Evolution of ER+ breast cancer cells and tumors during endocrine therapy. Homo sapiens

Estrogen receptor alpha (ER)-positive breast cancers are commonly treated with endocrine therapies that suppress ER activity. When used in the adjuvant setting, endocrine therapies prevent disease recurrence, but 1/3 of patients experience recurrent disease. Therefore, drug-tolerant persister cancer cells survive endocrine therapy that can ultimately lead to cancer recurrence. We performed exome sequencing of tumor specimens from 2 patients acquired before and after several months of neoadjuvant treatment with the endocrine agent letrozole. We performed exome sequencing of MCF-7 xenografts acquired from mice at baseline (during 17b-estradiol-stimulated growth), after 90 d of 17b-estradiol withdrawal, and after tumor regrowth in the absence of exogenous 17b-estradiol. We also performed single-cell RNA sequencing of MCF-7 xenografts acquired from mice treated with 17b-estradiol withdrawal for 60 days followed by treatment +/- the OXPHOS inhibitor IACS-010759 for 8 days.