Predicted sensitivity to endocrine therapy for stage II-III hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer prior to chemo-endocrine therapy.

BACKGROUND We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with Stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA). PATIENTS AND METHODS Patients with clinically high-risk, hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in a MDACC cohort (N=307, 11 years follow-up, U133A microarrays), cut-point was determined, then independent, blinded evaluation in the I-SPY2 trial (N=268, high-risk MammaPrint result, 3.8 years follow-up, Agilent-44K microarrays). Primary outcome measure was distant relapse-free survival (DRFS). Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3. RESULTS SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 (HR 0.23, P=0.004); RCB (HR 1.77, p<0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P=0.031); RCB (HR 1.68, P=0.008). SET2,3 provided similar prognostic information whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC p<0.001, I-SPY2 p<0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index. CONCLUSIONS SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.