Department of Obstetrics and Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Department of Obstetrics and Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
Fertil Steril. 2020 Jun;113(6):1251-1260.e1. doi: 10.1016/j.fertnstert.2020.01.033. Epub 2020 Apr 22.
To assess whether woman who have BRCA mutations (WBM) experience more declines in ovarian reserve after chemotherapy treatment, as it induces oocyte death by deoxyribonucleic acid (DNA) damage, and BRCA mutations result in DNA damage repair deficiency.
Longitudinal cohort study.
Academic centers.
PATIENT(S): The 108 evaluable women with breast cancer were stratified into those never tested (negative family history; n = 35) and those negative (n = 59) or positive (n = 14) for a pathogenic BRCA mutation.
INTERVENTION(S): Sera were longitudinally obtained before and 12-24 months after chemotherapy treatment, assayed for antimüllerian hormone (AMH), and adjusted for age at sample collection.
MAIN OUTCOME MEASURE(S): Ovarian recovery, defined as the geometric mean of the after chemotherapy age-adjusted AMH levels compared with baseline levels.
RESULT(S): Compared with the controls, the before chemotherapy treatment AMH levels were 24% and 34% lower in those negative or positive for BRCA mutations, consistent with accelerated ovarian aging in WBM. The WBM had a threefold difference in AMH recovery after chemotherapy treatment (1.6%), when compared with BRCA negative (3.7%) and untested/low risk controls (5.2%). Limiting the analysis to the most common regimen, doxorubicin and cyclophosphamide followed by paclitaxel, showed similar results. These findings were mechanistically confirmed in an in vitro mouse oocyte BRCA knockdown bioassay, which showed that BRCA deficiency results in increased oocyte susceptibility to doxorubicin.
CONCLUSION(S): Women who have pathogenic BRCA mutations are more likely to lose ovarian reserve after chemotherapy treatment, suggesting an emphasis on fertility preservation. Furthermore, our findings generate the hypothesis that DNA repair deficiency is a shared mechanism between aging, infertility, and cancer.
NCT00823654.
评估携带 BRCA 突变的女性（WBM）在化疗后卵巢储备功能下降是否更为明显，因为化疗会通过脱氧核糖核酸（DNA）损伤诱导卵母细胞死亡，而 BRCA 突变导致 DNA 损伤修复缺陷。
纵向队列研究。
学术中心。
108 例可评估的乳腺癌患者分为从未接受过检测的患者（阴性家族史；n=35）和阴性（n=59）或阳性（n=14）BRCA 致病性突变的患者。
在化疗前和化疗后 12-24 个月，分别采集血清，检测抗苗勒管激素（AMH），并根据样本采集时的年龄进行调整。
卵巢恢复情况，定义为与基线水平相比，化疗后年龄调整后的 AMH 水平的几何平均值。
与对照组相比，BRCA 阴性或阳性的患者化疗前 AMH 水平分别低 24%和 34%，提示 WBM 存在卵巢早衰。与 BRCA 阴性（3.7%）和未检测/低危对照组（5.2%）相比，WBM 在化疗后 AMH 恢复方面存在 3 倍差异（1.6%）。在多柔比星和环磷酰胺序贯紫杉醇的最常见方案中进行分析，也得到了类似的结果。在体外小鼠卵母细胞 BRCA 敲低生物测定中，这些发现得到了机制上的证实，该实验表明 BRCA 缺陷会导致卵母细胞对多柔比星的敏感性增加。
携带致病性 BRCA 突变的女性在化疗后更有可能失去卵巢储备，这表明应强调生育力保存。此外，我们的研究结果提出了一个假设，即 DNA 修复缺陷是衰老、不孕和癌症之间的共同机制。
NCT00823654。
