A 62-year-old woman with metastatic gastric adenocarcinoma (HER2-positive by IHC 3+ and FISH-positive) presents with ascites and hepatic metastases. She is chemotherapy-naïve and has good performance status (ECOG 0). Which agent should be added to the standard chemotherapy backbone (Cisplatin + 5-Fluorouracil) to improve her survival?

Explanation

## HER2-Directed Therapy in Metastatic Gastric Cancer ### Standard of Care for HER2-Positive Disease **Key Point:** Trastuzumab (anti-HER2 monoclonal antibody) is the standard first-line agent to add to chemotherapy (Cisplatin + 5-FU or Capecitabine) in HER2-positive metastatic gastric cancer [cite:Harrison 21e Ch 297]. ### Evidence Base **High-Yield:** The ToGA trial (Trastuzumab for Gastric Cancer) demonstrated that adding trastuzumab to chemotherapy improved median overall survival from 11.1 months to 13.8 months in HER2-positive (IHC 3+ or FISH-positive) gastric and gastroesophageal junction cancers. ### HER2 Testing and Patient Selection 1. **IHC scoring:** 3+ (strong, complete membrane staining) or 2+ (with FISH confirmation). 2. **FISH:** Positive if HER2/CEP17 ratio ≥2.0 or mean HER2 copy number ≥6.0. 3. **Prevalence in gastric cancer:** ~15–20% of gastric adenocarcinomas are HER2-positive. ### Mechanism and Dosing **Clinical Pearl:** Trastuzumab is a humanized monoclonal antibody targeting the HER2 extracellular domain, inducing antibody-dependent cellular cytotoxicity (ADCC) and blocking HER2 signaling. - **Loading dose:** 8 mg/kg IV over 90 minutes. - **Maintenance:** 6 mg/kg IV every 3 weeks (with chemotherapy cycles). - **Cardiac monitoring:** Baseline and periodic echocardiography or MUGA scan to assess LVEF (risk of cardiomyopathy). ### Comparison with Other Targeted Agents | Agent | Target | Indication | Rationale for Use/Non-Use | |-------|--------|-----------|---------------------------| | **Trastuzumab** | HER2 | HER2-positive metastatic GC | **First-line for HER2+ disease**; improves OS by ~2.7 months | | **Bevacizumab** | VEGF | Unselected metastatic GC | Second-line or in VEGF-high tumors; not HER2-dependent | | **Ramucirumab** | VEGFR2 | Second-line metastatic GC | Used after first-line failure; not first-line for HER2+ | | **Pembrolizumab** | PD-1 | MSI-H or PD-L1+ GC | Emerging role; not standard first-line for HER2+ disease | ### Why Trastuzumab in This Case? 1. **HER2-positive disease:** IHC 3+ and FISH-positive confirms HER2 overexpression. 2. **Proven survival benefit:** ToGA trial established ~2.7-month OS improvement. 3. **Synergy with chemotherapy:** Trastuzumab + Cisplatin/5-FU is the standard backbone. 4. **First-line indication:** Should be given upfront in HER2-positive metastatic disease, not reserved for later lines. **Mnemonic:** **ToGA = Trastuzumab + Gastric cancer** — the landmark trial that established HER2-directed therapy in gastric cancer.