Anastrozole has an association between degree of estrogen suppression and outcomes in early breast cancer and is a ligand for estrogen receptor

James N. Ingle, Junmei Cairns, Vera J. Suman, Lois E. Shepherd, Peter A. Fasching, Tanya L. Hoskin, Ravinder J. Singh, Zeruesenay Desta, Krishna R. Kalari, Matthew J. Ellis, Paul E. Goss, Bingshu E. Chen, Bernhard Volz, Poulami Barman, Erin E. Carlson, Tufia Haddad, Matthew P. Goetz, Barbara Goodnature, Matthew E. Cuellar, Michael A. WaltersCristina Correia, Scott H. Kaufmann, Richard M. Weinshilboum, Liewei Wang

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Purpose: To determine if the degree of estrogen suppression with aromatase inhibitors (AI: anastrozole, exemestane, letrozole) is associated with efficacy in early-stage breast cancer, and to examine for differences in the mechanism of action between the three AIs. Experimental Design: Matched case-control studies [247 matched sets from MA.27 (anastrozole vs. exemestane) and PreFace (letrozole) trials] were undertaken to assess whether estrone (E1) or estradiol (E2) concentrations after 6 months of adjuvant therapy were associated with risk of an early breast cancer event (EBCE). Preclinical laboratory studies included luciferase activity, cell proliferation, radio-labeled ligand estrogen receptor binding, surface plasmon resonance ligand receptor binding, and nuclear magnetic resonance assays. Results: Women with E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL after 6 months of AI treatment had a 2.2-fold increase in risk (P ¼ 0.0005) of an EBCE, and in the anastrozole subgroup, the increase in risk of an EBCE was 3.0-fold (P ¼ 0.001). Preclinical laboratory studies examined mechanisms of action in addition to aromatase inhibition and showed that only anastrozole could directly bind to estrogen receptor a (ERa), activate estrogen response element-dependent transcription, and stimulate growth of an aromatase-deficient CYP19A1-/- T47D breast cancer cell line. Conclusions: This matched case-control clinical study revealed that levels of estrone and estradiol above identified thresholds after 6 months of adjuvant anastrozole treatment were associated with increased risk of an EBCE. Preclinical laboratory studies revealed that anastrozole, but not exemestane or letrozole, is a ligand for ERa. These findings represent potential steps towards individualized anastrozole therapy.

Original languageEnglish (US)
Pages (from-to)2986-2996
Number of pages11
JournalClinical Cancer Research
Volume26
Issue number12
DOIs
StatePublished - Jun 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Ingle, J. N., Cairns, J., Suman, V. J., Shepherd, L. E., Fasching, P. A., Hoskin, T. L., Singh, R. J., Desta, Z., Kalari, K. R., Ellis, M. J., Goss, P. E., Chen, B. E., Volz, B., Barman, P., Carlson, E. E., Haddad, T., Goetz, M. P., Goodnature, B., Cuellar, M. E., ... Wang, L. (2020). Anastrozole has an association between degree of estrogen suppression and outcomes in early breast cancer and is a ligand for estrogen receptor. Clinical Cancer Research, 26(12), 2986-2996. https://doi.org/10.1158/1078-0432.CCR-19-3091