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?

Question

Accepted Answer

D. 5-Fluorouracil + Cisplatin + Trastuzumab. ## 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.

Answer

A. Ramucirumab monotherapy

Answer

B. Pembrolizumab monotherapy

Answer

C. Capecitabine alone

Explanation

First-Line Palliative Therapy for HER2-Positive Metastatic Gastric Cancer

Standard Approach

ToGA Trial Evidence

Mechanism of Action

Clinical Application

Why Trastuzumab Matters

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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