Journal Article

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

Pascual, Tomás, Galván, Patricia, Pernas, Sonia, Paré, Laia, Gomis, Roger R., Adamo, Barbara, Griguolo, Gaia, Nuciforo, Paolo, Brasó-Maristany, Fara, Garau, Isabel, Prat, Aleix, Morales, Serafín, López, Rafael, Martínez, Olga, Cortés, Javier, Manso, Luis, Bermejo, Begoña, Chic, Núria, Oliveira, Mafalda, Alarcón, Jesús, Muñoz, Montserrat, Gregorio, Sara, Ciruelos, Eva, Martínez, Eduardo, Vidal, Maria, Llombart-Cussac, Antonio, Martínez, Noelia, Villagrasa, Patricia

2020

Overview

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. HER2-enriched breast cancers within the HER2-positive subtype are addicted to the HER2 pathway. Here, the authors analyse gene expression before, during, and after treatment with anti-HER2-based therapies in the phase II PAMELA clinical trial, finding phenotypic changes induced by treatment.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38 / 38/39 / 45/90 / 631/208/199 / 631/67/1347 / 692/4028 / 82/51 / 96/1 / 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 cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - immunology / Breast Neoplasms - pathology / Cell Line, Tumor / Cell Survival - drug effects / Cyclin-dependent kinase 4 / Drug Resistance, Neoplasm - drug effects / ErbB-2 protein / Female / Gene expression / Gene Expression Profiling / Genotype & phenotype / Humanities and Social Sciences / Humans / Inhibitor drugs / Lapatinib - pharmacology / Lapatinib - therapeutic use / Monoclonal antibodies / multidisciplinary / Neoadjuvant Therapy - methods / Phenotypes / Receptor, ErbB-2 - antagonists & inhibitors / Receptor, ErbB-2 - immunology / Receptor, ErbB-2 - metabolism / Restoration / Science / Science (multidisciplinary) / Targeted cancer therapy / Therapy / Trastuzumab / Trastuzumab - pharmacology / Trastuzumab - therapeutic use / Treatment Outcome / Tumor cell lines / Tumors