Hertz Daniel L, Smith Karen Lisa, Zong Yuhua, Gersch Christina L, Pesch Andrea M, Lehman Jennifer, Blackford Amanda L, Henry N Lynn, Kidwell Kelley M, Rae James M, Stearns Vered
Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, United States.
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, United States.
Front Genet. 2021 Jun 15;12:662734. doi: 10.3389/fgene.2021.662734. eCollection 2021.
Aromatase inhibitors (AI) reduce recurrence and death in patients with early-stage hormone receptor-positive (HR +) breast cancer. Treatment-related toxicities, including AI-induced musculoskeletal symptoms (AIMSS), are common and may lead to early AI discontinuation. The objective of this study was to replicate previously reported associations for candidate germline genetic polymorphisms with AIMSS.
Women with stage 0-III HR + breast cancer initiating adjuvant AI were enrolled in a prospective clinic-based observational cohort. AIMSS were assessed by patient-reported outcomes (PRO) including the PROMIS pain interference and physical function measures plus the FACT-ES joint pain question at baseline and after 3 and 6 months. For the primary analysis, AIMSS were defined as ≥ 4-point increase in the pain interference T-score from baseline. Secondary AIMSS endpoints were defined as ≥ 4-point decrease in the physical function T-score from baseline and as ≥ 1-point increase on the FACT-ES joint pain question from baseline. The primary hypothesis was that rs11849538 would be associated with AIMSS. Twelve other germline variants in , , , , , , , and were also analyzed assuming a dominant genetic effect and prespecified direction of effect on AIMSS using univariate logistic regression with an unadjusted α = 0.05. Significant univariate associations in the expected direction were adjusted for age, race, body mass index (BMI), prior taxane, and the type of AI using multivariable logistic regression.
A total of 143 participants with PRO and genetic data were included in this analysis, most of whom were treated with anastrozole (78%) or letrozole (20%). On primary analysis, participants carrying rs11849538 were not more likely to develop AIMSS (odds ratio = 1.29, 95% confidence interval: 0.55-3.07, = 0.56). In the statistically uncorrected secondary analysis, rs2073618 was associated with AIMSS defined by worsening on the FACT-ES joint pain question (OR = 3.33, = 0.004), and this association maintained significance after covariate adjustment (OR = 3.98, = 0.003).
Carriers of rs2073618 may be at increased risk of AIMSS. If confirmed in other cohorts, genotyping can be used to identify individuals with HR + early breast cancer in whom alternate endocrine therapy or interventions to enhance symptom detection and implement strategies to reduce musculoskeletal symptoms may be needed.
芳香化酶抑制剂（AI）可降低早期激素受体阳性（HR+）乳腺癌患者的复发率和死亡率。包括AI诱导的肌肉骨骼症状（AIMSS）在内的治疗相关毒性很常见，可能导致AI提前停药。本研究的目的是重复先前报道的候选种系基因多态性与AIMSS的关联。
0-III期HR+乳腺癌患者开始辅助AI治疗，纳入一项基于临床的前瞻性观察队列。通过患者报告结局（PRO）评估AIMSS，包括PROMIS疼痛干扰和身体功能测量，以及基线、3个月和6个月后的FACT-ES关节疼痛问题。在初步分析中，AIMSS定义为疼痛干扰T评分较基线增加≥4分。次要AIMSS终点定义为身体功能T评分较基线降低≥4分，以及FACT-ES关节疼痛问题较基线增加≥1分。主要假设是rs11849538与AIMSS相关。还分析了位于、、、、、、、和中的其他12个种系变异，假设其具有显性遗传效应，并使用单变量逻辑回归预先指定对AIMSS的效应方向，未调整的α=0.05。在预期方向上的显著单变量关联通过多变量逻辑回归对年龄、种族、体重指数（BMI）、先前的紫杉烷和AI类型进行调整。
本分析共纳入143名有PRO和基因数据的参与者，其中大多数接受阿那曲唑（78%）或来曲唑（20%）治疗。在初步分析中，携带rs11849538的参与者发生AIMSS的可能性并不更高（优势比=1.29，95%置信区间：0.55-3.07，P=0.56）。在未经统计学校正的次要分析中，rs2073618与FACT-ES关节疼痛问题恶化所定义的AIMSS相关（OR=3.33，P=0.004），在协变量调整后该关联仍具有显著性（OR=3.98，P=0.003）。
rs2073618携带者发生AIMSS的风险可能增加。如果在其他队列中得到证实，基因分型可用于识别HR+早期乳腺癌患者，这些患者可能需要替代内分泌治疗或采取干预措施以加强症状检测并实施减轻肌肉骨骼症状的策略。
