Annals of Oncology

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

Du L, Yau C, Brown-Swigart L, Gould R, Krings G, Hirst GL, Bedrosian I, Layman RM, Carter JM, Klen M, Venters S, Sonal S, van der Noordaa M, Chien AJ, Haddad T, Isaacs C, Pusztai L, Albain K, Nanda R, Tripathy D, Liu MC, Boughey J, Schwab R, Hylton N, DeMichele A, Perlmutter J, Yee D, Berry D, van 't Veer L, Valero V, Esserman L, Symmans WF


•The SET2,3 assay added independent prognostic information to RCB after neoadjuvant chemotherapy.

•The SETER/PR index of endocrine transcriptional activity added to contemporary genomic signatures and assays.

•SET2,3 was prognostic within both luminal subtypes of breast cancer.

•Patients with a high SET2,3 result might be appropriate for clinical trials of neoadjuvant endocrine-based therapy.


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 (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2−) breast cancer received neoadjuvant taxane–anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. 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.


SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of 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.


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.

doi link