Division of Medical Oncology and Hematology, Department of Medicine, Biruni University School of Medicine, Istanbul, Turkey.
Departments of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Breast J. 2020 Aug;26(8):1572-1582. doi: 10.1111/tbj.13922. Epub 2020 Jun 4.
Germline variations in genes coding for proteins involved in the oxidative stress and DNA repair greatly influence drug response and toxicity. Because BRCA1 and BRCA2 proteins play a role in DNA damage repair, we postulated that taxane-related toxicity is potentially higher and clinical outcome in different in patients with BRCA pathogenic variants (PV). Seven hundred nineteen women who underwent BRCA genetic testing and were treated with taxane-containing chemotherapy for early-stage breast cancer between 1997 and 2018 were included in the study. Patients with BRCA variants of uncertain significance were excluded. The Kaplan-Meier product-limit method was used to estimate recurrence-free survival (RFS) and overall survival (OS) rates. Logistic regression models were used to assess the association between chemotherapy toxicity and factors of interest. Cox regression models were used to assess the association between RFS and OS and factors of interest. Ninety-four (13%) and 54 (7%) patients had BRCA1 and BRCA2-PVs, respectively. While anemia (P = .0025) and leukopenia (P = .001) were more frequently seen in BRCA noncarriers, there was no difference in regards to peripheral neuropathy or other toxicities between the groups. Increasing doses of taxane were associated with increased risk of neutropenia, stomatitis, nausea, vomiting, acne/rash, and peripheral neuropathy across all groups. In a multivariate logistic regression model, BRCA2 status remained as an independent significant predictor for decreased hematologic toxicity (HR: 0.36; 95% CI: 0.20-0.67; P = .001) and increased gastrointestinal toxicity (HR: 1.93; 95% CI: 1.02-3.67; P = .04). Being overweight, obese and African-American race were significant predictors for peripheral neuropathy (P = .04; P = .03; P = .06, respectively). Total taxane dose received did not have any impact on survival outcomes. Our study demonstrates that taxane-containing chemotherapy regimens do not increase risk of peripheral neuropathy or hematologic toxicity in patients with BRCA PVs. The mechanisms for this finding need to be further investigated as it may provide an opportunity to combine taxanes with other agents, such as platinum salts or PARP inhibitors, with less anticipated toxicity.
种系变异在编码参与氧化应激和 DNA 修复的蛋白质的基因中，极大地影响了药物反应和毒性。由于 BRCA1 和 BRCA2 蛋白在 DNA 损伤修复中发挥作用，我们假设在具有 BRCA 致病性变异（PV）的患者中，紫杉烷类相关毒性可能更高，临床结局也不同。本研究纳入了 1997 年至 2018 年间接受 BRCA 基因检测并接受含紫杉烷化疗的早期乳腺癌 719 例女性患者。排除了具有不确定意义的 BRCA 变异患者。使用 Kaplan-Meier 乘积限法估计无复发生存率（RFS）和总生存率（OS）。使用逻辑回归模型评估化疗毒性与感兴趣因素之间的关联。使用 Cox 回归模型评估 RFS 和 OS 与感兴趣因素之间的关联。94（13%）和 54（7%）例患者分别携带 BRCA1 和 BRCA2-PV。BRCA 非携带者更常出现贫血（P =.0025）和白细胞减少（P =.001），但两组间周围神经病变或其他毒性无差异。在所有组中，增加紫杉烷剂量与中性粒细胞减少症、口腔炎、恶心、呕吐、痤疮/皮疹和周围神经病变的风险增加相关。在多变量逻辑回归模型中，BRCA2 状态仍然是血液学毒性降低的独立显著预测因子（HR：0.36；95%CI：0.20-0.67；P =.001）和胃肠道毒性增加的独立显著预测因子（HR：1.93；95%CI：1.02-3.67；P =.04）。超重、肥胖和非裔美国人种族是周围神经病变的显著预测因子（P =.04；P =.03；P =.06）。接受的总紫杉烷剂量对生存结果没有影响。我们的研究表明，在携带 BRCA PV 的患者中，含紫杉烷的化疗方案不会增加周围神经病变或血液学毒性的风险。需要进一步研究这种发现的机制，因为它可能为联合使用紫杉烷与其他药物（如铂盐或 PARP 抑制剂）提供机会，而这些药物的毒性预计会更小。
