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Updated: Jan 25, 2026

Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
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HER2-Enriched Subtype and ERBB2 Expression in HER2-Positive Breast Cancer Treated with Dual HER2 Blockade

Aleix Prat1,2,3, Tomás Pascual1,2,3, Carmine De Angelis4,5

  • 1Department of Medical Oncology, Hospital Clínic de Barcelona, Spain.

Journal of the National Cancer Institute
|May 1, 2019
PubMed
Abstract

Insights

A new RNA-based assay combining HER2-enriched (HER2-E) subtype and ERBB2 levels identifies HER2-positive breast cancers highly responsive to HER2-targeted therapy, potentially enabling chemotherapy de-escalation.

Area of Science:

  • Oncology
  • Molecular Diagnostics
  • Genomics

Background:

  • HER2-positive breast cancer treatment often involves chemotherapy alongside HER2-targeted therapies.
  • Identifying patients with high sensitivity to HER2-blockade could allow for de-escalation of chemotherapy, reducing treatment toxicity.
  • Current methods for predicting response to HER2-targeted therapy can be refined.

Purpose of the Study:

  • To evaluate a novel RNA-based assay combining ERBB2 gene expression and the HER2-enriched (HER2-E) intrinsic subtype.
  • To determine if this assay can identify HER2-positive breast cancers with high sensitivity to dual HER2-blockade therapy without chemotherapy.
  • To assess the clinical utility of this assay in both early and advanced stages of HER2-positive breast cancer.

Main Methods:

  • A PAM50-based RNA assay was applied to 422 HER2-positive tumors from five clinical trials.
  • Patients received neoadjuvant dual HER2-blockade (lapatinib or pertuzumab plus trastuzumab) for early-stage disease, with pathological complete response (pCR) as the primary outcome.
  • For advanced-stage disease, patients were randomized to lapatinib alone or with trastuzumab, with progression-free survival (PFS), overall response rate (ORR), and overall survival (OS) evaluated.

Main Results:

  • The combined HER2-E/ERBB2-high subtype was identified in a significant proportion of HER2-positive tumors.
  • In early-stage disease, HER2-E/ERBB2-high tumors showed significantly higher pCR rates with dual HER2-blockade compared to other subtypes (44.5% vs 11.6% with lapatinib/trastuzumab; 66.7% vs 14.7% with pertuzumab/trastuzumab).
  • In advanced-stage disease, HER2-E/ERBB2-high tumors were independently associated with longer PFS (HR=0.52), higher ORR (16.3% vs 3.7%), and longer OS (HR=0.66).

Conclusions:

  • The combined HER2-E subtype and ERBB2 mRNA assay effectively identifies tumors with high responsiveness to HER2-targeted therapy.
  • This biomarker has the potential to guide de-escalation of chemotherapy in approximately 40% of patients with HER2-positive breast cancer.
  • The assay offers a clinically applicable tool for personalized treatment strategies in HER2-positive breast cancer.

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