PDF(Pubmed)
Abstract：
BRCA1 and BRCA2 play a central role in DNA repair and their germline pathogenic variants (gBRCA) confer a high risk for developing breast and ovarian cancer. Standard chemotherapy regimens for these cancers include DNA-damaging agents. We hypothesized that gBRCA carriers might be at higher risk of developing chemotherapy-related hematologic toxicity and therapy-related myeloid neoplasms (t-MN). We conducted a retrospective study of women newly diagnosed with invasive breast or ovarian cancer who were screened for gBRCA1/gBRCA2 at Geneva University Hospitals. All patients were treated with (neo-)adjuvant chemotherapy. We evaluated acute hematologic toxicities by analyzing the occurrence of febrile neutropenia and severe neutropenia (grade 4) at day 7-14 of the first cycle of chemotherapy and G-CSF use during the entire chemotherapy regimen. Characteristics of t-MN were collected. We reviewed medical records from 447 patients: 58 gBRCA1 and 40 gBRCA2 carriers and 349 non-carriers. gBRCA1 carriers were at higher risk of developing severe neutropenia (32% vs. 14.5%, p = 0.007; OR = 3.3, 95% CI [1.6-7], p = 0.001) and of requiring G-CSF for secondary prophylaxis (58.3% vs. 38.2%, p = 0.011; OR = 2.5, 95% CI [1.4-4.8], p = 0.004). gBRCA2 carriers did not show increased acute hematologic toxicities. t-MN were observed in 2 patients (1 gBRCA1 and one non-carrier). Our results suggested an increased acute hematologic toxicity upon exposure to chemotherapy for breast and ovarian cancer among gBRCA1 but not gBRCA2 carriers. A deeper characterization of t-MN is warranted with the recent development of PARP inhibitors in frontline therapy in gBRCA breast and ovarian cancer.
摘要：
BRCA1和BRCA2在DNA修复中起着核心作用，它们的种系致病变异体（gBRCA）赋予发展乳腺癌和卵巢癌的高风险。这些癌症的标准化疗方案包括DNA损伤剂。我们假设gBRCA携带者可能有更高的发生化疗相关血液学毒性和治疗相关髓系肿瘤（t-MN）的风险。我们对在日内瓦大学医院接受gBRCA1/gBRCA2筛查的新诊断为浸润性乳腺癌或卵巢癌的女性进行了回顾性研究。所有患者均接受（新）辅助化疗。我们通过分析第一个化疗周期第7-14天发热性中性粒细胞减少症和严重中性粒细胞减少症（4级）的发生以及整个化疗方案中使用G-CSF来评估急性血液学毒性。收集t-MN的特征。我们回顾了447名患者的医疗记录：58gBRCA1和40gBRCA2携带者和349名非携带者。gBRCA1携带者患严重中性粒细胞减少症的风险较高(32%vs.14.5%,p=0.007；OR=3.3，95%CI[1.6-7]，p=0.001）和需要G-CSF进行二级预防（58.3％vs.38.2%,p=0.011；OR=2.5，95%CI[1.4-4.8]，p=0.004)。gBRCA2携带者未显示急性血液学毒性增加。在2例患者(1gBRCA1和1例非携带者)中观察到t-MN。我们的结果表明，在gBRCA1而不是gBRCA2携带者中，暴露于乳腺癌和卵巢癌化疗后的急性血液学毒性增加。随着PARP抑制剂在gBRCA乳腺癌和卵巢癌一线治疗中的最新发展，必须对t-MN进行更深入的表征。
