Genetic and clinical predictors of arthralgia during letrozole or anastrozole therapy in breast cancer patients
Genetic and clinical predictors of arthralgia during letrozole or anastrozole therapy in breast cancer patients
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DOI：
10.1007/s10549-020-05777-1
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发表时间：
2020-07-06
影响因子：
3.8
通讯作者：
Kim, Richard B.
中科院分区：
文献类型：
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作者：
Borrie, Adrienne E.;Rose, Finnley A.;Kim, Richard B.
目的女性乳腺癌患者在使用芳香化酶抑制剂（aromatase inhibitors，AI）治疗时常发生关节痛。虽然AI诱导的关节痛的机制尚不清楚，但已经确定了潜在的生物标志物。本研究的目的是在雌激素受体阳性乳腺癌患者的前瞻性队列中调查AI诱导的关节痛的临床和遗传预测因素。方法196例患者在开始接受来曲唑或阿那曲唑治疗时入组。患者在基线时完成两份经验证的自我报告问卷，评估疼痛、僵硬和身体功能，并在开始AI治疗后2个月和6个月重复问卷。所有患者的生殖系DNA基因分型为7个单核苷酸多态性（SNP），先前通过遗传筛查和全基因组关联研究确定为与AI诱导的关节痛相关。结果50%以上的研究组患者出现关节疼痛症状。基因分析显示，CYP19A1（rs4775936）和ESR1（rs9322336，rs2234693，rs9340799）中的4个SNP与关节痛的发生相关（校正后P = 0.016，0.018，0.017，0.047）。高体重指数（BMI）也与关节痛症状的发生有关（调整后P = 0.001）。服用来曲唑的患者比服用阿那曲唑的患者更有可能发生关节痛（P = 0.018），也更有可能因关节痛而停止AI治疗。CYP19A1（rs4775936）SNP与由于无法忍受的关节痛而停止治疗显著相关。结论我们的研究结果表明，BMI和AI药物（来曲唑与阿那曲唑）是关节痛的临床预测因子，而遗传变异rs4775936，rs9322336，rs2234693和rs9340799是AI诱导的关节痛的遗传预测因子。值得注意的是，rs4775936也是终止治疗的预测因子。
Purpose Female patients with breast cancer frequently develop arthralgia when treated with aromatase inhibitors (AI). Although the mechanism of AI-induced arthralgia is unknown, potential biomarkers have been identified. The purpose of this study was to investigate the clinical and genetic predictors of AI-induced arthralgia in a prospective cohort of patients with estrogen receptor-positive breast cancer. Methods One hundred and ninety-six patients were enrolled at initiation of AI therapy with either letrozole or anastrozole. Patients completed two validated self-report questionnaires assessing pain, stiffness, and physical function at baseline, and repeated the questionnaires at two and at six months after the initiation of treatment with an AI. Germline DNA of all patients was genotyped for seven single-nucleotide polymorphisms (SNPs) previously identified by genetic screens and genome-wide association studies as associated with AI-induced arthralgia. Results More than 50% of the study group experienced arthralgia symptoms. Genetic analysis revealed that four SNPs, inCYP19A1(rs4775936) andESR1(rs9322336, rs2234693, rs9340799), were associated with the development of arthralgia (adjustedP = 0.016, 0.018, 0.017, 0.047). High body mass index (BMI) was also associated with the development of arthralgia symptoms (adjustedP = 0.001). Patients prescribed letrozole were significantly more likely to develop arthralgia than patients on anastrozole (P = 0.018), and also more likely to discontinue AI therapy due to arthralgia. TheCYP19A1(rs4775936) SNP was significantly associated with discontinuation of therapy due to intolerable arthralgia. Conclusions Our results suggested that BMI and AI drug (letrozole versus anastrozole) were clinical predictors of arthralgia, while genetic variants rs4775936, rs9322336, rs2234693, and rs9340799 were genetic predictors of AI-induced arthralgia. Significantly, rs4775936 was also a predictor of discontinuation of therapy.