Department of Clinical Pharmacy, University of Michigan College of Pharmacy, 428 Church St., Room 3054, Ann Arbor, MI, 48109-1065, USA.
Department of Mathematics and Statistics, Skidmore College, Saratoga Springs, NY, 12866, USA.
Support Care Cancer. 2022 Oct;30(10):8059-8067. doi: 10.1007/s00520-022-07243-8. Epub 2022 Jul 1.
Aromatase inhibitors (AIs) are commonly used to treat hormone receptor positive (HR +) breast cancer. AI-induced musculoskeletal syndrome (AIMSS) is a common toxicity that causes AI treatment discontinuation. The objective of this genome-wide association study (GWAS) was to identify genetic variants associated with discontinuation of AI therapy due to AIMSS and attempt to replicate previously reported associations.
In the Exemestane and Letrozole Pharmacogenetics (ELPh) study, postmenopausal patients with HR + non-metastatic breast cancer were randomized to letrozole or exemestane. Genome-wide genotyping of germline DNA was conducted followed by imputation. Each imputed variant was tested for association with time-to-treatment discontinuation due to AIMSS using a Cox proportional hazards model assuming additive genetic effects and adjusting for age, baseline pain score, prior taxane treatment, and AI arm. Secondary analyses were conducted within each AI arm and analyses of candidate variants previously reported to be associated with AIMSS risk.
Four hundred ELPh participants were included in the combined analysis. Two variants surpassed the genome-wide significance level in the primary analysis (p value < 5 × 10), an intronic variant (rs79048288) within CCDC148 (HR = 4.42, 95% CI: 2.67-7.33) and an intergenic variant (rs912571) upstream of PPP1R14C (HR = 0.30, 95% CI: 0.20-0.47). In the secondary analysis, rs74418677, which is known to be associated with expression of SUPT20H, was significantly associated with discontinuation of letrozole therapy due to AIMSS (HR = 5.91, 95% CI: 3.16-11.06). We were able to replicate associations for candidate variants previously reported to be associated with AIMSS in this cohort, but were not able to replicate associations for any other variants previously reported in other patient cohorts.
Our GWAS findings identify several candidate variants that may be associated with AIMSS risk from AI generally or letrozole specifically. Validation of these associations in independent cohorts is needed before translating these findings into clinical practice to improve treatment outcomes in patients with HR + breast cancer.
芳香化酶抑制剂（AIs）常用于治疗激素受体阳性（HR+）乳腺癌。芳香化酶抑制剂诱导的肌肉骨骼综合征（AIMSS）是一种常见的毒性，导致 AI 治疗中断。本全基因组关联研究（GWAS）的目的是确定与因 AIMSS 而停止 AI 治疗相关的遗传变异，并尝试复制先前报道的关联。
在依西美坦和来曲唑药物遗传学（ELPh）研究中，绝经后 HR+非转移性乳腺癌患者被随机分配至来曲唑或依西美坦组。对来源于外周血的基因组 DNA 进行全基因组基因分型，然后进行 imputation。使用 Cox 比例风险模型，根据加性遗传效应，对每个推测的变异与因 AIMSS 而导致的治疗中断时间进行关联分析，调整因素包括年龄、基线疼痛评分、先前紫杉烷治疗和 AI 臂。在每个 AI 臂内进行二次分析，并对先前报道与 AIMSS 风险相关的候选变异进行分析。
共有 400 名 ELPh 参与者纳入联合分析。在主要分析中，有两个变异超过了全基因组显著性水平（p 值<5×10），一个位于 CCDC148 内含子的变异（rs79048288）（HR=4.42，95%CI：2.67-7.33）和一个位于 PPP1R14C 上游的基因间变异（rs912571）（HR=0.30，95%CI：0.20-0.47）。在二次分析中，rs74418677 与 SUPT20H 的表达有关，与因 AIMSS 而停止来曲唑治疗显著相关（HR=5.91，95%CI：3.16-11.06）。我们能够复制在该队列中与 AIMSS 相关的候选变异的关联，但未能复制在其他患者队列中先前报道的任何其他变异的关联。
我们的 GWAS 结果确定了几个候选变异，这些变异可能与 AI 一般或来曲唑特异性的 AIMSS 风险相关。在将这些发现转化为临床实践以改善 HR+乳腺癌患者的治疗结果之前，需要在独立队列中验证这些关联。
