A 62-year-old woman is found to have metastatic gastric adenocarcinoma with HER2 overexpression (IHC 3+, FISH-positive) involving the liver and peritoneum. She is deemed unfit for surgery. What is the drug of choice for first-line palliative chemotherapy in this HER2-positive metastatic gastric cancer?

Explanation

## First-Line Palliative Therapy for HER2-Positive Metastatic Gastric Cancer ### Standard Approach **Key Point:** Trastuzumab combined with chemotherapy (5-FU + Cisplatin) is the gold-standard first-line treatment for HER2-positive metastatic gastric cancer, based on the landmark ToGA trial. ### ToGA Trial Evidence **High-Yield:** The ToGA trial (2010) demonstrated that adding trastuzumab to chemotherapy (5-FU/cisplatin) improved median overall survival from 11.1 to 13.8 months in HER2-positive gastric cancer. This was the first targeted therapy to show survival benefit in gastric cancer. ### Mechanism of Action | Drug | Mechanism | Role | |------|-----------|------| | **5-Fluorouracil** | Antimetabolite; inhibits thymidylate synthase | Backbone chemotherapy | | **Cisplatin** | Alkylating agent; DNA cross-linking | Synergistic with 5-FU | | **Trastuzumab** | Anti-HER2 monoclonal antibody; blocks HER2 signaling | Targeted therapy; improves survival | ### Clinical Application **Key Point:** HER2 testing (IHC and/or FISH) is mandatory before initiating trastuzumab. Only IHC 3+ or FISH-positive tumors benefit. **Clinical Pearl:** Trastuzumab is NEVER used as monotherapy in gastric cancer—it must always be combined with chemotherapy. The combination is continued until progression or intolerable toxicity. **Mnemonic:** **HER2 + Gastric = ToGA** (Trastuzumab + chemotherapy in gastric adenocarcinoma) ### Why Trastuzumab Matters - Blocks HER2 receptor signaling and antibody-dependent cell-mediated cytotoxicity (ADCC) - Improves response rate and prolongs progression-free survival - Well-tolerated; main concern is cardiotoxicity (baseline echocardiography required) - Cost-effective in resource-limited settings when HER2+ confirmed **Warning:** Ramucirumab (VEGFR2 inhibitor) is reserved for second-line therapy after chemotherapy failure. Pembrolizumab (PD-L1 inhibitor) is used in microsatellite-instability-high (MSI-H) or PD-L1-positive tumors, not as first-line in HER2+ disease.