Genome-wide case-control study of musculoskeletal adverse events and functional genomics in women receiving aromatase inhibitors: going beyond associations

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In postmenopausal women with early breast cancer, the third-generation aromatase inhibitors (AIs; anastrozole, exemestane, and letrozole) have been proven to be of value in multiple large well-conducted clinical trials as initial adjuvant endocrine therapy, after several years of tamoxifen, and as extended adjuvant endocrine therapy after about 5 years of tamoxifen [1-8]. A recent American Society of Clinical Oncology clinical practice guideline stated that an AI should be used in the adjuvant setting either initially or after some period of tamoxifen therapy [9]. Despite the proven value of the AIs, many women are not adherent [10]. About one-half of women treated with an AI have new or worsening joint complaints [11]. The importance of musculoskeletal complaints was identified in reviewing the experience with MA.27, a large phase III trial comparing the non-steroidal AI anastrozole with the steroidal AI exemestane as adjuvant therapy for early breast cancer. These musculoskeletal adverse events (MS-AEs) were the most common reason why patients discontinued AI therapy. We had previously demonstrated marked variability in metabolism and pharmacodynamics of one of the AIs, anastrozole [12]. We hypothesized that the variability seen with respect to MS-AEs in women treated with anastrozole or exemestane on MA.27 could be related to genetic variability of the patients. We proceeded to perform a genome-wide association study (GWAS) aimed at identifying SNPs associated with MS-AEs. The results of this GWAS and the functional genomic laboratory studies performed have recently been published [13]. This short communication summarizes the highlights of this work plus a commentary on future pharmacogenomic studies of anti-cancer agents.