Copy number heterogeneity identifies ER+ breast cancer patients with adverse outcome after adjuvant endocrine therapy

Background − Endocrine therapy forms the backbone of adjuvant treatment for estrogen-receptor positive (ER+) breast cancer. However, it remains unclear whether adjuvant treatment improves survival rates in low-risk patients . Low intra-tumor heterogeneity (ITH) has been shown to confer low-risk for recurrent disease. Here, it is studied if chromosomal copy number ITH (CNH) can identify low-risk ER+, lymph node-negative breast cancers patients who do not benefit from adjuvant endocrine therapy. Methods − Lymph node-negative ER+ patients from the METABRIC dataset were retrospectively analyzed (n=708). CNH was determined from a single bulk copy number measurement for each patient. Patients were stratified by CNH score as low, medium or high. Overall survival (OS) was compared between patients that did, or did not receive adjuvant endocrine therapy per CNH group with Cox proportional-hazards models, using propensity score weights to correct for confounders. Results − Adjuvant endocrine therapy improved the relapse free survival (RFS) for high-CNH/high-risk patients treatment (Hazard Ratio [HR] = 0.55, 95% Confidence Interval [CI] = 0.35 to 0.87), but not for low CNH/risk patients treatment (HR = 0.88, 95% CI = 0.50 to 1.55). For low-CNH/low-risk patients adjuvant endocrine therapy was associated with impaired OS (HR = 1.62, 95% CI = 1.10 to 2.40). Multivariable Cox analysis identified a significant interaction between CNH and endocrine therapy for OS (HR = 0.77, 95% CI = 0.62 to 0.96). Conclusions − This retrospective study of lymph node-negative, ER+ breast cancer finds that patients identified as low-risk using CNH display reduced OS when treated with adjuvant endocrine therapy.