Increased chemotherapy-induced ovarian reserve loss in women with germline BRCA mutations due to oocyte deoxyribonucleic acid double strand break repair deficiency

Abstract

Objective: 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. Design: Longitudinal cohort study. Setting: Academic centers. Patient(s): The 108 evaluable women with breast cancer were stratified into those never tested (negative family history; n ¼ 35) and those negative (n ¼ 59) or positive (n ¼ 14) for a pathogenic BRCA mutation. Intervention(s): Sera were longitudinally obtained before and 12-24 months after chemotherapy treatment, assayed for antim€ ullerian 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.

Longitudinal Ovarian Reserve Changes in Women With Breast Cancer Receiving Adjuvant Chemotherapy or Tamoxifen-Alone

“…The copyright holder for this preprint this version posted June 25, 2020. ; https://doi.org/10.1101/2020.06.21.20136689 doi: medRxiv preprint report, women with BRCA mutations who received chemotherapy had 3-fold lower AMH recovery compared to those BRCA-mutation-negative or untested during the 12-24 month follow up. These findings were confirmed in a mouse oocyte BRCA knock-out model, where knock-down of BRCA function resulted in a significant increase in oocyte death after in vitro exposure to doxorubicin (7). These findings, when used collectively with the current study, provide valuable information for fertility preservation counselling before breast cancer treatment in women with and without BRCA mutations.…”

DNA Damaged Induced Cell Death in Oocytes

“…Oocyte-specific knockdown of ATM in mice resulted in an increase in DSBs and reduced the number of oocytes, similar to knockdown of other repair proteins such as BRCA1, MRE11 or Rad51 [146]. Consistently, germline BRCA1 mutations in women cause a decrease in the ovarian reserve due to impaired DSB repair [146,147], which is accelerated (relative to women without BRCA mutations) by treatment with chemotherapy [148].…”

Fertility preservation in patients with BRCA mutations or Lynch syndrome

“…In our search, 11 articles [17][18][19][20][21][22][23][24][25][26][27] considered anti-Mullerian hormone and antral follicular count as indexes of ovarian function in BRCA mutation carriers compared with wild-type controls (Table 1). In fact, anti-Müllerian hormone levels and antral follicular count are considered predictors of ovarian response during in vitro fertilization techniques, with lower levels suggestive of a poor response.…”

“…Several studies have validated anti-Müllerian hormone as a direct biomarker for ovarian aging, which reflects the decline in reproductive capacity. 29 30 In our search, we considered 11 studies [17][18][19][20][21][22][23][24][25][26][27] evaluating anti-Müllerian hormone levels as an index of the ovarian reserve, comparing BRCA carriers with wild-type controls. Four studies concluded that BRCA mutation carriers had lower levels of anti-Müllerian hormone compared with BRCA wild-type patients 17 20 22 23 while five studies had the opposite results, reporting BRCA patients who had higher anti-Müllerian hormone levels compared with BRCA wild-type patients.…”