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

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. TripathyM. 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

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16 Scopus citations


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 (SET ER/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 SET ER/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 SET ER/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.

Original languageEnglish (US)
Pages (from-to)642-651
Number of pages10
JournalAnnals of Oncology
Issue number5
StatePublished - May 2021

Bibliographical note

Publisher Copyright:
© 2021 European Society for Medical Oncology


  • chemo-endocrine
  • hormonal
  • prediction
  • prognosis
  • response
  • treatments
  • Receptors, Progesterone/genetics
  • Prognosis
  • Humans
  • Neoplasm Recurrence, Local
  • Receptor, ErbB-2/genetics
  • Biomarkers, Tumor/genetics
  • Antineoplastic Combined Chemotherapy Protocols/therapeutic use
  • Female
  • Neoadjuvant Therapy
  • Hormones/therapeutic use
  • Breast Neoplasms/drug therapy

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Randomized Controlled Trial
  • Clinical Trial, Phase II
  • Journal Article


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