Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer.

Abstract

Tumor evolution is shaped by many variables, potentially involving external selective pressures induced by therapies1. After surgery, estrogen receptor (ERα) positive breast cancer (BCa) patients are treated with adjuvant endocrine therapy2 including selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs)3. However, over 20% of patients relapse within 10 years and eventually progress to incurable metastatic disease4. Here we demonstrate that the choice of therapy has a fundamental influence on the genetic landscape of relapsed diseases: in this study, 21.5% of AI-treated, relapsed patients had acquired CYP19A1 gene (aromatase) amplification (CYP19A1amp). Relapsed patients also developed numerous mutations targeting key breast cancer genes including ESR1 and CYP19A1. Strikingly, CYP19A1amp cells also emerge in vitro but only in AI resistant models. CYP19A1 amplification causes increased aromatase activity and estrogen-independent ERα binding to target genes resulting in CYP19A1amp cells displaying decreased sensitivity to AI treatment. Collectively these data suggest that AI treatment itself selects for acquired CYP19A1 amplification and promotes local autocrine estrogen signalling in AI resistant metastatic patients.