The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins School of Medicine, Baltimore, Maryland.
Dana Farber Cancer Institute-ECOG-ACRIN Biostatistics Center, Boston, Massachusetts.
Clin Cancer Res. 2024 Jul 1;30(13):2709-2718. doi: 10.1158/1078-0432.CCR-23-2137.
Aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) are common and frequently lead to AI discontinuation. SNPs in candidate genes have been associated with AIMSS and AI discontinuation. E1Z11 is a prospective cohort study designed to validate the association between 10 SNPs and AI discontinuation due to AIMSS.
Postmenopausal women with stage I to III hormone receptor-positive breast cancer received anastrozole 1 mg daily and completed patient-reported outcome measures to assess AIMSS (Stanford Health Assessment Questionnaire) at baseline, 3, 6, 9, and 12 months. We estimated that 40% of participants would develop AIMSS and 25% would discontinue AI treatment within 12 months. Enrollment of 1,000 women with a fixed number per racial stratum provided 80% power to detect an effect size of 1.5 to 4. SNPs were found in ESR1 (rs2234693, rs2347868, and rs9340835), CYP19A1 (rs1062033 and rs4646), TCL1A (rs11849538, rs2369049, rs7158782, and rs7159713), and HTR2A (rs2296972).
Of the 970 evaluable women, 43% developed AIMSS and 12% discontinued AI therapy within 12 months. Although more Black and Asian women developed AIMSS than White women (49% vs. 39%, P = 0.017; 50% vs. 39%, P = 0.004, respectively), the AI discontinuation rates were similar across groups. None of the SNPs were significantly associated with AIMSS or AI discontinuation in the overall population or in distinct cohorts. The OR for rs2296972 (HTR2A) approached significance for developing AIMSS.
We were unable to prospectively validate candidate SNPs previously associated with AI discontinuation due to AIMSS. Future analyses will explore additional genetic markers, patient-reported outcome predictors of AIMSS, and differences by race.
芳香化酶抑制剂（AI）相关的肌肉骨骼症状（AIMSS）很常见，并且经常导致 AI 停药。候选基因中的 SNP 与 AIMSS 和 AI 停药有关。E1Z11 是一项前瞻性队列研究，旨在验证 10 个 SNP 与因 AIMSS 而导致的 AI 停药之间的关联。
患有 I 期至 III 期激素受体阳性乳腺癌的绝经后妇女每天接受阿那曲唑 1mg，并在基线、3、6、9 和 12 个月时完成评估 AIMSS（斯坦福健康评估问卷）的患者报告结局测量。我们估计，40%的参与者会出现 AIMSS，25%的参与者会在 12 个月内停止 AI 治疗。按每个种族分层固定人数招募 1000 名女性，可提供 80%的效力来检测 1.5 至 4 的效应大小。在 ESR1（rs2234693、rs2347868 和 rs9340835）、CYP19A1（rs1062033 和 rs4646）、TCL1A（rs11849538、rs2369049、rs7158782 和 rs7159713）和 HTR2A（rs2296972）中发现了 SNP。
在 970 名可评估的女性中，43%出现 AIMSS，12%在 12 个月内停止 AI 治疗。尽管黑人和亚洲女性比白人女性更易出现 AIMSS（分别为 49%比 39%，P=0.017；50%比 39%，P=0.004），但各组的 AI 停药率相似。在总体人群或特定队列中，没有一个 SNP 与 AIMSS 或 AI 停药显著相关。rs2296972（HTR2A）的 OR 接近因 AIMSS 而出现 AIMSS 的显著水平。
我们未能前瞻性验证先前与因 AIMSS 而导致的 AI 停药相关的候选 SNP。未来的分析将探索其他遗传标记物、预测 AIMSS 的患者报告结局预测因子以及种族差异。
