AIM:This study reconstructed patient-level data to provide updated evidence on survival outcomes across PD-L1 expression subgroups. MATERIALS AND METHODS:A systematic search was conducted on March 2, 2025, using PubMed, Embase, Web of Science, Cochrane, and Scopus for RCTs comparing ICIs to chemotherapy in advanced ESCC. Kaplan-Meier curves were reconstructed using a time-to-event algorithm for all patients and for PD-L1 subgroups. KMSubtraction was used to retrieve unpublished survival data. A patient-level meta-analysis was performed using a stratified Cox model. RESULTS:Thirteen phase III trials (6,672 patients) were included. In the first-line setting, patients with TPS <1% (from CheckMate-648 and ESCORT-1st) showed no overall survival (OS) benefit (HR: 0.88, p = 0.187), whereas those with TPS ≥1% from the same trials showed a significant benefit (HR: 0.61, p < 0.001). For a combined positive score (CPS) ≥10, pooled data from ASTRUM-007, KEYNOTE-590, ORIENT-15, and GEMSTONE-304 showed significant OS benefit (HR: 0.60, p < 0.001). CPS <10 (KEYNOTE-590, ORIENT-15, and GEMSTONE-304) also showed benefit (HR: 0.81, p = 0.02), but no survival benefit was seen in CPS 1-9 (ASTRUM-007 and GEMSTONE-304) (HR: 0.82, p = 0.117). CONCLUSION:PD-L1 appears to be a useful biomarker in advanced ESCC. Patients with PD-L1 levels of 10 or higher consistently showed survival benefits. For PD-L1 <10, treatment decisions may be less clear; further research on combining PD-L1 with other biomarkers is needed. Patients with PD-L1 <1 showed minimal benefit and should be informed about the limited efficacy of ICIs.

BACKGROUND:Advanced esophageal cell carcinoma (ESCC) is associated with poor survival outcomes. PD-1/PD-L1 inhibitors have been approved for the treatment of advanced ESCC. We aim to study PD-1/PD-L1 inhibitors across other variables in advanced ESCC, including data presented at the September 2024 FDA Oncologic Drugs Advisory Committee (ODAC) meeting. METHODS:On February 28, 2025, we conducted a comprehensive search using PubMed, Web of Science, Scopus, and the Cochrane Library to identify randomized clinical trials evaluating PD-1/PD-L1 inhibitors in advanced ESCC. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Subgroup analyses were performed based on the following variables: age, gender, smoking status, ECOG performance status, liver metastasis, disease stage (locally advanced vs. metastatic), combined positive score (CPS; particularly with cutoff values of CPS 5 and CPS 1-9), and tumor area positivity (TAP). Effect sizes were estimated using the hazard ratio (HR) with random effects model. RESULTS:Out of 5514 articles screened, only 13 papers were included, involving 6672 patients. PD-1/PD-L1 inhibitors significantly improved OS in both first- and second-line. In the first-line setting (combined with chemotherapy), they reduced the risk of death by 32 % (HR: 0.68; 95 % CI: 0.63-0.74, p < 0.001), while in the second-line setting (used as monotherapy), they reduced mortality by 27 % (HR: 0.73; 95 % CI: 0.66-0.81, p < 0.001). For PFS, a significant benefit was seen only in first-line treatment (HR: 0.62; 95 % CI: 0.58-0.67, p < 0.001) but not in second-line (HR: 0.89; 95 % CI: 0.76-1.04, p = 0.128), with a significant difference between treatment lines (p < 0.001). Most subgroups in our study demonstrated significant survival benefits, except for current smokers (HR: 0.58; 95 % CI: 0.31-1.09; p = 0.089). Finally, all CPS subgroups showed survival benefits in the first-line setting except those with CPS < 1 (PD-L1 negative). A similar pattern was observed in the second-line setting. CONCLUSIONS:PD-1/PD-L1 inhibitors significantly improve OS over chemotherapy in both first- and second-line advanced ESCC. PFS improved only in the first line. More effective therapies for the second line are still needed. Current smokers showed no survival benefit, unlike former or never smokers. OS benefit was absent in PD-L1-negative patients (CPS <1) and greatest in those with CPS ≥ 10.

BACKGROUND:Perioperative FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel) is a standard therapy for resectable gastric and gastroesophageal junction adenocarcinomas, but recurrence rates remain high. Immunotherapy plus chemotherapy may improve outcomes. METHODS:In a phase 3, multinational, double-blind, randomized trial, we assigned participants with resectable gastric or gastroesophageal junction adenocarcinoma, in a 1:1 ratio, to receive durvalumab at a dose of 1500 mg or placebo every 4 weeks plus FLOT for 4 cycles (2 cycles each of neoadjuvant and adjuvant therapy), followed by durvalumab or placebo every 4 weeks for 10 cycles. The primary end point was event-free survival; secondary end points included overall survival and pathological complete response. RESULTS:A total of 474 participants were randomly assigned to the durvalumab group, and 474 to the placebo group (median follow-up, 31.5 months; interquartile range, 26.7 to 36.6). Two-year event-free survival (Kaplan-Meier estimate) was 67.4% among the participants in the durvalumab group and 58.5% among those in the placebo group (hazard ratio for event or death, 0.71; 95% confidence interval [CI], 0.58 to 0.86; P<0.001). Two-year overall survival was 75.7% in the durvalumab group and 70.4% in the placebo group (piecewise hazard ratio for death during months 0 to 12, 0.99 [95% CI, 0.70 to 1.39], and during the period from month 12 onward, 0.67 [95% CI, 0.50 to 0.90]; P = 0.03 by a stratified log-rank test [exceeding the significance threshold of P<0.0001]). The percentage of participants with a pathological complete response was 19.2% in the durvalumab group and 7.2% in the placebo group (relative risk, 2.69 [95% CI, 1.86 to 3.90]). Adverse events with a maximum grade of 3 or 4 were reported in 340 participants (71.6%) in the durvalumab group and in 334 (71.2%) in the placebo group. The percentage of participants with delayed surgery was 10.1% and 10.8%, respectively, and the percentage with delayed initiation of adjuvant treatment was 2.3% and 4.6%. CONCLUSIONS:Perioperative durvalumab plus FLOT led to significantly better event-free survival outcomes than FLOT alone among participants with resectable gastric or gastroesophageal junction adenocarcinoma. (Funded by AstraZeneca; MATTERHORN ClinicalTrials.gov number, NCT04592913.).

INTRODUCTION:Tislelizumab plus investigator-chosen chemotherapy (ICC) demonstrated a statistically significant improvement in overall survival (OS) versus placebo plus ICC in RATIONALE-305 in patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric cancer/gastroesophageal junction cancer (GC/GEJC) in the intent-to-treat population and in patients with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥ 5%. The United States Food and Drug Administration Oncologic Drugs Advisory Committee voted (September 2024) against first-line treatment with programmed cell death protein-1 inhibitors in this setting in patients with a PD-L1 combined positive score < 1 or TAP score < 1%, due to an unfavorable benefit-risk profile. Thus, we retrospectively analyzed data from RATIONALE-305 in patients with a PD-L1 TAP score ≥ 1%. METHODS:Adult patients with locally advanced unresectable or metastatic HER2-negative GC/GEJC were randomized to tislelizumab 200 mg or placebo with ICC every 3 weeks. Efficacy and safety outcomes of tislelizumab plus ICC versus placebo plus ICC were retrospectively assessed in those with a PD-L1 TAP score ≥ 1%. RESULTS:At the final analysis cutoff (February 28, 2023), 432 patients received tislelizumab plus ICC and 453 received placebo plus ICC, and had a PD-L1 TAP score ≥ 1%. Clinically meaningful improvements to OS were observed with tislelizumab plus ICC compared with placebo plus ICC [15.0 months (95% confidence interval [CI] 13.3-16.7) vs. 12.8 months (95% CI 12.1-14.1), respectively; stratified hazard ratio 0.77 (95% CI 0.67-0.90)]. Progression-free survival, overall response rate, duration of response, and disease control rate, were also improved. OS improvements were maintained at a 3-year data cutoff (February 28, 2024). Tislelizumab plus ICC had an acceptable safety profile with no new safety signals. CONCLUSIONS:Tislelizumab plus ICC is an effective and tolerable first-line treatment for patients with locally advanced unresectable or metastatic HER2-negative GC/GEJC with a PD-L1 TAP score ≥ 1%. TRIAL REGISTRATION NUMBER:NCT03777657.

Tislelizumab plus investigator-chosen chemotherapy (ICC) demonstrated a statistically significant improvement in overall survival (OS) versus placebo plus ICC in RATIONALE-305 in patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric cancer/gastroesophageal junction cancer (GC/GEJC) in the intent-to-treat population and in patients with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥ 5

First-line nivolumab-plus-chemotherapy demonstrated superior overall survival (OS) and progression-free survival versus chemotherapy for advanced gastroesophageal adenocarcinoma with programmed death ligand 1 combined positive score ≥ 5, meeting both primary end points of the randomized phase 3 CheckMate 649 trial. Nivolumab-plus-ipilimumab provided durable responses and higher survival rates versus chemotherapy; however, the prespecified OS significance boundary was not met. To identify biomarkers predictive of differential efficacy outcomes, post hoc exploratory analyses were performed using whole-exome sequencing and RNA sequencing. Nivolumab-based therapies demonstrated improved efficacy versus chemotherapy in hypermutated and, to a lesser degree, Epstein–Barr virus-positive tumors compared with chromosomally unstable and genomically stable tumors. Within the KRAS-altered subgroup, only patients treated with nivolumab-plus-chemotherapy demonstrated improved OS benefit versus chemotherapy. Low stroma gene expression signature scores were associated with OS benefit with nivolumab-based regimens; high regulatory T cell signatures were associated with OS benefit only with nivolumab-plus-ipilimumab. Our analyses suggest that distinct and overlapping pathways contribute to the efficacy of nivolumab-based regimens in gastroesophageal adenocarcinoma. Exploratory post hoc analysis of molecular residual disease (MRD) from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR-mutated stage IB–IIIA non-small cell lung cancer shows that MRD detection predicts disease recurrence with long term adjuvant osimertinib treatment.

4000 Background: At 24.4-month (mo) median follow-up, adjuvant nivolumab demonstrated a statistically significant and clinically meaningful improvement in disease-free survival (DFS) vs placebo with a well-tolerated safety profile in patients (pts) with resected EC/GEJC with residual pathologic disease following neoadjuvant CRT and surgery in the primary analysis from the global, phase 3 CheckMate 577 study (NCT02743494). We report the final analysis of the hierarchically tested secondary endpoint of OS along with longer follow-up of DFS. Methods: Adults with resected (R0) stage II/III EC/GEJC who received neoadjuvant CRT and had residual pathologic disease were randomized 2:1 to nivolumab 240 mg or placebo Q2W for 16 weeks, followed by nivolumab 480 mg or placebo Q4W. Maximum treatment duration was 1 year. The primary endpoint was DFS. OS was a secondary endpoint, and exploratory endpoints included safety, distant metastasis-free survival (DMFS), and progression-free survival on subsequent systemic therapy (PFS2). Results: 794 pts were randomized (nivolumab, n = 532; placebo, n = 262). With a median follow-up of 78.3 (range, 60.1–96.6) mo, adjuvant nivolumab continued to show DFS benefit vs placebo (HR 0.76 [95% CI 0.63–0.91]; Table). Median OS was numerically longer with nivolumab vs placebo (51.7 vs 35.3 mo), although the difference was not statistically significant (HR 0.85 [95.87% CI 0.70–1.04]; P = 0.1064; Table). OS rates at 3 and 5 years with nivolumab vs placebo were 57% vs 50% and 46% vs 41%, respectively. OS subgroup analyses will be presented. Clinically meaningful improvement in DMFS with nivolumab vs placebo was maintained (Table). PFS2 favored nivolumab vs placebo (HR 0.81 [95% CI 0.67–0.98]). In the nivolumab group, 46% of pts received subsequent therapy vs 60% in the placebo group; 5% vs 15% received subsequent immunotherapy. No new safety signals were identified. Conclusions: Adjuvant nivolumab demonstrated sustained long-term DFS benefit and numerical improvement in OS vs placebo in pts with resected EC/GEJC and residual pathologic disease following neoadjuvant CRT. The safety profile of adjuvant nivolumab remained well-tolerated with longer follow-up. These results further support the use of adjuvant nivolumab in this pt population. Clinical trial information: NCT02743494 . Efficacy Nivolumab(n = 532) Placebo(n = 262) Median DFS (95% CI), mo 21.8 (16.6–29.7) 10.8 (8.3–14.3) HR (95% CI) 0.76 (0.63–0.91) Median OS (95% CI), mo 51.7 (41.0–61.6) 35.3 (30.7–48.8) HR (95.87% CI; P value) 0.85 (0.70–1.04; P = 0.1064) Median DMFS (95% CI), mo 27.3 (21.4–36.0) 14.6 (10.9–20.3) HR (95% CI) 0.75 (0.62–0.90) Safety, n (%) n = 532 n = 260 Any-grade/grade 3–4 TRAEs 379 (71)/75 (14) 124 (48)/17 (7) Any-grade/grade 3–4 TRAEs leading to discontinuation 48 (9)/26 (5) 8 (3)/7 (3) TRAE, treatment-related adverse event.

LBA5 Background: FLOT is a perioperative standard of care (SoC) in resectable GC/GEJC, yet recurrence rates remain high. Immune checkpoint inhibitors are approved in combination with chemotherapy in metastatic GC/GEJC, but not in the perioperative setting. The randomized, double-blind, global, Phase 3 MATTERHORN study (NCT04592913) assesses the combination of perioperative durvalumab (D) + FLOT vs placebo (P) + FLOT in participants (pts) with locally advanced, resectable GC/GEJC. The primary endpoint is EFS. Pathologic complete response (pCR) and overall survival (OS) are key secondary endpoints. The trial previously showed a statistically significant gain in pCR for D + FLOT. Here, we report efficacy and safety from the pre-planned interim analysis 2. Methods: Pts aged ≥18 years with histologically confirmed, resectable (Stage II–IVa per American Joint Committee on Cancer 8th edition) untreated G/GEJ adenocarcinoma were randomized 1:1 to D 1500 mg or P every 4 weeks (Q4W) on Day 1 + FLOT on Days 1 and 15 for 4 cycles (2 cycles each neoadjuvant/adjuvant), followed by D 1500 mg or P on Day 1 Q4W for 10 cycles. Pts were stratified by Asia vs non-Asia, clinical lymph node status (positive vs negative) and programmed cell death ligand-1 Tumor Area Positivity score (≥1% vs <1%). Data cutoff was Dec 20, 2024. EFS (time from randomization to progression, local or distant recurrence, or death) superiority for D + FLOT vs P + FLOT was assessed in all randomized pts by a stratified log-rank test (2-sided significance level threshold: 0.0239) on data according to RECIST v1.1 per BICR and/or locally by pathology testing. Results: In total, 948 pts were randomized to receive D + FLOT (n=474) or P + FLOT (n=474); median (m) follow-up duration was 31.5 months (mo). Demographic/baseline characteristics were generally similar across treatment arms. D + FLOT demonstrated a statistically significant improvement in EFS vs P + FLOT (hazard ratio [HR] 0.71; 95% confidence interval [CI], 0.58–0.86; p<0.001), mEFS was not reached (NR) with D + FLOT vs 32.8 mo with P + FLOT. The 24-mo EFS rate was higher for D + FLOT vs P + FLOT (Table). mOS was NR for D + FLOT vs 47.2 mo for P + FLOT (HR 0.78; 95% CI, 0.62–0.97; p=0.025; 33.9% maturity) and will be formally assessed at the final analysis. Maximum Grade 3 or 4 adverse event rates were similar between treatment arms; D + FLOT did not delay surgery or initiation of adjuvant therapy vs P + FLOT. Conclusion: D + FLOT demonstrated a statistically significant improvement in EFS vs P + FLOT in pts with resectable GC/GEJC, with an encouraging OS trend. These results support D + FLOT as a potential new global SoC for resectable GC/GEJC. Clinical trial information: NCT04592913 . D + FLOT (n=474) P + FLOT (n=474) mEFS (95% CI), mo NR (40.7–NR) 32.8 (27.9–NR) EFS rate (95% CI), %12 mo24 mo 78.2 (74.1–81.7)67.4 (62.9–71.6) 74.0 (69.7–77.8)58.5 (53.8–63.0)

Patients with colorectal cancer liver metastases have long represented a unique and thoroughly investigated population. Nevertheless, the optimal management of these is still controversial with a number of open questions which are only partially addressed by available studies and existing guidelines. The European Organisation for Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cancer Group (GITCG) sought to fill this knowledge gap and promoted the development of a European consensus on this subject. By using the Delphi methodology and leveraging a multidisciplinary team of 43 international experts, including gastrointestinal oncologists, hepatobiliary surgeons, interventional radiologists, radiation oncologists, radiologists, nuclear medicine physicians and pathologists from 12 European countries, 34 practical recommendations and two consensus statements were proposed. These cover varying aspects of the optimal management of colorectal cancer liver metastases such as baseline imaging, selection criteria for liver-directed therapies, treatment strategies, assessment of treatment response, follow-up, care delivery, clinical research and future perspectives. This roadmap document is intended to complement national and international guidelines, and to provide practical guidance for clinicians and multidisciplinary teams, ultimately promoting practice standardisation, optimal management and better patient outcomes across Europe. Also, it provides a unique opportunity to highlight grey areas and unmet needs, and to give a strategic direction to future research in the field by identifying topics where there is no consensus among experts.

LBA246 Background: FLOT was established as a perioperative therapy for GC/GEJC following the Phase 2/3 FLOT4 study conducted in Germany, with a pCR rate of 16% (Al-Batran et al, Lancet Oncol 2016). The global MATTERHORN study (NCT04592913) showed a statistically significant improvement in pCR with perioperative D + FLOT vs placebo (P) + FLOT in GC/GEJC at first interim analysis (Janjigian et al, ESMO Congress 2023). Subgroup analyses by region and country were completed to assess pCR rates with FLOT and benefit of D + FLOT across the global study population. Methods: Participants (pts) with resectable GC/GEJC were randomized 1:1 to D 1500 mg or P every 4 weeks (Q4W) on Day 1 plus FLOT Q2W on Days 1 and 15 for 4 cycles (2 doses of D or P and 4 doses of FLOT pre- and post-operative), followed by D 1500 mg or P on Day 1 Q4W for 10 further cycles. Randomization was stratified by Asia vs non-Asia. pCR (Modified Ryan; central review) was assessed in prespecified (Asia) and post hoc regional subgroups, including 6 countries with the highest numbers of randomized pts. Results: Of 948 pts randomized globally, 180 pts (19%) were in Asia. pCR outcomes with FLOT in Asia were consistent with the global outcomes. pCR rates were improved with D + FLOT vs P + FLOT in all regions (Asia, Europe, North America and South America; Table), despite some imbalances in baseline characteristics and numerical differences in pCR rates by geographic location. The pCR rate with P + FLOT in the German subgroup (13%; 95% CI, 6.1–23.0) was similar to that with FLOT in the FLOT4 study. Improvement in pCR with D + FLOT vs P + FLOT was observed across subgroups by country. Similar trends across regional subgroups were observed for combined complete and near-complete response rate. Conclusions: In MATTERHORN, pCR was consistently improved with the addition of D to perioperative FLOT in GC/GEJC across geographic regions. The study is ongoing for the primary objective of event-free survival. Clinical trial information: NCT04592913 .[Table: see text]

Abstract Background FLOT was established as a perioperative therapy for GC/GEJC following the Phase 2/3 FLOT4 study conducted in Germany, with a pCR rate of 16% (Al-Batran et al, Lancet Oncol 2016). The global MATTERHORN study (NCT04592913) showed a statistically significant improvement in pCR with perioperative D+FLOT vs placebo (P) + FLOT in GC/GEJC at first interim analysis (Janjigian et al, ESMO Congress 2023). Subgroup analyses by region and country were completed to assess pCR rates with FLOT and benefit of D+FLOT across the global study population. Methods Participants (pts) with resectable GC/GEJC were randomized 1:1 to D 1500 mg or P every 4 weeks (Q4W) on Day 1 plus FLOT Q2W on Days 1 and 15 for 4 cycles (2 doses of D or P and 4 doses of FLOT pre- and post-operative), followed by D 1500 mg or P on Day 1 Q4W for 10 further cycles. Randomization was stratified by Asia vs non-Asia. pCR (Modified Ryan; central review) was assessed in prespecified (Asia) and post hoc regional subgroups, including 6 countries with the highest numbers of randomized pts. Results Of 948 pts randomized globally, 180 (19%) were in Asia. pCR outcomes with FLOT in Asia were consistent with global outcomes. pCR rates were improved with D+FLOT vs P+FLOT in all regions (Asia, Europe, North America and South America; Table), despite some imbalances in baseline characteristics and numerical differences in pCR rates by geographic location. The pCR rate with P+FLOT in the German subgroup (13%; 95% CI, 6.1–23.0) was similar to that with FLOT in the FLOT4 study. Improvement in pCR with D+FLOT vs P+FLOT was observed across subgroups by country. Similar trends across regional subgroups were observed for combined complete and near-complete response rate. Conclusions In MATTERHORN, pCR was consistently improved with the addition of D to perioperative FLOT in GC/GEJC across geographic regions. The study is ongoing for the primary objective of event-free survival.

BACKGROUND:Local treatment improves the outcomes for oligometastatic disease (OMD, i.e. an intermediate state between locoregional and widespread disseminated disease). However, consensus about the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer is lacking. The aim of this study was to develop a multidisciplinary European consensus statement on the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer. METHODS:In total, 65 specialists in the multidisciplinary treatment for oesophagogastric cancer from 49 expert centres across 16 European countries were requested to participate in this Delphi study. The consensus finding process consisted of a starting meeting, 2 online Delphi questionnaire rounds and an online consensus meeting. Input for Delphi questionnaires consisted of (1) a systematic review on definitions of oligometastatic oesophagogastric cancer and (2) a discussion of real-life clinical cases by multidisciplinary teams. Experts were asked to score each statement on a 5-point Likert scale. The agreement was scored to be either absent/poor (<50%), fair (50%-75%) or consensus (≥75%). RESULTS:A total of 48 experts participated in the starting meeting, both Delphi rounds, and the consensus meeting (overall response rate: 71%). OMD was considered in patients with metastatic oesophagogastric cancer limited to 1 organ with ≤3 metastases or 1 extra-regional lymph node station (consensus). In addition, OMD was considered in patients without progression at restaging after systemic therapy (consensus). For patients with synchronous or metachronous OMD with a disease-free interval ≤2 years, systemic therapy followed by restaging to consider local treatment was considered as treatment (consensus). For metachronous OMD with a disease-free interval >2 years, either upfront local treatment or systemic treatment followed by restaging was considered as treatment (fair agreement). CONCLUSION:The OMEC project has resulted in a multidisciplinary European consensus statement for the definition, diagnosis and treatment of oligometastatic oesophagogastric adenocarcinoma and squamous cell cancer. This can be used to standardise inclusion criteria for future clinical trials.

BACKGROUND:Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture.METHODS:We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO.FINDINGS:Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level.INTERPRETATION:Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO.FUNDING:German Research Foundation (DFG).