Phenotypic changes of HER2-positive breast cancer during and after dual HER2 blockade

Nat Commun. 2020 Jan 20;11(1):385. doi: 10.1038/s41467-019-14111-3.

Abstract

The HER2-enriched (HER2-E) subtype within HER2-positive (HER2+) breast cancer is highly addicted to the HER2 pathway. However, ∼20-60% of HER2+/HER2-E tumors do not achieve a complete response following anti-HER2 therapies. Here we evaluate gene expression data before, during and after neoadjuvant treatment with lapatinib and trastuzumab in HER2+/HER2-E tumors of the PAMELA trial and breast cancer cell lines. Our results reveal that dual HER2 blockade in HER2-E disease induces a low-proliferative Luminal A phenotype both in patient's tumors and in vitro models. These biological changes are more evident in hormone receptor-positive (HR+) disease compared to HR-negative disease. Interestingly, increasing the luminal phenotype with anti-HER2 therapy increased sensitivity to CDK4/6 inhibition. Finally, discontinuation of HER2-targeted therapy in vitro, or acquired resistance to anti-HER2 therapy, leads to restoration of the original HER2-E phenotype. Our findings support the use of maintenance anti-HER2 therapy and the therapeutic exploitation of subtype switching with CDK4/6 inhibition.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antineoplastic Agents, Immunological / pharmacology*
  • Antineoplastic Agents, Immunological / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor / antagonists & inhibitors
  • Biomarkers, Tumor / immunology
  • Biomarkers, Tumor / metabolism*
  • Biopsy
  • Breast / drug effects
  • Breast / pathology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / immunology
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Gene Expression Profiling
  • Humans
  • Lapatinib / pharmacology
  • Lapatinib / therapeutic use
  • Neoadjuvant Therapy / methods
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / immunology
  • Receptor, ErbB-2 / metabolism*
  • Trastuzumab / pharmacology
  • Trastuzumab / therapeutic use
  • Treatment Outcome

Substances

  • Antineoplastic Agents, Immunological
  • Biomarkers, Tumor
  • Lapatinib
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Trastuzumab