Phenotypic changes of HER2-positive breast cancer during and after dual HER2 blockade
Fara Brasó‐Maristany, Gaia Griguolo, Tomás Pascual, Laia Paré, Paolo Nucíforo, Antonio Llombart‐Cussac, Begoña Bermejo, Mafalda Oliveira, Serafín Morales, Noelia Martínez-Jáñez, María Vidal, Bárbara Adamo, Olga Martínez‐Sáez, Sònia Pernas, Rafael López‐López, Montserrat Muñoz-Mateu, Núria Chic, Patricia Galván, Isabel Garau, Luís Manso, Jesús Alarcón, Eduardo Martínez de Dueñas, Sara Gregorio, Roger R. Gomis, Patricia Villagrasa, Javier Cortés, Eva Ciruelos, Aleix Prat
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.