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

Abstract

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 (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.

RESULTS:

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.

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.

• Authors: L Du, C Yau, L Brown-Swigart, R Gould, G Krings, G L Hirst, I Bedrosian, R M Layman, J M Carter, M Klein, S Venters, S Shad, M van der Noordaa, A J Chien, T Haddad, C Isaacs, L Pusztai, K Albain, R Nanda, D Tripathy, M C Liu, J Boughey, R Schwab, N Hylton, A DeMichele, J Perlmutter, D Yee, D Berry, L Van't Veer, V Valero, L J Esserman, W F Symmans
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 32 Issue 5 Pg. 642-651 (05 2021) ISSN: 1569-8041 [Electronic] England
• PMID: 33617937 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Biomarkers, Tumor
• Hormones
• Receptors, Progesterone
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers, Tumor (genetics)
• Breast Neoplasms (drug therapy, genetics)
• Female
• Hormones (therapeutic use)
• Humans
• Neoadjuvant Therapy
• Neoplasm Recurrence, Local
• Prognosis
• Receptor, ErbB-2 (genetics)
• Receptors, Progesterone (genetics)