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Old 05-03-2021, 08:01 AM   #1
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Phenotypic changes of HER2-positive breast cancerduring and after dual HER2 blockade

Phenotypic changes of HER2-positive breast cancerduring and after dual HER2 blockade


The HER2-enriched (HER2-E) subtype within HER2-positive (HER2+) breast cancer is highlyaddicted to the HER2 pathway. However,∼20–60% of HER2+/HER2-E tumors do notachieve a complete response following anti-HER2 therapies. Here we evaluate geneexpression data before, during and after neoadjuvant treatment with lapatinib and trastu-zumab in HER2+/HER2-E tumors of the PAMELA trial and breast cancer cell lines. Ourresults reveal that dual HER2 blockade in HER2-E disease induces a low-proliferative LuminalA phenotype both in patient’s tumors and in vitro models. These biological changes are moreevident in hormone receptor-positive (HR+) disease compared to HR-negative disease.Interestingly, increasing the luminal phenotype with anti-HER2 therapy increased sensitivityto CDK4/6 inhibition. Finally, discontinuation of HER2-targeted therapy in vitro, or acquiredresistance to anti-HER2 therapy, leads to restoration of the original HER2-E phenotype. Ourfindings support the use of maintenance anti-HER2 therapy and the therapeutic exploitationof subtype switching with CDK4/6 inhibition
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