Anastrozole has an Association between Degree of Estrogen Suppression and Outcomes in Early Breast Cancer and is a Ligand for Estrogen Receptor α.

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 = 0.0005) of an EBCE, and in the anastrozole subgroup, the increase in risk of an EBCE was 3.0-fold (P = 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 α (ERα), 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 ERα. These findings represent potential steps towards individualized anastrozole therapy.

• Authors: 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 Walters, Cristina Correia, Scott H Kaufmann, Richard M Weinshilboum, Liewei Wang
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 12 Pg. 2986-2996 (06 15 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 32098767 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents, Hormonal
• ESR1 protein, human
• Estrogen Receptor alpha
• Estrogens
• Anastrozole

Topics

• Adult
• Aged
• Aged, 80 and over
• Anastrozole (therapeutic use)
• Antineoplastic Agents, Hormonal (therapeutic use)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Case-Control Studies
• Clinical Trials, Phase III as Topic
• Clinical Trials, Phase IV as Topic
• Estrogen Receptor alpha (metabolism)
• Estrogens (metabolism)
• Female
• Follow-Up Studies
• Humans
• Middle Aged
• Multicenter Studies as Topic
• Prognosis
• Prospective Studies
• Randomized Controlled Trials as Topic