Gastric Cancer

H. pylori carcinogenesis, CDH1 hereditary risk, late-stage presentation, and perioperative chemotherapy plus checkpoint inhibitor strategies

Key Points

• Gastric cancer is the 5th most common cancer globally but ranks higher in East Asia, Eastern Europe, and South America.
• H. pylori infection is the most important modifiable risk factor — it causes ~89% of non-cardia gastric cancers.
• CDH1 germline mutations cause hereditary diffuse gastric cancer (HDGC); prophylactic gastrectomy is recommended for pathogenic variant carriers.
• Most patients present with advanced disease due to vague, nonspecific early symptoms (dyspepsia, early satiety).
• HER2 overexpression (~20% of gastric/GEJ adenocarcinomas) is the most important predictive biomarker — trastuzumab + chemotherapy improves OS.
• Perioperative FLOT chemotherapy (docetaxel + oxaliplatin + leucovorin + 5-FU) is the European/US standard for resectable gastric cancer.
• Nivolumab + chemotherapy is the current first-line standard for advanced gastric/GEJ adenocarcinoma (CPS ≥5) per CheckMate 649.
• Zolbetuximab + FOLFOX/CAPOX (FDA-approved 2024) is a first-line option for CLDN18.2-positive (≥75% of cells IHC ≥2+), HER2-negative disease per SPOTLIGHT and GLOW.

Epidemiology & Incidence

Gastric cancer is the fifth most commonly diagnosed cancer and fourth leading cause of cancer death globally. Incidence varies dramatically by geography: very high in East Asia (Japan, South Korea, China), Eastern Europe, and Latin America; lower in North America and Western Europe. In the US, approximately 26,890 new cases and 10,880 deaths were projected in 2024. Asian Americans have the highest incidence among US racial/ethnic groups. Two anatomic subtypes have different epidemiology: Proximal (cardia/gastroesophageal junction, GEJ) gastric cancer is rising in Western countries and is…

Genetic Predispositions & Risk Factors

H. pylori is classified as a Group I carcinogen by IARC and is the primary cause of gastric cancer worldwide. Infection leads to chronic active gastritis → atrophic gastritis → intestinal metaplasia → dysplasia → adenocarcinoma (Correa cascade). H. pylori eradication reduces the risk of metachronous gastric cancer after endoscopic resection of early cancers. Population-level eradication programs in Japan and South Korea have reduced gastric cancer incidence. Other environmental risk factors: High salt intake (traditional preserved/pickled foods, salted fish, processed meats), smoking (2×…

Clinical Presentation

Gastric cancer has notoriously nonspecific early symptoms, which explains why >70% of patients in Western countries present with stage III–IV disease. Early gastric cancer symptoms (often incidental or attributed to benign disease): • Dyspepsia and epigastric discomfort — the most common early symptom; indistinguishable from functional dyspepsia or peptic ulcer disease • Nausea and early satiety • Mild weight loss • These symptoms are common in the general population; the challenge is identifying which patients warrant endoscopy Alarm features mandating prompt upper endoscopy: • Weight loss…

Staging & Biomarkers

Gastric/GEJ adenocarcinoma is staged using AJCC 8th Edition TNM: Stage IA: T1 N0 M0 (lamina propria or muscularis mucosae/submucosa) Stage IB: T2 N0 or T1 N1 M0 Stage IIA: T3 N0, T2 N1, T1 N2 M0 Stage IIB: T4a N0, T3 N1, T2 N2, T1 N3a M0 Stage IIIA–IIIC: Various T3–T4 with N2–N3 combinations Stage IV: M1 (distant metastases — liver, peritoneum, lung, etc.) Workup: Upper endoscopy with multiple biopsies, CT chest/abdomen/pelvis, endoscopic ultrasound (EUS) for T and N staging in early-stage candidates, diagnostic laparoscopy ± peritoneal washings (for resectable disease >T1b — ~25–30% of…

Stage I–III Treatment

Endoscopic resection for early gastric cancer: Endoscopic submucosal dissection (ESD) is the standard of care in Japan/South Korea for T1a (mucosal) well-differentiated tumors <2 cm (expanded criteria include larger tumors and T1a undifferentiated tumors without ulceration in experienced hands). Western adoption is increasing. Resectable stage I–III gastric cancer: Surgery — D2 subtotal or total gastrectomy + D2 lymphadenectomy (removal of perigastric nodes AND second-tier nodes along celiac axis, left gastric, common hepatic, splenic artery) — is the cornerstone. D2 is the standard in…

Stage IV (Metastatic) Treatment

First-line therapy for metastatic gastric/GEJ adenocarcinoma has been substantially transformed by checkpoint inhibitors: HER2-positive (IHC 3+ or IHC 2+/FISH+) — ~20% of tumors: • Trastuzumab + cisplatin + 5-FU/capecitabine (ToGA trial): First biologic-based regimen to improve OS vs. chemotherapy alone (16 vs. 11.8 months for HER2 IHC 3+). • Trastuzumab + chemotherapy + pembrolizumab (KEYNOTE-811): Added pembrolizumab to trastuzumab + chemotherapy — significantly improved PFS and ORR; FDA-approved 2023 for HER2+ metastatic gastric/GEJ. HER2-negative — PD-L1 (CPS ≥5) — majority of patients:…

Second-Line Therapy

After progression on first-line platinum-fluoropyrimidine ± immunotherapy, the standard options are ramucirumab-based regimens, with HER2-directed therapy for tumors that remain HER2-positive. **Ramucirumab ± paclitaxel:** Ramucirumab (anti-VEGFR2 monoclonal antibody) is the only FDA-approved biologic for gastric/GEJ second-line therapy. REGARD demonstrated a statistically significant OS benefit with ramucirumab monotherapy vs. placebo (5.2 vs. 3.8 months; HR 0.776) — the first single agent to improve OS as second-line therapy. RAINBOW showed that ramucirumab + paclitaxel further improved OS…