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.
Bibliographical noteFunding Information:
1Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, Minnesota. 2Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota. 3Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. 4Canadian Cancer Trials Group, Kingston, Ontario, Canada. 5Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, University Hospital, Erlangen, Germany. 6Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. 7Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana. 8Department of Medicine, Baylor University College of Medicine, Houston, Texas. 9Massachusetts General Hospital Cancer Center, Harvard University, Boston, Massachusetts. 10Department of Business Informatics, University of Applied Sciences Ansbach, Ansbach, Germany. 11Patient advocate, Mayo Clinic Breast Cancer Specialized Program of Research Excellence, Rochester, Minnesota. 12Institute for Therapeutics Discovery and Development, University of Minnesota, Minneapolis, Minnesota. 13Division of Oncology Research, Mayo Clinic, Rochester, Minnesota.
© 2020 American Association for Cancer Research.
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, Non-P.H.S.
- Research Support, N.I.H., Extramural