Pharmacogenomics of aromatase inhibitors in postmenopausal breast cancer and additional mechanisms of anastrozole action.

Abstract

Aromatase inhibitors (AIs) reduce breast cancer recurrence and prolong survival, but up to 30% of patients exhibit recurrence. Using a genome-wide association study of patients entered on MA.27, a phase III randomized trial of anastrozole versus exemestane, we identified a single nucleotide polymorphism (SNP) in CUB And Sushi multiple domains 1 (CSMD1) associated with breast cancer-free interval, with the variant allele associated with fewer distant recurrences. Mechanistically, CSMD1 regulates CYP19 expression in an SNP- and drug-dependent fashion, and this regulation is different among 3 AIs: anastrozole, exemestane, and letrozole. Overexpression of CSMD1 sensitized AI-resistant cells to anastrozole but not to the other 2 AIs. The SNP in CSMD1 that was associated with increased CSMD1 and CYP19 expression levels increased anastrozole sensitivity, but not letrozole or exemestane sensitivity. Anastrozole degrades estrogen receptor α (ERα), especially in the presence of estradiol (E2). ER+ breast cancer organoids and AI- or fulvestrant-resistant breast cancer cells were more sensitive to anastrozole plus E2 than to AI alone. Our findings suggest that the CSMD1 SNP might help to predict AI response, and anastrozole plus E2 serves as a potential new therapeutic strategy for patients with AI- or fulvestrant-resistant breast cancers.

• Authors: Junmei Cairns, James N Ingle, Tanda M Dudenkov, Krishna R Kalari, Erin E Carlson, Jie Na, Aman U Buzdar, Mark E Robson, Matthew J Ellis, Paul E Goss, Lois E Shepherd, Barbara Goodnature, Matthew P Goetz, Richard M Weinshilboum, Hu Li, Mehrab Ghanat Bari, Liewei Wang
• Journal: JCI insight (JCI Insight) Vol. 5 Issue 16 (08 20 2020) ISSN: 2379-3708 [Electronic] United States
• PMID: 32701512 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Hormonal
• Aromatase Inhibitors
• CSMD1 protein, human
• ESR1 protein, human
• Estrogen Receptor alpha
• Membrane Proteins
• Tumor Suppressor Proteins
• Anastrozole
• Estradiol
• Aromatase
• CYP19A1 protein, human

Topics

• Anastrozole (administration & dosage, pharmacokinetics, pharmacology)
• Antineoplastic Agents, Hormonal (pharmacokinetics, pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Aromatase (genetics)
• Aromatase Inhibitors (pharmacokinetics)
• Breast Neoplasms (drug therapy, genetics, mortality)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Estradiol (administration & dosage, pharmacology)
• Estrogen Receptor alpha (metabolism)
• Female
• Genome-Wide Association Study
• Humans
• Membrane Proteins (genetics)
• Pharmacogenetics
• Polymorphism, Single Nucleotide
• Postmenopause
• Tumor Suppressor Proteins (genetics)