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

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.

• Authors: Fara Brasó-Maristany, Gaia Griguolo, Tomás Pascual, Laia Paré, Paolo Nuciforo, Antonio Llombart-Cussac, Begoña Bermejo, Mafalda Oliveira, Serafín Morales, Noelia Martínez, Maria Vidal, Barbara Adamo, Olga Martínez, Sonia Pernas, Rafael López, Montserrat Muñoz, Núria Chic, Patricia Galván, Isabel Garau, Luis Manso, Jesús Alarcón, Eduardo Martínez, Sara Gregorio, Roger R Gomis, Patricia Villagrasa, Javier Cortés, Eva Ciruelos, Aleix Prat
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 385 (01 20 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 31959756 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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