Genetic and phenotypic evolution of breast cancer through years of treatment

Acquired drug resistance is a frequent challenge in breast cancer. A tumor may initially respond to chemotherapy, but later become resistant and relapse. This is largely due to intra-tumoral heterogeneity; tumor genetic subclones with higher fitness in response to chemotherapy survive, and the patient’s cancer becomes drug-resistant. In additional, non-genetic phenotypic alterations in response to chemotherapy may promote drug resistance. How breast cancers evolve to become drug-resistant is unclear. A better understanding of how this occurs could lead to alternative therapeutic regimens to treat drug-resistant breast cancer or prevent its development. To address this problem, we performed genomic and phenotypic analysis of four breast cancers through 2 to 15 years of diverse treatments, using a unique set of longitudinal samples from these patients. This revealed genetic events likely leading to drug resistance, including acquisition of BRCA2 reversions and ABCB1 fusions. Further, cancer phenotypes evolved dramatically after treatment, including increased post-treatment mesenchymal, receptor tyrosine kinase, and immune avoidance gene expression profiles. In one patient, treatment of cultured patient cells with drugs targeting the receptor tyrosine kinase phenotype was more effective in post-treatment, receptor tyrosine kinase-high cells compared to the pre-treatment cells. Thus, we have identified both mutations and phenotypes that may promote breast cancer drug resistance, some of which may be targeted to treat drug-resistant cancers.