Development and validation of multivariate predictors of primary endocrine resistance to tamoxifen and aromatase inhibitors in luminal breast cancer reveal drug-specific differences

In the WSG-ADAPT trial (NCT01779206), HR+/HER2-EBC patients underwent pre-operative short-term endocrine therapy (pET). Treatment response was determined by immunohistochemical in-situ labeling of cycling cells (G1 to M-phase) with Ki67 before and after pET. We performed targeted next generation sequencing and Infinium MethylationEPIC-based DNA methylation analysis post-pET in a discovery cohort (n=364, responder (R) and non-responder (NR) pairs matched for clinicopathologic features) and a validation cohort (n=270, unmatched). Predictive indices of endocrine resistance under both treatments were constructed using lasso penalized logistic regression. DNA was submitted for DNA methylation analysis using HumanMethylationEPIC (EPIC) BeadChips (Illumina, CA, USA), including an additional restore step for FFPE material.