Tumor evolution is shaped by many variables, potentially involving external selective pressures induced by therapies1. After surgery, patients with estrogen receptor (ERα)-positive breast cancer are treated with adjuvant endocrine therapy2, including selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs)3. However, more than 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. We found that 21.5% of AI-treated, relapsed patients had acquired CYP19A1 (encoding aromatase) amplification (CYP19A1amp). Relapsed patients also developed numerous mutations targeting key breast cancer–associated genes, including ESR1 and CYP19A1. Notably, CYP19A1amp cells also emerged in vitro, but only in AI-resistant models. CYP19A1 amplification caused increased aromatase activity and estrogen-independent ERα binding to target genes, resulting in CYP19A1amp cells showing decreased sensitivity to AI treatment. These data suggest that AI treatment itself selects for acquired CYP19A1amp and promotes local autocrine estrogen signaling in AI-resistant metastatic patients.
Gene Expression Omnibus
We thank all participants and their families. We thank A. Bardelli for his comments. We thank D. Patten for help with the exemestane study. We thank L. Watson for her help with the manuscript. We thank J.Bean for support. For these studies, S.M. and G.P. were supported by Associazione Italiana Ricerca sul Cancro (AIRC) (5x1000 campaign). L.M. was supported by the Imperial College Junior Research Fellowship. S.-P.H. was supported by Cancer Research UK (CRUK) grant C37/A18784. Y.P. was supported by CRUK PhD studentship P55374. G.C. was supported by the EpiPredict project (European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement 642691).
Integrated supplementary information
Probe lists for mutational profiling using Ion Torrent technology BEDFILE containing the genomic coordinates of the probes used for the AmpliSeq custom panel.
Ion Torrent called mutations in patients treated with tamoxifen Report summaries for each patient treated with single adjuvant tamoxifen were generated using Ion Reporter (https://ionreporter.thermofisher.com/ir/). Each tab contains the results from paired analyses (normal-metastasis). Labeling of each patient is concordant with the labeling from the main text.
Ion Torrent called mutations in patients treated with aromatase inhibitors Report summaries for each patient treated with single adjuvant aromatase inhibitors were generated using Ion Reporter (https://ionreporter.thermofisher.com/ir/). Each tab contains the results from paired analyses (normal-metastasis). Labeling of each patient is concordant with the labeling in the main text.