ 59 ]. Recently, LIF cytokine treatment was found target GCSCs through LATS2-induced repression of YAP1/TAZ/TEAD oncogenic activity [ 60 ].

Summary of potential Drug and/or Molecules for the targeting of GCSCs.

Most GCSC-targeting based strategies are directed against CD44+ cells (panCD44) which is ubiquitously expressed in non-tumorous cells even though its expression is exacerbated in GCSCs. Thus, using anti-panCD44 as GCSC target could cause non-specificity problems. CD44 variants, which seem to be less expressed in non-tumorous tissue compared to panCD44, are an interesting alternative for GCSC targeting. Studies have shown the increased expression CD44v8-10 and CD44v9 in GCSCs but also their functional role in the maintenance of this chemo-resistant cell population [ 63 ].

Vismodegib, an antagonist of the Shh signalling pathway has been associated with leucovorin, 5-FU and oxaliplatin in the treatment of GC. It binds to SMO, in GCSCs, thus preventing the downstream activation of GLI family of transcription factors and inhibiting Shh signalling. CD44+ GC cells present an overexpression of Shh pathway proteins linked to low patient survival, which was improved after the combined treatment [ 106 ]. Similarly, Napabucasin, a STAT3 inhibitor, repressing CSC self-renewal and inducing cell-death in GCSCs by targeting STAT3 was tested for GCSC targeting. Napabucasin was used in combination with paclitaxel in patients with advanced tumours and showed an anti-tumour activity. These studies show that combining chemotherapy to targeted strategies seems to be an interesting approach for anti-GCSC directed GC treatment [ 106 ].

High production and low elimination of reactive oxygen species (ROS) by the organism is another cancer risk factor. ROS are tightly controlled under physiological conditions through antioxidant mechanisms since excessive ROS in cells can lead to DNA damage. This property of ROS makes them interesting in therapeutic strategies in order to induce cancer cell damage and death. Unfortunately, cancer cells specially CSCs seem to possess defence capacities against ROS making them resistant to therapies. CD44v9 found in GCSCs can activate xCT, glutamate-cystine exchange transporters, which help increase levels of intracellular reduced glutathione (GSH) and contribute to CSC survival in ROS-high environment [ 63 ]. Exogenous CD44v9 expression in cells increase resistance to 5-FU, a chemotherapy agent using ROS production mechanism to kill cancer cells. Inhibition of xCT involved in the anti-ROS mechanism of GCSCs enhances 5-FU anti-GC efficiency [ 110 ].

Apart from their use in diagnosis, miRNA targeting, or overexpressing strategies can also be considered as GC therapeutic solutions. miR-7-5p normally exerts its tumour-suppressing effect, through the downregulation of its target genes SMO and HES1 (members of the Shh and Notch signalling pathways respectively), which is lost in GCSCs where this miRNA is under-expressed. So, targeting SMO and HES1 in GC could serve as target for GCSCs [ 106 ]. Seed-targeting locked nucleic acid (LNA) can be used as specific miRNA inhibitors and target miR-372/373 thus decreasing GC cell growth and targeting GCSCs [ 111 ].

4.3. Liquid Biopsies as Biomarkers

Certain subpopulations of GCSC, metastasis-initiating cells (MIC), overexpress MMPs, which are physiologically involved in extracellular matrix breakdown and promote invasion and metastasis. MMP10, MMP15 and MMP9 are found to be increased in GC and to correlate with poor patient prognosis [ 38 , 112 ] During the metastasis process, tumour cells originating from primary tumour or metastases can be found circulating in blood, either single or in clusters. New techniques have allowed the detection of these circulating tumour cells (CTCs) which are characteristic of disease progression and metastatic processes and can be used as surveillance markers [ 112 ]. CTCs analysis allows the detection of early metastasis stages and are used to identify patients fit for chemotherapy after primary tumour resection. CTC properties can be evaluated to see whether they carry CSC or EMT-like properties allowing better prognosis prediction. In GC, the presence of CD44+ GC CTCs has been correlated to tumour metastasis and relapse. Some studies show that circulating cell-free DNA are more sensitive than CTCs for diagnosis and prognosis. Circulating tumour DNA (ctDNA) originates from primary tumours or metastases and allows more specific diagnosis of patients as well as the assessment of therapeutic response [ 112 ].

In addition, miRNA differential expression in GC and high efficiency of circulating-miRNA detection assays make them interesting non-invasive biomarkers for GC [ 112 ]. miR-192-5p and miR-9-5p are highly decreased in GC tissues compared to non-tumorous gastric tissues and can thus be candidate for GC diagnosis [ 113 ]. Moreover, miR-9-5p and a combined miRNA group (miR-9-5p + miR-9-3p + miR-433-3p) were found to distinguish chemo-resistant GC patients from chemo-sensitive ones [ 114 ], confirming the interest of miRNA as novel non-invasive diagnostic tool in GC.

Furthermore, exosomes which are small vesicles produced by cells carry RNAs and miRNAs which remain protected from degradation when exposed to RNAses. Cancer cells or CAFs use exosomes to communicate and exchange material. These vesicles are a great promise for GC diagnosis and prognosis. Studies show that miRNA can be identified in serum-circulating exosomes, allowing the staging of patients. For example, exosomes containing miR-29s are found to play a suppressive role in the growth of peritoneal-disseminated tumour cells and are under-expressed in patients with peritoneal metastases [ 115 ]. Low expression of this miRNA in exosomes is correlated to bad prognosis of patients. The use of exosomes as biomarkers and even in therapy (as described above) seems to be an interesting strategy which will surely evolve in the next few years [ 116 ]. In addition, long non-coding RNAs (lncRNAs) can also be detected in exosomes. lncRNA MIAT, for example, has been described as overexpressed in GC patients and associated to lower survival rates. Serum exosomal MIAT can be detected, decreases post-treatment and is highly increased in patients suffering from GC relapse. This serum exosomal level of MIAT could thus be used to monitor GC progression using liquid biopsies [ 117 ].

4.4. Immunotherapy

Immunotherapy is becoming a promising anti-cancer strategy for many cancers. PD-L1 can be used as biomarker of GC involving immune checkpoint escape. Nivolumab (Opdivo, Bristol-Myers Squibb, USA), an antibody targeting PD1 and disrupting its interaction with PD-L1 and PD-L2 and increasing T lymphocytes anti-tumoral activity has been recently approved in Japan as third-line treatment for unresectable or recurrent GC patients having already undergone 2 chemotherapeutical strategies. Furthermore, US Food and Drug Administration (FDA)-approved anti-PD-L1 antibody Pembrolizumab (Keytruda, Merck & Co., USA) is used for treating PD-L1+ recurrent or advanced GC patients with 2 or more prior lines of therapy [ 98 , 118 ]. Although PD1 and PD-L1 inhibitors seem to improve the outcome of a small group of GC patients, the way to identify the patients that would respond still needs to be improved. Trials indeed show heterogenous responses and even the way PD-L1 is used as biomarker needs to be considered since qualitative or quantitative PD-L1 expression-based selected patients will not have similar responses [ 98 , 118 ].

Finally, the use of CAR T-cell therapy with T-cells binding CSC-specific antigens could be an interesting path to follow. These cells could specifically target GCSCs and eliminate them. Unfortunately, GCSC markers are not specific since they are ubiquitously expressed in other non-pathologic cells and imply a non-specific targeting of tumours even if these markers are more intensively expressed in tumour cells. Despite all this, two CAR T-cell therapies have been approved for the treatment of children with acute lymphoblastic leukaemia and adults with advanced lymphomas, showing the positive evolution of this field. In GC, several in vitro and in vivo trials can be found in literature. HER2 CART-T cells showed positive response in vitro and persisted in blood circulation, specifically travelled to and accumulated in HER2 overexpressing tumours and contributed to their regression in human GC xenograft models [ 119 ]. Another study describes the production of anti-GC cells monoclonal antibody mAb-3H11 by the hybridoma technique with spleen cells from mice immunised with five different human GC cell lines. mAb-3H11 was selected for its high specificity for GC cells and no reaction with normal cells. A single-chain variable fragment (scFV) of mAb-311, displaying the same reaction as the whole antibody, was used to design CAR-T cells which were able to kill tumour cells in vitro and GC cell lines as well as patient-derived xenograft tumours in vivo [ 119 ]. The same in vitro and in vivo anti-tumoral effects were observed when Folate receptor 1 (FOL1), overexpressed in more than one third GC patients, coupled to CAR-T cells were used [ 120 ]. Among the 38% clinical trials being performed for CAR-T cells on solid tumours, only 2.96% account for GC with 12 registered clinical trials (ClinicalTrial.gov) distributed between China and the USA. These trials target different antigens (EPCAM, MUC1, CEA, HER2, Mesothelin, BPX-601 and EGFR) and most are still in the recruiting stage [ 121 ]. High toxicity mainly due to cytokine release syndrome, one of the main side effects which occurs due to the rapid and high activation of numerous cytokines, is what restrains this field for now [ 121 ]. More research deserves to be carried out with the perspective of finding even more specific targets for GCSCs and limiting the toxicity [ 98 ].

5. New Experimental Models

Research issues are in constant evolution and so must be the strategies used to understand and resolve them. Helicobacter pylori infection has been for long known to be a major GC risk factor and the studies relating GC and this bacterium mostly depends on the use of transformed cell lines as infection models. This artificial approach can be criticised for its lack of pragmatism in terms of signalling pathways study, crucial in this context. Barker et al. found, using lineage tracing, that Lgr5+ cells were the multipotent stem cells responsible for the long-term self-renewal of the gastric epithelium and were among the first to generate organoids resembling mature pyloric epithelium using single Lgr5+ cells in vitro [ 122 ]. Afterwards, a new gastric primary cell culture system was developed for modelling H. pylori infection in vitro. Using gastric glands isolated from healthy human stomach tissue and growth factors-supplemented Matrigel, the authors were able to grow 3-dimensional (3D) spheroids which can differentiate into gastric organoids after the withdrawal of Wnt3A and spondin-1 from the culture medium leading to the formation of cultures of polarised epithelial cells when transferred into 2D [ 123 ]. However, these structures offer only suboptimal conditions for studying consequences of bacterial infection due to their closed spherical shape. A recent study proposes a “mucosoid culture” model using antrum-derived gastric glands and air-liquid interface culture technique. The polarised epithelial monolayers formed secrete mucus at the apical surface, reproduce normal human gastric epithelium and can even differentiate into a base-like gland phenotype under the influence of Wnt signalling [ 124 ].

Studying gastric carcinogenesis also involve the use of proper in vivo models reflecting the underlying process. The major limitation of mouse models using H. pylori infection or carcinogens to induce gastric carcinogenesis is that they only rarely develop in situ carcinomas since most of the lesions are pre-neoplastic ones. In addition, these models do not metastasize or invade like in humans. Likewise, subcutaneous xenograft of PDX cells reflect the heterogeneity of patient tumours but still do not metastasize to distant organs [ 55 ]. In a recent study, Giraud et al. developed orthotopic PDX models in which patient-derived GC cells were xenografted directly into the stomach wall of immunodeficient mice and led after 8 weeks to distant metastases [ 109 ]. In these pre-clinical models, luciferase-encoding GC cells were traced all through the in vivo experiment allowing the monitoring of primary tumour establishment and kinetic of GC cells spread and metastasis development. Using these models, the authors showed that Buparlisib treatment significantly inhibited GCSC properties in vitro and reduced the number of distant metastases in vivo when the treatment was done in the metastases starting time-lapse determined by the model [ 109 ]. This preclinical mouse model of metastatic GC represents a major advance to study anti-metastatic efficiency of new GCSC-based therapies.

6. Conclusions

Gastric cancer, as many other cancers, is a complex and multifactorial disease. H. pylori remains the main cause for GC, despite the participation of other extrinsic and intrinsic factors. Gastric tumours are highly heterogenous both at intra-tumoral and inter-tumoral levels, with different histological and molecular subtypes and cellular hierarchy within the tumour as well as in the TME composition. The complexity of this disease makes it such that despite research advances and all the highlighted potential biomarkers and therapeutical strategies, there are still only few targeted strategies like Trastuzumab, Ramucirumab and anti-PD1/PD-L1 immunotherapies used in clinic [ 98 ]. A better understanding of this gastric disease’s cellular, molecular, and infectious processes, at the basis of this tumour heterogeneity, is critical for the development of other diagnosis and therapeutic strategies against GC.

Abbreviations

Author Contributions

Conceptualization, C.V. and L.S.; methodology, C.V., L.S., E.B.; validation, L.S., E.B., F.M., P.L., P.D. and C.V.; investigation and data curation, L.S., C.V. and E.B.; writing—original draft preparation, L.S., E.B., F.M., P.D., P.L. and C.V.; writing—review and editing, L.S., C.V. and E.B; visualization, L.S. and C.V.; supervision, P.D., P.L. and C.V.; project administration, C.V and P.D.; funding acquisition, L.S., C.V. and P.L. All authors have read and agreed to the published version of the manuscript.

The PhD fellowship of Lornella Seeneevassen was funded by the French Ministry of Tertiary Education, Research and Innovation. This work was supported by the “Centre National de Référence des Helicobacters et Campylobacters” and the French “Ligue Contre Le Cancer”.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Data availability statement, conflicts of interest.

The authors declare no conflict of interest.

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The expansion of MDSCs induced by exosomal PD-L1 promotes the progression of gastric cancer

Affiliations.

• 1 Jiangsu Province Key Laboratory of Tumor Systems Biology and Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210029, Jiangsu, China.
• 2 No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, Jiangsu, China.
• 3 Department of General Surgery, Yixing Traditional Chinese Medicine Hospital, Wuxi, 214200, Jiangsu, China. [email protected].
• 4 Jiangsu Province Key Laboratory of Tumor Systems Biology and Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210029, Jiangsu, China. [email protected].
• PMID: 39227816
• PMCID: PMC11373121
• DOI: 10.1186/s12967-024-05611-y

Background: Myeloid-derived suppressor cells (MDSCs) are the major factor in gastric cancer (GC) immune evasion. Nevertheless, the molecular process underlying the expansion of MDSCs induced by tumor-derived exosomes (TDEs) remains elusive.

Methods: The levels of exosomal and soluble PD-L1 in ninety GC patients were examined via enzyme-linked immunosorbent assay (ELISA) to determine their prognostic value. To investigate the correlation between exosomal PD-L1 and MDSCs, the percentage of MDSCs in the peripheral blood of 57 GC patients was assessed via flow cytometry. Through ultracentrifugation, the exosomes were separated from the GC cell supernatant and detected via Western blotting, nanoparticle tracking analysis (NTA), and transmission electron microscopy (TEM). The function of exosomal PD-L1 in MDSCs was evaluated via immunofluorescence, Western blotting and flow cytometry in a GC cell-derived xenograft (CDX) model.

Results: The overall survival (OS) of GC patients in the high exosomal PD-L1 group was significantly lower than that of patients in the low exosomal PD-L1 group (P = 0.0042); however, there was no significant correlation between soluble PD-L1 and OS in GC patients (P = 0.0501). Furthermore, we found that the expression of exosomal PD-L1 was positively correlated with the proportions of polymorphonuclear MDSCs (PMN-MDSCs, r = 0.4944, P < 0.001) and monocytic MDSCs (M-MDSCs, r = 0.3663, P = 0.005) in GC patients, indicating that exosomal PD-L1 might induce immune suppression by promoting the aggregation of MDSCs. In addition, we found that exosomal PD-L1 might stimulate MDSC proliferation by triggering the IL-6/STAT3 signaling pathway in vitro. The CDX model confirmed that exosomal PD-L1 could stimulate tumor development and MDSC amplification.

Conclusions: Exosomal PD-L1 has the potential to become a prognostic and diagnostic biomarker for GC patients. Mechanistically, MDSCs can be activated by exosomal PD-L1 through IL-6/STAT3 signaling and provide a new strategy against GC through the use of exosomal PD-L1 as a treatment target.

Keywords: Exosomes; Gastric cancer; MDSCs; PD-L1.

© 2024. The Author(s).

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Schematic illustration depicting the intrinsic relationship between…

Schematic illustration depicting the intrinsic relationship between GC cells and MDSCs in the tumor microenvironment

Exosomal PD-L1 was positively associated…

Exosomal PD-L1 was positively associated with poorer prognosis in GC patients. ( A…

Associations between exosomal and soluble…

Associations between exosomal and soluble PD-L1 and the clinicopathological characteristics of patients with…

Exosomal PD-L1 was strongly associated…

Exosomal PD-L1 was strongly associated with the levels of MDSCs in GC patients.…

Gastric cancer cell-derived exosomes can…

Gastric cancer cell-derived exosomes can promote the expansion and immunosuppression of MDSCs. (…

Exosomal PD-L1 increased the MDSCs…

Exosomal PD-L1 increased the MDSCs expansion through IL-6/STAT3 signaling pathway. ( A )…

Exosomal PD-L1 promoted MDSC expansion…

Exosomal PD-L1 promoted MDSC expansion in vivo. ( A ) Representative images of…

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Risk factors, chemoprevention.

Important research on stomach cancer (also known as gastric cancer) is being done in many medical centers and other institutions around the world. Scientists are learning more about what causes the disease and how best to prevent, detect, and treat it.

Research has clearly shown that differences in diet are an important factor in explaining variations in stomach cancer risk around the world. Research in countries with relatively low stomach cancer risk has provided some insight into risk factors. For example, diets high in preserved meats and low in fresh fruits and vegetables have been linked with higher risk.

Helicobacter pylori infection

Helicobacter pylori ( H  pylori ) is a common type of bacteria that has been linked with an increased risk of stomach cancer . Some studies have shown that certain types of H pylori (especially the cagA strains) are more strongly linked to stomach cancer than others. Some inherited traits related to blood groups may also affect whether someone infected with H pylori will develop cancer. Further research is needed to help doctors determine how to use this information to test which people might be at higher risk for developing stomach cancer.

Research has also found that a healthy diet is important for reducing stomach cancer risk for people infected with H pylori.

Chemoprevention is the use of natural or man-made chemicals to lower the risk of developing cancer.

Antioxidants

One of the ways cancer might form is by the creation of chemicals inside cells called free radicals . Free radicals can sometimes damage the genes inside cells, which in some cases might lead to cancer.

Antioxidants are a group of nutrients and other chemicals that can destroy free radicals or prevent them from forming. These nutrients include vitamin C, beta-carotene, vitamin E, and the mineral selenium.

Studies that have looked at using dietary supplements to lower stomach cancer risk have had mixed results so far. There is some evidence that antioxidant supplements might reduce the risk of stomach cancer in people with poor nutrition to begin with, but it's not clear if they'd have the same effects in people who eat healthier diets. Further research in this area is needed.

Antibiotics

Some studies have found that treating chronic H pylori infection with antibiotics may help prevent pre-cancerous stomach abnormalities, but more research is needed.

Although not truly chemoprevention, antibiotics may help prevent stomach cancer from recurring (coming back) in some cases. Research has shown that antibiotics may lower the risk that the cancer will come back in another part of the stomach in people who have been treated for early-stage stomach cancer. Unfortunately, stomach cancers are more often found at a later stage in the United States, so it's not clear how useful these results might be here.

Non-steroidal anti-inflammatory drugs (including aspirin)

Some (but not all) studies have found that people who take non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin or ibuprofen might have a lower risk of stomach cancer. More research is needed to better define this possible link. In the meantime, doctors generally don't recommend taking these medicines just to try to lower your risk of cancer, because they can cause serious side effects in some people.

Sentinel lymph node biopsy

In people diagnosed with stomach cancer, it’s important to find out if it has spread to nearby lymph nodes. Doctors are studying whether sentinel lymph node biopsy (SLNB) can help find the spread of stomach cancer. This technique has proved successful in melanoma and breast cancer .

In this procedure, the surgeon injects a blue dye and/or a radioactive tracer substance into the cancer. These travel to the sentinel lymph nodes , the nearby lymph nodes that would be the first site of cancer spread. Once these nodes are found with the help of the dye or tracer, the doctors can remove these lymph nodes and look for cancer. If no cancer is found in these lymph nodes, then the cancer is unlikely to have reached others, and a full lymph node removal might not be needed. If cancer is found in the sentinel lymph node(s), then all the lymph nodes in the area would need to be removed.

This technique has been shown to help find more lymph nodes to remove, and to find lymph nodes that are more likely to contain cancer cells. But it's not yet clear if this technique is ready for widespread use.

Doctors are constantly working to improve the surgical techniques used to treat stomach cancer. 

For some very early stage stomach cancers, surgery can be done using endoscopy , in which long, thin instruments are passed down the throat to remove the cancer and some layers of the stomach wall (see Surgery for Stomach Cancer ). Surgeons are looking for ways to improve this approach. Unfortunately, most stomach cancers in the United States are not found early enough for this type of surgery.

Surgeons are also studying different approaches to removing part or all of the stomach. For example, some surgeons now do these operations laparoscopically, in which long, thin instruments are passed through small cuts in the abdomen to remove the cancer. This can be done with the surgeon holding the instruments directly, or while sitting at a control panel to move robotic arms with instruments on the ends. While laparoscopic surgery usually results in a shorter hospital stay and a quicker recovery, it’s not yet clear how it compares to standard surgery (using a longer abdominal incision) in terms of other results.

Chemotherapy

Many chemotherapy (chemo) drugs can be used to treat stomach cancer, often in combination with each other. Newer chemo drugs are also being studied. For example, S-1 is an oral chemo drug related to 5-FU. This drug is commonly used for stomach cancer in some other parts of the world, but it is not yet available in the United States.

New ways of giving chemo are also being studied. For example, some doctors are looking at infusing chemo directly into the abdomen ( intraperitoneal chemotherapy ) to see if it might work better with fewer side effects.

Other studies are testing the best ways to combine chemo with other treatments such as radiation therapy , targeted therapy drugs, or immunotherapy.

A good deal of effort is being directed at improving the results of surgery by adding chemo and/or radiation therapy either before or after surgery. Some studies are also looking at benefits of giving chemo during surgery. Several clinical trials are in progress.

Targeted therapy drugs

Chemo drugs affect cells that divide rapidly, which is why they work against cancer cells. But there are other aspects of cancer cells that make them different from normal cells. In recent years, researchers have developed newer targeted drugs to try to exploit these differences. Targeted drugs sometimes work when standard chemo drugs don't. They also tend to have different side effects than chemo drugs.

Drugs that block HER2: Some stomach cancers have too much of the HER2 protein on the surface of their cells, which helps them grow. Drugs that target this protein, such as trastuzumab (Herceptin) and fam-trastuzumab deruxtecan (Enhertu), can be used to help treat these cancers. Many other drugs that target HER2, such as lapatinib (Tykerb), pertuzumab (Perjeta), trastuzumab emtansine (Kadcyla), and margetuximab, are now being studied for use against stomach cancer in clinical trials.

Drugs that block VEGF and its receptors: VEGF is a protein that helps tumors develop new blood vessels, which they need to grow. Drugs that target VEGF (or the VEGF receptors on the surface of cells) can help stop some stomach cancers from growing. Ramucirumab (Cyramza), a drug that blocks VEGF receptors, can be used to treat some advanced stomach cancers. Other targeted drugs that target VEGF receptors, such as apatinib, are also being studied.

Other targeted drugs: Many other drugs that target different parts of cancer cells are now being studied for use against stomach cancer as well.

Research is also looking at combining targeted drugs with chemotherapy or immunotherapy, or with other targeted drugs.

Immunotherapy

Immunotherapy is an approach that uses drugs to help the body's immune system fight the cancer.

In recent years, drugs called immune checkpoint inhibitors have been shown to be helpful in treating many types of cancer. One of these drugs, pembrolizumab (Keytruda) is now approved to treat advanced stomach cancer in some people, typically after other treatments have been tried. Doctors are now studying whether this drug might be helpful earlier in the course of treatment, or if combining it with other drugs might be helpful. Several other checkpoint inhibitors are also being studied for use in stomach cancer.

Other types of immunotherapy are now being tested for use against stomach cancer as well.

For more information on this type of treatment, see  Immunotherapy .

The American Cancer Society medical and editorial content team

Our team is made up of doctors and oncology certified nurses with deep knowledge of cancer care as well as editors and translators with extensive experience in medical writing.

Bendell J, Yoon HH. Progressive, locally advanced unresectable, and metastatic esophageal and gastric cancer: Approach to later lines of systemic therapy. UpToDate. 2020. Accessed at https://www.uptodate.com/contents/progressive-locally-advanced-unresectable-and-metastatic-esophageal-and-gastric-cancer-approach-to-later-lines-of-systemic-therapy on July 15, 2020.

Ku GY, Ilson DH. Chapter 72: Cancer of the Stomach. In: Niederhuber JE, Armitage JO, Doroshow JH, Kastan MB, Tepper JE, eds. Abeloff’s Clinical Oncology . 6th ed. Philadelphia, Pa: Elsevier; 2020.

Mansfield PF. Surgical management of invasive gastric cancer. UpToDate. 2020. Accessed at https://www.uptodate.com/contents/surgical-management-of-invasive-gastric-cancer on July 15, 2020.

National Cancer Institute. Physician Data Query (PDQ). Gastric Cancer Prevention. 2020. Accessed at: https://www.cancer.gov/types/stomach/hp/stomach-prevention-pdq on July 15, 2020.

Shah M. Future directions in improving outcomes for patients with gastric and esophageal cancer.  Hem Onc Clinics North America . 2017;31:545.

Shida A, Mitsumori N, Nimura H, et al. Prediction of lymph node metastasis and sentinel node navigation surgery for patients with early-stage gastric cancer.  World J Gastroenterol . 2016;22:7431-7439.

Last Revised: January 22, 2021

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JSmol Viewer

Anoikis-related long non-coding rna signatures to predict prognosis and immune infiltration of gastric cancer.

1. Introduction

2. materials and methods, 2.1. the capture and pre-processing of patients’ data, 2.2. screening of ar-lncrnas, 2.3. creation and validation of risk signature, 2.4. establishment of an anoikis-related nomogram, 2.5. analysis of gene set enrichment, 2.6. analysis of the immunity signature, 2.7. investigation of the model in clinical therapy, 2.8. consensus clustering, 2.9. statistical analysis, 3.1. identification of ar-lncrna, 3.2. construction and evaluation of prognostic model, 3.3. construction of nomogram, 3.4. analyses of functional enrichment, 3.5. analyses of immune characteristics and clinical treatment in groups, 3.6. prognosis and immunotherapy prospects of each gc subgroup, 4. discussion, 5. conclusions, supplementary materials, author contributions, institutional review board statement, informed consent statement, data availability statement, acknowledgments, conflicts of interest.

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Meng, W.-J.; Guo, J.-M.; Huang, L.; Zhang, Y.-Y.; Zhu, Y.-T.; Tang, L.-S.; Wang, J.-L.; Li, H.-S.; Liu, J.-Y. Anoikis-Related Long Non-Coding RNA Signatures to Predict Prognosis and Immune Infiltration of Gastric Cancer. Bioengineering 2024 , 11 , 893. https://doi.org/10.3390/bioengineering11090893

Meng W-J, Guo J-M, Huang L, Zhang Y-Y, Zhu Y-T, Tang L-S, Wang J-L, Li H-S, Liu J-Y. Anoikis-Related Long Non-Coding RNA Signatures to Predict Prognosis and Immune Infiltration of Gastric Cancer. Bioengineering . 2024; 11(9):893. https://doi.org/10.3390/bioengineering11090893

Meng, Wen-Jun, Jia-Min Guo, Li Huang, Yao-Yu Zhang, Yue-Ting Zhu, Lian-Sha Tang, Jia-Ling Wang, Hong-Shuai Li, and Ji-Yan Liu. 2024. "Anoikis-Related Long Non-Coding RNA Signatures to Predict Prognosis and Immune Infiltration of Gastric Cancer" Bioengineering 11, no. 9: 893. https://doi.org/10.3390/bioengineering11090893

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Staying on Top of the Latest Gastric Cancer News

Read our monthly newsletter and connect with us on social media to stay up to date on the latest gastric cancer news.

Gastric Cancer Foundation Newsletter

Click below to read the latest newsletters from Gastric Cancer Foundation.

Speak Up – Ask for Biomarker Testing – 6/10

Community Support is Good Medicine – 5/13

Registry Progress Spurs $9M NCI Grant – 4/21

Going the Distance for a Cure – 3/11

A Key to Finding the Right Treatment – 2/12

Foundation Launches New Clinical Trial Finder – 1/9

Seed Grant Leads to Major Research Progress – 12/4

Investigating New Approaches to Treatment-Resistant Complication – 11/20

$300,000 Granted for New Research Studies – 11/13

Progress in Study of Peritoneal Spread – 11/6

New Discoveries from the Gastric Cancer Registry – 10/30

New Research Scholar Pursues Novel Target in Gastric Cancer – 7/12

U.S. Researchers Invited to Apply for Seed Grants to Discover New Treatments – 3/4

Information & Involvement for Improved Outcomes – 1/29

Early Stage Grant Awardees Report Progress in Research – 12/15

Research Scholar Reports New Findings – 11/28

Major Gastric Cancer Registry Expansion Updates – 11/18

Grant to Dana-Farber Researcher Announced – 11/10

New Research Grants Announced – 10/30

Gastric Cancer Registry Makes Unique Contribution to Research – 8/16

Foundation Launches Grant Process for Early-Stage Funding – 4/4

Clinical Trial Navigators Help Patients Find Matching Trials – 1/25

Major Data Expansion Underway at Gastric Cancer Registry – 11/8

Progress in Research Focused on Peritoneal Spread – 11/1

Foundation Awards New Grants to Researchers Pursuing Novel Approaches in Gastric Cancer – 10/25

Gastric Cancer Registry Team Reports Major Progress – 5/24

Free Workshop: Advances in the Treatment of Gastric Cancer – 3/23

Foundation Funds Major Expansion of Gastric Cancer Registry – 1/26

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Stomach (Gastric) Cancer

• Stomach Cancer Stages 0, 1, 2, 3 & 4
• Stomach Cancer Surgery: Gastrectomy & Laparoscopy
• Chemotherapy and Other Drugs for Stomach (Gastric) Cancer
• Radiation Therapy for Stomach (Gastric) Cancer

Surgeon and stomach cancer expert Vivian Strong consults with Jorge Carrasquillo, a doctor with special training in molecular imaging and targeted radiotherapy. MSK treats more people with gastric cancer than any other cancer center in the United States.

Request an Appointment

• Make an appointment

What is stomach cancer?

Stomach cancer is also known as gastric cancer. It starts when the cells in the lining of the stomach grow and divide in an abnormal and uncontrolled way. Over time, the cells form a tumor that is cancer. The tumor may stay in the stomach. It also could spread to other organs, such as the liver, lungs, or the lining of the wall of the abdomen (belly).

Early-stage stomach cancer often causes almost no  symptoms . Sometimes, people have an upset stomach and general stomach discomfort. But these symptoms also are common signs of other things, such as indigestion or a stomach virus. That’s why it’s hard to  diagnose stomach cancer in its earliest stages.

Later stage (stage 4) stomach cancer already has spread. Symptoms of advanced stomach cancer are easier to spot. That often leads to testing, and then to a diagnosis of stomach cancer. 

Stomach cancer starts in the upper gastrointestinal system.

There are a few things you can do to lower your risk for stomach cancer. For example, you can change your diet and lifestyle.

There are other risk factors we cannot change, including the genes you were born with.

You can learn more about the risk factors for stomach cancer and how to prevent it .

MSK diagnoses stomach cancer using many new technologies that we developed or improved. We’re always researching ways to diagnose cancer with greater accuracy, which lets us improve treatment results.

You can learn more about  how MSK diagnoses cancer.

The MSK difference

Why chose msk to diagnose and treat gastric cancer.

Memorial Sloan Kettering Cancer Center (MSK) is known for its team of  gastric cancer experts .   We see more people with gastric cancer than any other cancer center in the United States.

MSK’s robotic gastric cancer program does more robotic gastrectomies than any other hospital in the country. Our surgeons have done nearly 1,000 gastric cancer procedures, using the latest robotic methods.

Each year, MSK gastric cancer experts:

• Treat more than 200 people just diagnosed with gastric cancer.
• Do about 150 gastric cancer procedures.

MSK is one of the few National Cancer Institute-designated cancer centers that has a program just for upper gastrointestinal tract cancers.

Better treatment results

Our surgeons are experts in gastric cancer, so they have better treatment results with fewer complications. MSK has among the lowest mortality rates in the country. Our stomach cancer survival and cure rates are better than the nationally published averages.

MSK’s stomach cancer treatment locations in NYC and beyond

You can visit MSK stomach cancer experts closer to home, not just in Manhattan. We offer the same outstanding care from MSK doctors at our locations in:

• Brooklyn: Boerum Hill and  Flatbush
• Long Island:  Commack and  Nassau
• New Jersey:  Basking Ridge ,  Bergen , and  Monmouth
• Westchester County:  West Harrison

See all MSK locations.

About MSK’s guide to stomach cancer

This guide can support you and your loved ones as you learn more about this disease. We’re experts in diagnosing and treating stomach cancer, and this guide helps MSK share what we know.

We share expert information about stomach cancer symptoms and the latest treatments. We have information about stomach cancer research studies, also known as  clinical trials , that you may be able to join.

Who is this stomach cancer guide for?

You’re waiting to learn if you have stomach cancer

This guide gives you information about stomach cancer so you’re better prepared. If you want to know right away if you have cancer, we have information about  MSK’s rapid diagnosis program .

You want a second opinion

This guide explains new treatments. Learning about them can help you decide if you want a  second opinion . MSK’s stomach cancer experts offer second opinions about both diagnosis and treatment options, no matter where you live.

You’re worried about your current treatment plan

This guide can help you learn about other stomach cancer treatment options. MSK experts only use the latest treatments for stomach cancer. Some are only offered at MSK and very few other hospitals. We have information about MSK’s  stomach cancer doctors, surgeons, and other experts . You can also learn about  becoming a patient at MSK .

You’re worried about your risk for stomach cancer

This guide can help you learn about your risk for cancer. We offer cancer  genetic risk assessments  to see if you’re at higher risk for some forms of cancer. MSK offers advanced tumor genomic tests and DNA sequencing. These tests give us important details about the kind of cancer you have. You can visit our  tumor genetic testing page to learn more.

MSK also can help you learn about your risk if recent tests, such as an  endoscopy, showed  changes that can become cancer . If you’re at high risk, we can monitor you to watch for signs these changes are turning into stomach cancer. Learn about  becoming a patient at MSK .

You’re a caregiver to someone who has cancer

This guide has information about how to  support a loved one who has cancer , even if they’re not an MSK patient. At MSK, supporting caregivers is as important as caring for people with cancer.

Related topics:

What 5 Doctors Are Excited About in Kidney Cancer Research

W ith multiple game-changing developments over the past two decades, kidney cancer patients are now living longer and better.

A big part of the reason is that many are being diagnosed at earlier stages of the disease, when it can often be more easily treated and sometimes cured. Even when cancers are caught later, advances in medications and in methods of targeting cancer cells are significantly extending survival.

“When I started two decades ago, the average survival for patients with advanced kidney cancer was one year,” says Dr. Brian Rini, a professor of medicine at the Vanderbilt University Medical Center in Nashville. “Now, the median survival is between five and six years. It’s amazing.”

The growing use of scanning technologies in medicine overall has been one of the most important changes over the last couple of decades: Tumors are being detected during scans for non-cancerous conditions.

“Most kidney cancers are found by accident quite early, because people get scans for unrelated reasons,” says Dr. William Huang, a professor of urology and radiology at the NYU Grossman School of Medicine and a urologic oncologist at NYU Langone’s Perlmutter Cancer Center in New York City. “People get scanned for almost everything now: heartburn, back pain, car accidents. Eight out of 10 newly diagnosed patients who come to see me were scanned for something completely different.”

Because these cancers are caught early, they may be “completely curable, and sometimes so early that nothing needs to be done,” Huang says. “We can just keep an eye on them, and unless they change, we don’t need to do any intervention.” Advances in imaging have also led to novel ways of determining whether a tumor is benign or malignant. Scanners allow doctors to see growths in much greater detail nowadays, which allows for diagnosis in some cases without a biopsy. For example, scans using radioactive tracers can detect fat, which can be a signal that a growth is benign, Huang says.

Here's a look at additional kidney cancer advances that doctors are excited to see come down the pipeline.

Killing cancer without surgery

Surgeons used to remove the entire kidney when a tumor was found. “Now you can remove just part of the kidney,” Huang says. Some methods of eliminating tumors don’t even involve cutting. “You can ablate a tumor with heat or you can freeze it,” says Huang. “Right now we are involved in a clinical trial that uses a method that is completely non-invasive. There is no incision, no radiation, no needles. We just ablate the tumor using ultrasound waves, which rupture the cancer cells.”

Read More:   Coping With the Side Effects of Kidney-Cancer Treatment

Radiation by itself can eliminate tumors, too

For patients who aren’t good candidates for surgery because of underlying health issues, there’s another option that will eradicate the main tumor and some metastases. “This is something that has been evolving, and it’s very, very exciting,” says Dr. Catherine Spina, a kidney cancer specialist and an assistant professor of radiation oncology at Columbia University’s Vagelos College of Physicians and Surgeons in New York City. “Traditionally, radiation has been given over long courses in small doses.”

Over the years, however, specialists have discovered they could give much higher doses of radiation over a much shorter period of time, so long as the radiation was tightly targeted to hit the cancerous tissue, while giving a very low dose to the surrounding areas.

The result is that patients with a moderate-sized main tumor and cancer that has metastasized to just a few other sites can completely avoid surgery, with their cancer treated after just five or fewer radiation treatments. The technique is mostly limited to 8-centimeter main tumors, though some clinicians are also using it in tumors that are as large as 11 centimeters, Spina says.

When surgery is needed

Some patients prefer to have surgery or won’t qualify for non-invasive therapies because their cancer is too advanced. Surgical breakthroughs over the past decade or so have allowed these procedures to be more targeted and less invasive. 

Many operations are now done with robotic instruments that are inserted into the body through tiny incisions, while surgeons sitting at consoles view the operation and remotely control the instruments, says Dr. George Schade, an associate professor in urology at the University of Washington and a physician with the Fred Hutchinson Cancer Center in Seattle.

Robotic surgeries are a big advance over the original minimally invasive laparoscopic operations, in which tools at the end of stiff rods were inserted through small incisions with the surgeon standing over the patient and viewing the procedure on a computer screen. The new robotic instruments, by contrast, use a jointed probe rather than a straight one, offering more mobility. “They are like tiny arms inside of the patient with wrists and fingers,” Huang says.

Fluorescent dyes can help surgeons tell the difference between healthy tissue and cancer, as well as shine a light on the location of blood vessels feeding tumors. And in what may be another big step, some specialists are using robotic equipment that allows them to have depth perception. As the surgeons peer into a patient’s body, they see a 3D image overlaying the area that they're operating on. “This is not in wide use yet, but there are several groups working on improving the technology to bring it to the mainstream,” Schade says.

Looking forward, as high-speed internet access spreads around the country and throughout the world, it’s possible that the surgeon controlling the robot in the operating room might not even be at the same hospital. “I don’t see that as too far in the future,” Huang says.

Read More: How to Manage Anxiety and Depression When You Have Kidney Cancer

Targeted medications 

It wasn’t that long ago that specialists had little to offer cancer patients after surgery, outside of chemotherapy, which wasn’t very effective against kidney cancer. But in the past two decades, there's been an explosion of new cancer medications. Some pump up a patient’s immune response, while others target a variety of pathways to slow or stop cancer growth and development.

Drugs known as checkpoint inhibitors stop the immune system from being fooled into quitting before the cancer is conquered, says Dr. Bobby Liaw, clinical director of genitourinary oncology for the Mount Sinai Health System and an assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai.

Checkpoints are the part of a normally functioning immune system that act as a set of brakes to turn down the system’s response once an infection or other pathology such as cancer has been defeated. That way the immune system doesn’t start turning its attack on healthy cells.

By blocking the action of a checkpoint, these medications keep the immune system on target. There can be immune system side effects—such as skin inflammation, and less commonly, autoimmune-like effects on certain organs, as well as endocrine disturbances—from cutting one of the immune system’s brake lines.

“Any time we plan to initiate any kind of new therapy for any cancer patient, there needs to be consideration for the benefits versus the risks,” Liaw says. 

In the case of serious side effects, particularly the immune system attacking healthy cells, the checkpoint inhibitor is stopped and the patient is given corticosteroids, says Dr. Toni Choueiri, director of the Lank Center for Genitourinary Cancer at the Dana Farber Cancer Institute in Boston. 

A study published in April in the New England Journal of Medicine that followed patients for nearly five years showed that the checkpoint inhibitor pembrolizumab, when given after surgery, reduced the risk of death by 38%.

Read More: These Factors Increase the Risk of Kidney Cancer

“Prior to the approval of pembrolizumab, there was no wide-spread accepted standard of care for patients with [the most common form of kidney cancer] after treatment with surgery,” says Choueiri, the lead author of the study. The next step, he says, is to study whether combining it with another therapy, like belzutifan, will reduce the risk of death even further.

Other drugs take aim at blood vessel formation. “Tumors are more dependent on the growth of new blood vessels than organs are,” Rini explains. “These medications choke off the blood supply to the tumor.” 

One other type of drug, called a tyrosine kinase inhibitor, blocks an enzyme that’s needed for tumor cells to grow and divide. There are currently numerous tyrosine kinase inhibitors approved by the U.S. Food and Drug Administration (FDA).

At the end of 2023, kidney cancer specialists got yet another arrow to add to their quivers: The FDA approved the drug belzutifan, a medication that effectively suffocates tumors by blocking a protein involved in regulating oxygen levels.

Doctors have traditionally liked to give one cancer drug at a time, but that's changing. Specialists believe that cancers may have a harder time surviving when multiple medications are taken at once.

A number of ongoing clinical trials are looking at the impact of this strategy and exploring which combinations work the best. “There’s absolutely an additive effect of giving more drugs at the same time,” Rini says.

A kidney cancer vaccine? 

The mRNA technology that was used to create a vaccine to combat COVID-19 was initially developed as a potential way to battle cancer. Only recently has that research started to pan out.

Once a patient’s tumor has been removed, doctors identify proteins that are specific to cells in the tumor but not found anywhere else in the patient’s body. Then they determine which of those proteins are likely to be able to call the immune system’s attention to the cancer. Those proteins become the targets for the patient’s personalized mRNA vaccine.

There have already been promising results using mRNA technology to create personalized vaccines to help treat advanced melanoma. In a phase 2 trial that ended in mid-2023, researchers compared the checkpoint inhibitor pembrolizumab plus personalized vaccines to pembrolizumab alone. They found that the vaccine reduced the risk of recurrence by nearly a half. 

The same strategy is being tested in a phase 2 trial that will soon be recruiting patients with advanced kidney cancer, says Choueiri, co-lead investigator of the trial.

Read More: 7 Myths About Kidney Cancer, Debunked

The results of the phase 1 trial, which was testing just for safety, found “the vaccine to be well tolerated,” Choueiri says. “We and many others have been trying to do vaccines for several decades now.” The goal is to find the specific proteins in the vaccine that will be “the ones that elicit the most intense immune response that will lead to killing the cancer.”

Experts like Choueiri have high hopes for mRNA cancer vaccines. And with numerous other therapies being developed by pharmaceutical companies at the same time as others are making their way through clinical trials, the future for kidney cancer patients is getting brighter with each passing year.

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Gastric cancer articles within Nature Reviews Clinical Oncology

Review Article | 19 March 2024

Claudin 18.2 as a novel therapeutic target

The development and successful phase III testing of the anti-claudin 18.2 antibody zolbetuximab has provided a novel targeted therapy for the 30–40% of patients with strongly claudin 18.2-positive gastric cancers. Furthermore, the development of an effective targeted therapy for a target that does not have a driver role in cancer development provides a novel drug development paradigm. In this Review, the authors describe the development of claudin 18.2-targeted therapies, including zolbetuximab, as well as novel therapies, including chimeric antigen receptor (CAR) T cells, antibody–drug conjugates and bispecific antibodies, all of which have the potential to expand the number of patients who can derive benefit from claudin 18.2-targeted therapies in the near future.

• Izuma Nakayama
• , Changsong Qi
•  &  Kohei Shitara

Review Article | 01 June 2023

Early stage gastric adenocarcinoma: clinical and molecular landscapes

Long-term survival rates of patients with gastric cancer remain low, particularly in Western countries. This lack of progress, among other aspects, is likely to reflect a focus on empirical approaches that fail to account for the heterogeneity of gastric cancers. In this Review, the authors summarize the available evidence on the management of patients with early stage gastric cancers, with an emphasis on understanding the underlying biology in order to improve the outcomes in patients with these historically difficult-to-treat tumours.

• Yuki Hirata
• , Ayesha Noorani
•  &  Jaffer A. Ajani

Research Highlight | 03 May 2023

Zolbetuximab moves into the SPOTLIGHT

• Diana Romero

Research Highlight | 02 November 2022

Bemarituzumab enters the FIGHT

• Peter Sidaway

Research Highlight | 24 June 2022

HSP90 inhibition improves GIST survival

• David Killock

Review Article | 25 February 2022

New treatment strategies for advanced-stage gastrointestinal stromal tumours

Gastrointestinal stromal tumour (GIST) is the most common form of sarcoma and has become a paradigm of precision medicine owing to the fact that almost all patients harbour one of several known molecule drivers, most of which can be targeted therapeutically. Nevertheless, novel therapeutic strategies are required to overcome the intrinsic resistance of certain subtypes of GIST to existing treatments as well as the acquired resistance that eventually arises in initially sensitive subtypes. This Review describes the biology of GIST, the evolution of the current treatments for this cancer, and the emerging therapeutic agents and approaches that might overcome the remaining clinical challenges.

• Lillian R. Klug
• , Homma M. Khosroyani
•  &  Michael C. Heinrich

Research Highlight | 22 December 2021

Pembrolizumab for HER2 + gastric cancer

Review Article | 31 March 2021

Biomarker-targeted therapies for advanced-stage gastric and gastro-oesophageal junction cancers: an emerging paradigm

Despite considerable progress in the development of targeted therapies, only three biomarkers are currently used to guide the treatment of patients with gastric or gastro-oesophageal junction cancers using approved targeted therapies. Nonetheless, owing to advances in our understanding of tumour biology and sequencing technologies, several novel therapies are expected to soon become available. In this Review, the authors describe current and future biomarker-guided therapies for patients with G/GEJ cancers.

• Yoshiaki Nakamura
• , Akihito Kawazoe

Research Highlight | 12 June 2020

Trastuzumab deruxtecan improves survival

Research Highlight | 12 May 2020

Activity of regorafenib plus nivolumab

Research Highlight | 24 April 2019

Perioperative FLOT superior to ECF/X

• Conor A. Bradley

Year in Review | 21 December 2018

Two steps forward and one step back

Perioperative chemotherapy is the standard of care for localized gastric cancer (GC). In 2018, additional postoperative radiotherapy was found to be ineffective; although, docetaxel was found to be superior to epirubicin in perioperative three-drug chemotherapy regimens. Validated biomarkers are needed for benefit from immunotherapy in advanced-stage GC. Metachronous GC can be prevented by Helicobacter pylori eradication.

• Florian Lordick
•  &  Elizabeth C. Smyth

News & Views | 05 October 2018

A balancing act: dual immune-checkpoint inhibition for oesophagogastric cancer

A minority of patients with gastroesophageal adenocarcinoma derive benefit from immune-checkpoint inhibition (ICI). In a large-cohort phase III study, the nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) arm (which was based on promising preliminary data from CheckMate 032) was closed owing to unacceptably high levels of mortality and morbidity. Our quest for better biomarkers than programmed cell death 1 ligand 1 (PD-L1) and safer dual ICI strategies must continue.

• Kazuto Harada
• , Ahmed A. F. Abdelhakeem

Research Highlight | 30 July 2018

Immunotherapy-responsive gastric cancers identified

In Brief | 22 May 2018

Genomics reveals distinct gastric cancer subtypes

News & Views | 26 April 2018

How to eliminate gastric cancer-related death worldwide?

Helicobacter pylori eradication therapy is effective in preventing gastric cancer, even in patients with advanced pre-neoplastic lesions (gastric atrophy and/or intestinal metaplasia). We must now focus on how to accomplish the goal of eliminating gastric cancer-related death worldwide; strategies for screening and treatment of gastric neoplasia (primary prevention) and post-treatment surveillance (secondary prevention) are discussed herein.

• Yoshio Yamaoka

Review Article | 04 April 2017

Targeting c-MET in gastrointestinal tumours: rationale, opportunities and challenges

Patients with c-MET-expressing colorectal or gastrointestinal cancers generally have worse outcomes than those of patients whose tumours have low levels of, or absent c-MET expression. However, c-MET targeted agents have, thus far, failed to show clinical efficacy. In this Review, the authors describe the opportunities and challenges created by the clinical implementation of c-MET targeted therapies.

• , Manuel Salto-Tellez
•  &  Sandra Van Schaeybroeck

Research Highlight | 14 February 2017

Leveraging ADCC to enhance anti-HER2 therapy

Research Highlight | 24 January 2017

Oesophageal cancer — not all alike

Research Highlight | 08 November 2016

Keeping aFLOaT with new combination

News & Views | 13 April 2016

Apatinib — new third-line option for refractory gastric or GEJ cancer

Apatinib significantly improves both the progression-free survival (PFS) and overall survival in patients with advanced-stage gastric cancer who are refractory to two or more lines of chemotherapy. In the context of previous phase III trials of angiogenesis inhibitors for this disease, we discuss the role of apatinib, and the advantages and limitations of VEGFR-2 blockade in the advanced disease setting.

• Toru Aoyama
•  &  Takaki Yoshikawa

Review Article | 01 March 2016

Clinical impact of tumour biology in the management of gastroesophageal cancer

The characterization of gastroesophageal cancer into subtypes on the basis of diverse genotypes has evolved; however, patients require new treatment options, particularly when standard therapies are exhausted. Improved molecular classification of gastroesophageal cancer subtypes enhances patient selection for biological therapy. The authors of this Review summarize the current awareness of the unique biology of gastroesophageal cancer and discuss the clinically applicability of these findings.

•  &  Yelena Y. Janjigian

Year in Review | 15 December 2015

The development of new agents and molecular classifications

In a little over the past year, several clinical trials have evaluated new drugs in patients with metastatic colorectal cancer and gastric cancer. Furthermore, genomics studies that attempted to unravel the molecular characteristics of colorectal and gastric cancer were published in 2015. The results of these endeavours will influence clinical practice in 2016 and beyond.

• Eric Van Cutsem
•  &  Michel Ducreux

Research Highlight | 20 October 2015

mDCF—new standard-of-care?

Opinion | 11 August 2015

Does surgery have a role in managing incurable gastric cancer?

Stage IV gastric cancer is incurable and has a very poor prognosis. Although palliative chemotherapy remains the standard of care, increasing evidence indicates that palliative surgery can provide a prognostic and symptomatic benefit. This Perspectives summarizes the recent evidence underpinning the medical and surgical management of incurable gastric cancer, and provides evidence-based recommendations on treatment strategies and avenues for future research.

• Sri G. Thrumurthy
• , M. Asif Chaudry
•  &  William Allum

News & Views | 18 November 2014

Over the RAINBOW—renaissance in antiangiogenesis

The RAINBOW study has demonstrated that ramucirumab plus paclitaxel as second-line treatment for advanced-stage gastric cancer prolongs survival compared with paclitaxel alone. These data confirm that ramucirumab represents a new effective treatment option for gastric cancer. Nevertheless, new treatment options remain eagerly awaited in this disease with dismal outcomes.

Research Highlight | 21 October 2014

FOLFIRI—improving toxicity in first-line treatment of advanced gastric cancer

• Alessia Errico

Research Highlight | 12 August 2014

New molecular classification of gastric adenocarcinoma proposed by The Cancer Genome Atlas

• Mina Razzak

Reply | 03 June 2014

Gastric cancer drug trials—are women second class citizens?

• Manish A. Shah

Correspondence | 03 June 2014

•  &  Weikuan Gu

Research Highlight | 11 February 2014

A master KLASS in laparoscopic gastrectomy

• M. Teresa Villanueva

News & Views | 03 December 2013

Targeted therapies in gastric cancer—the dawn of a new era

The international phase III REGARD study demonstrated improved overall survival with ramucirumab as second-line therapy for patients with advanced-stage gastric and gastroesophageal junction adenocarcinoma. As a novel biological treatment, is ramucirumab also the harbinger of a new era of targeted therapies in this prevalent and highly morbid disease?

Review Article | 24 September 2013

Gastric cancer—molecular and clinical dimensions

Momentum is building for carrying out more phase III comparative trials in gastric cancer, with some using biomarker-based patient selection strategies. In this Review, the authors discuss representative molecular and clinical dimensions of gastric cancer, the fourth most common cancer in men and fifth most common cancer in women.

• Roopma Wadhwa
• , Shumei Song

Research Highlight | 20 August 2013

Hope for antiangiogenic therapy in advanced gastric cancer

In Brief | 07 May 2013

Reduced risk of gastric cancer associated with statins

Year in Review | 08 January 2013

Defining treatment standards and novel insights into disease biology

Gastric cancer is a heterogeneous disease with almost one million new cases occurring annually worldwide. The year 2012 saw important successes and failures in gastric cancer treatment, and also novel insights into the molecular characterization of this disease, which may lead to the development of more-effective targeted therapies.

• Elizabeth C. Smyth
•  &  David Cunningham

In Brief | 24 July 2012

An extended optimal interval for gastric cancer

News & Views | 01 May 2012

Salvage chemotherapy in gastric cancer—more than a straw?

The benefit of salvage chemotherapy in gastric cancer refractory to first-line platinum and fluoropyrimidine therapy was previously unknown. A randomized multicentre study has shown that irinotecan or docetaxel administered as single agents improved survival compared with best supportive care alone. Hence, salvage chemotherapy is now a proven option in pretreated gastric cancer.

News & Views | 28 February 2012

Adjuvant chemotherapy after D2 gastrectomy for gastric cancer

In the CLASSIC study, capecitabine–oxaliplatin was an effective chemotherapy after D2 gastrectomy for stage II–IIIB gastric cancer. We compared these data with the ACTS-GC study, which was the only pivotal study proving the benefit of adjuvant chemotherapy in these patients. Long-term survival data from CLASSIC are awaited with interest. boxed-text

• Takaki Yoshikawa
•  &  Mitsuru Sasako

Research Highlight | 01 November 2011

Update on gastric cancer in East Asia

Research Highlight | 06 September 2011

Should we be aghast at the AVAGAST data?

• Rebecca Kirk

Research Highlight | 28 October 2010

New standard of therapy for HER2-positive gastric cancers?

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