# HER2-positive gastric cancer

Source: https://onco.cc/cancers/gastric-her2-positive/  
OnCo record `gastric-her2-positive` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

HER2-positive gastric cancer overexpresses the HER2 growth receptor and is treated with trastuzumab added to chemotherapy, now usually with pembrolizumab as well. After progression the antibody-drug conjugate trastuzumab deruxtecan gives responses that plain chemotherapy cannot.

## Summary

HER2 positivity is defined in stomach cancer as immunohistochemistry 3+ or 2+ with amplification on in situ hybridisation, and every advanced gastric or junctional adenocarcinoma is tested at diagnosis. HER2-positive tumours are more often intestinal type and sit more often at the junction than in the distal stomach; staining is heterogeneous, so biopsies from several sites are recommended and a negative result on a small sample can be wrong.

ToGA (Lancet 2010) added trastuzumab to cisplatin and a fluoropyrimidine and extended median overall survival from 11.1 to 13.8 months, and to 16.0 months in patients with strong HER2 expression; it made trastuzumab the first targeted therapy in stomach cancer. KEYNOTE-811 then added pembrolizumab to trastuzumab and chemotherapy, raising response rates and improving survival in PD-L1-positive tumours, so the triplet is now first-line standard where PD-L1 is expressed. Zanidatamab, a bispecific HER2 antibody, is being tested against trastuzumab in the same setting in HERIZON-GEA-01.

DESTINY-Gastric01 (NEJM 2020) showed that trastuzumab deruxtecan, an antibody-drug conjugate carrying a topoisomerase inhibitor payload, produced responses in 51 percent of previously treated patients against 14 percent with chemotherapy and improved median survival from 8.4 to 12.5 months, earning FDA approval in 2021. DESTINY-Gastric04 confirmed the benefit in the second line against ramucirumab and paclitaxel, with median survival of 14.7 against 11.4 months. Interstitial lung disease is the toxicity that needs watching. HER2 expression is often lost after trastuzumab, so a fresh biopsy before second-line HER2 therapy is advised.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: HER2-positive gastro-oesophageal adenocarcinoma; ERBB2-amplified gastric cancer; HER2+ GEA
- Tags: subtype-page
- Group: gastrointestinal
- Burden: About one in six advanced gastric and junctional adenocarcinomas, commoner in intestinal-type and junctional tumours than in diffuse-type disease; it was the first molecular subgroup of stomach cancer to get its own treatment.
- Subtypes: HER2 3+ by immunohistochemistry; HER2 2+ with amplification on in situ hybridisation; HER2-positive, PD-L1 CPS 1 or above (trastuzumab, pembrolizumab and chemotherapy); HER2-positive junctional adenocarcinoma; HER2 loss after trastuzumab
- Biomarkers: HER2 by immunohistochemistry and in situ hybridisation (multiple biopsy sites); PD-L1 combined positive score (decides pembrolizumab in first line); HER2 status on repeat biopsy at progression; ERBB2 amplification on plasma ctDNA (trials)

## Standard of care

- Advanced, first line: Trastuzumab with a platinum and a fluoropyrimidine (ToGA), plus pembrolizumab when PD-L1 CPS is 1 or above (KEYNOTE-811). ([ToGA](https://onco.cc/trials/toga/), [Trastuzumab](https://onco.cc/drugs/trastuzumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Oxaliplatin](https://onco.cc/drugs/oxaliplatin/), [Capecitabine](https://onco.cc/drugs/capecitabine/), [Fluorouracil (5-FU)](https://onco.cc/drugs/fluorouracil/), [HER2](https://onco.cc/targets/her2/), [HER2 sequence in gastric cancer: zanidatamab/trastuzumab + chemo ± PD-1 → T-DXd](https://onco.cc/pairings/her2-gastric-sequence/))
- Second line: Trastuzumab deruxtecan (DESTINY-Gastric01 and DESTINY-Gastric04); ramucirumab with paclitaxel where the conjugate is unavailable. ([Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [DESTINY-Gastric04](https://onco.cc/trials/destiny-gastric04/), [Ramucirumab](https://onco.cc/drugs/ramucirumab/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/))
- Later lines: Trifluridine-tipiracil; trials of zanidatamab and other HER2 agents. ([Trifluridine/tipiracil](https://onco.cc/drugs/trifluridine-tipiracil/), [Zanidatamab](https://onco.cc/drugs/zanidatamab/), [HERIZON-GEA-01](https://onco.cc/trials/herizon-gea-01/))
- Localised disease: Perioperative FLOT and gastrectomy as for HER2-negative disease; adding HER2 therapy before surgery is unproven. ([FLOT (5-FU, leucovorin, oxaliplatin, docetaxel)](https://onco.cc/drugs/flot/), [Gastrectomy](https://onco.cc/terms/gastrectomy/))

## State of the art

- ToGA made HER2 the first biomarker in stomach cancer and trastuzumab-chemotherapy the standard first line for fifteen years.
- Trastuzumab deruxtecan gives a second HER2-directed line with a real survival gain, unlike lapatinib and trastuzumab emtansine before it.
- Pembrolizumab added to trastuzumab and chemotherapy is now the first-line triplet in PD-L1-positive tumours.

## Open problems

- HER2 heterogeneity and loss after treatment make a single biopsy unreliable.
- No HER2-directed therapy has yet improved cure rates in resectable disease.
- Interstitial lung disease with trastuzumab deruxtecan needs early recognition.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Stomach_cancer
- ToGA (Lancet 2010): https://pubmed.ncbi.nlm.nih.gov/20728210/
- DESTINY-Gastric01 (NEJM 2020): https://www.nejm.org/doi/full/10.1056/NEJMoa2004413
- Wikipedia: https://en.wikipedia.org/wiki/Stomach_cancer

## Connected records

- trials: [DESTINY-Gastric04](https://onco.cc/trials/destiny-gastric04/), [HERIZON-GEA-01](https://onco.cc/trials/herizon-gea-01/), [ToGA](https://onco.cc/trials/toga/)
- drugs: [Capecitabine](https://onco.cc/drugs/capecitabine/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Disitamab vedotin](https://onco.cc/drugs/disitamab-vedotin/), [FLOT (5-FU, leucovorin, oxaliplatin, docetaxel)](https://onco.cc/drugs/flot/), [Fluorouracil (5-FU)](https://onco.cc/drugs/fluorouracil/), [Oxaliplatin](https://onco.cc/drugs/oxaliplatin/), [Paclitaxel / nab-paclitaxel](https://onco.cc/drugs/paclitaxel/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Ramucirumab](https://onco.cc/drugs/ramucirumab/), [Trastuzumab](https://onco.cc/drugs/trastuzumab/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [Trifluridine/tipiracil](https://onco.cc/drugs/trifluridine-tipiracil/), [Zanidatamab](https://onco.cc/drugs/zanidatamab/)
- pairings: [HER2 sequence in gastric cancer: zanidatamab/trastuzumab + chemo ± PD-1 → T-DXd](https://onco.cc/pairings/her2-gastric-sequence/)
- targets: [HER2](https://onco.cc/targets/her2/)
- terms: [Gastrectomy](https://onco.cc/terms/gastrectomy/)
- cancers: [Gastric & gastro-oesophageal junction cancer](https://onco.cc/cancers/gastric/)

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