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.
Highlights
About 70% of primary breast cancers express estrogen receptor α (ERα)
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
Our findings suggest that the CSMD1 SNP might help to predict Aromatase inhibitors (AIs) response, and anastrozole plus E2 serves as a potential new therapeutic strategy for patients with AI- or fulvestrant-resistant breast cancers
Summary
About 70% of primary breast cancers express estrogen receptor α (ERα). Adjuvant endocrine therapy, including aromatase inhibitors (AIs), is a standard treatment for these patients, regardless of tumor size or nodal status. For postmenopausal women with primary ER+ breast cancer, AIs are the standard-of-care to prevent relapse and prolong survival [1, 2]. AI-based therapy is a standard initial treatment. Despite their efficacy, about 19% of patients with early-stage disease suffer a recurrence by 10 years [1], and resistance to AIs in advanced or metastatic tumors invariably occurs [3]. There is a great need to understand the underlying mechanisms associated with AI response and resistance
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