trastuzumab

Overview

Humanized monoclonal antibody targeting ERBB2 (HER2).

Evidence in the corpus

  • One female germ cell tumor with ERBB2 amplification was treated with trastuzumab through the Make-an-IMPACT rare-cancer program; no durable response was observed PMID:36862133.
  • Pembrolizumab + trastuzumab + capecitabine + oxaliplatin (PTC) in HER2-positive metastatic esophagogastric cancer (phase II, n=37): median PFS 13 months, median OS 27 months, ORR 89%; uniform HER2 IHC 3+ predicts longer PFS vs heterogeneous/2+ (15 vs 8.5 months, P=0.004) PMID:37406106.
  • In endometrial carcinoma, ERBB2 amplification enriched in Black patients (12% vs 3%) represents a therapeutic target for trastuzumab and trastuzumab deruxtecan PMID:37651310.
  • In preclinical HER2+ xenograft models (OE19 esophageal, NCI-N87 gastric), trastuzumab alone had no significant radiosensitizing effect; it was used as antibody-only control showing that ERBB2 binding without cytotoxic payload does not alter radiation response PMID:27698471.
  • T-DM1 was more potent than trastuzumab, paclitaxel, cisplatin, lapatinib, or erlotinib in HER2+ OE19 cells at sub-nanomolar IC50 (<1 nM vs >100 nM in HER2− lines) PMID:27698471.
  • In the AURORA US Metastasis Project (n=55 metastatic breast cancer), one participant (AFE4) exhibited loss of ERBB2 amplification under trastuzumab selective pressure — the HER2 amplification present at primary diagnosis was absent in the metastatic biopsy, representing a genomic resistance event to HER2-targeted therapy PMID:36585450
  • 10 metastatic gallbladder carcinoma patients received trastuzumab-based regimens targeting ERBB2 amplification/mutation (OncoKB level 3B); ERBB2 amplification present in 10% and GOF mutations in 6% of 244 GBC samples profiled with MSK-IMPACT PMID:36228155
  • METABRIC identified ERBB2-amplified IntClust5 subtype (~15% of tumors) as the primary trastuzumab-relevant subgroup in breast cancer PMID:22522925
  • ERBB2 amplification at 17q21.1 identified in 4% of colorectal carcinomas (TCGA, n=276); trastuzumab cited as a potential therapeutic based on precedent in ERBB2-amplified breast and gastric cancers PMID:22810696
  • ERBB2 amplification in HER2-enriched breast cancer subtype identified as therapeutic target for trastuzumab in TCGA comprehensive analysis PMID:23000897
  • Trastuzumab is the only approved targeted agent for EAC/GEJ adenocarcinoma at time of Dulak 2013 study; ERBB2 kinase-domain mutations (p.D769Y, p.G776V; 5/145 tumors) and co-occurring ERBB2 amplification+mutation in 3% of EAC samples justify exploring ERBB2 mutation as an additional biomarker for HER2-directed therapy PMID:23525077
  • ERBB2 focal amplification with protein overexpression in 25% of uterine serous/serous-like endometrial tumors supports prospective trials of HER2-targeted therapy; a prior small trastuzumab trial accrued few FISH-amplified serous cases and was underpowered PMID:23636398
  • Cited among ERBB-targeting agents in the list of 31 potentially actionable alterations in HCC; ERBB family members represent candidate therapeutic targets identified in the HCC genomic landscape PMID:24735922
  • ERBB2-altered CCA: MyPathway phase IIa basket ORR 23% in combination with pertuzumab; ERBB2 amplification/overexpression in 4–6% iCCA and 3–20% eCCA PMID:25526346
  • Standard targeted therapy for ERBB2-amplified/mutated gastric adenocarcinoma (STAD); defines a candidate biomarker-selected population; NRG1 and ERBB4 mutations (11.6% of GC) define a potentially targetable subset beyond the <15% ERBB2-positive GC patients eligible for trastuzumab PMID:25583476
  • Comprehensive TCGA molecular profiling of 164 oesophageal carcinomas shows ERBB2 alteration in 32% of oesophageal adenocarcinomas (EAC); the authors note ERBB2-positive EACs are routinely treated off-label with trastuzumab and that ERBB2-mutant (non-amplified) EAC patients may also benefit; functional consequence of the EAC-specific ERBB2-JUP fusion transcript (lacking transmembrane/kinase domains) on trastuzumab response remains unresolved PMID:28052061
  • RPPA HER2-high clusters 1 and 2 (elevated ERBB2 protein) in MIBC are candidates for trastuzumab or ado-trastuzumab-emtansine; ERBB2 is mutated in 12% and recurrently amplified in the TCGA 412-tumor MIBC cohort PMID:28988769
  • In a 295-patient metastatic EGC cohort (MSK-IMPACT), ERBB2 amplification level by NGS predicted trastuzumab PFS (top-quartile patients: median PFS 24.3 months); 16% of post-trastuzumab samples showed ERBB2 amplification loss; RTK-RAS-PI3K co-alterations independently shortened trastuzumab PFS in multivariate analysis PMID:29122777
  • Cited as context for HER2-targeted therapy in SUMMIT; ERBB2-amplified breast cancer (trastuzumab-indicated) differs from ERBB2-mutant (non-amplified) disease targeted by neratinib — 95% of HER2 mutations in SUMMIT were clonal and 17% co-occurred with amplification, but amplification did not correlate with additional clinical benefit from neratinib PMID:29420467
  • In the TCGA pan-cancer fusion atlas (n=9,624), four ERBB2 fusions were identified (partners PPP1R1B and IKZF3, genomic neighbors at 17q; 3 of 4 had HPV integration within 1 Mb of ERBB2), representing a fusion-driven mechanism of HER2 dysregulation distinct from — but potentially complementary to — the trastuzumab-targetable amplification in BRCA PMID:29617662

Resistance mechanisms

  • Lineage/context in ovarian germ cell tumor appears unfavorable for trastuzumab response in ERBB2-amplified disease PMID:36862133.
  • Loss of HER2 expression was a major resistance mechanism in 48% of progressing EGC patients on pembrolizumab+trastuzumab regimen; acquired KRAS, PIK3CA, and MET alterations also conferred resistance PMID:37406106.
  • Loss of ERBB2 amplification at the metastatic site observed in one AURORA US participant (AFE4), implicating clonal selection under trastuzumab pressure as a genomic resistance mechanism in metastatic breast cancer PMID:36585450.

Cancer types (linked)

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:36228155

This page was processed by crosslinker on 2026-05-14. - PMID:22522925

This page was processed by crosslinker on 2026-05-14. - PMID:22810696

This page was processed by crosslinker on 2026-05-14. - PMID:23000897

This page was processed by crosslinker on 2026-05-14. - PMID:23525077

This page was processed by crosslinker on 2026-05-14. - PMID:23636398

This page was processed by crosslinker on 2026-05-14. - PMID:24735922

This page was processed by crosslinker on 2026-05-14. - PMID:25526346

This page was processed by crosslinker on 2026-05-14. - PMID:25583476

This page was processed by crosslinker on 2026-05-14. - PMID:28052061 — TCGA oesophageal carcinoma comprehensive molecular characterization; ERBB2 altered in 32% of EAC; trastuzumab used off-label in ERBB2+ EAC; ERBB2-JUP fusion in 6 amplified EACs with unknown functional significance for trastuzumab response.

*This page was processed by entity-page-writer on 2026-05-15. - PMID:28988769

This page was processed by wiki-cli on 2026-05-15. - PMID:29122777

This page was processed by wiki-cli on 2026-05-15. - PMID:29420467 - PMID:29617662 — Gao et al. 2018, Cell Reports. TCGA pan-cancer fusion atlas (n=9,624); four ERBB2 fusions identified with PPP1R1B/IKZF3 partners, likely arising from HPV-driven local instability; contextualized against trastuzumab-targetable ERBB2 amplification.

This page was processed by entity-page-writer on 2026-05-15.