Abstract PD6-06: Impact of BRCA mutations on chemotherapy-induced loss of ovarian reserve: A prospective longitudinal study
Authors: Oktay K , Bedoschi G , Goldfarb SB , Taylan E , Titus S , Palomaki GE , Cigler T , Robson M , Dickler MN 
Published: May 2019

Abstract
Background: The BRCA1/2 genes are key members of the ataxia-telangiectasia mutated (ATM)-mediated DNA double strand break (DSB) repair pathway. Recent research showed that germline mutations in these genes result in DNA repair deficiency in oocytes, leading to accelerated ovarian aging as manifested by lower ovarian reserve and earlier age at natural menopause. Because we discovered that oocyte DNA repair is similarly critical in chemotherapy-induced ovarian follicle loss, we hypothesized that women with pathogenic mutations in BRCA1/2 genes may experience larger declines in ovarian reserve after chemotherapy. To gauge the degree of the chemotherapy-induced ovarian damage, we utilized serum anti-mullerian hormone (AMH), which is the most reliable current marker for assessing oocyte reserve.
Methods: Women with early stage breast cancer were enrolled before chemotherapy (Trial registration number: NCT00823654) between January 2009 and November 2017. Sera were obtained at baseline, before the initiation of treatment, and 18 to 24 months after the completion of chemotherapy. Stored sera were assayed at once for anti-mullerian hormone (AMH) and the results were adjusted for the women's age at sample collection. Of the 235 enrolled, 117 evaluable women were stratified into three groups, those never tested (based on NCCN Guidelines V 1.2018 ; n=38) and those negative (n=65) or positive (n=14) for a pathogenic BRCA mutation. Ovarian recovery was defined as the geometric mean of the post chemotherapy age-adjusted AMH levels compared to baseline.
Results: Compared to the lower risk (BRCA-untested) control group, AMH levels averaged 76% and 66% in those negative or positive for BRCA mutations (p=0.078). The geometric mean recoveries for the three groups (not tested, BRCA negative and BRCA positive) were 3.7%, 5.2% and 1.6%, respectively. The mean recovery in the BRCA mutation positive group was about one-third the 4.6% recovery in the other two groups combined (two group ANOVA, p=0.034, F=4.89). Given the potential of the ovarian recovery to be dependent on type of chemotherapy, the data were reanalyzed for all three BRCA groups after restriction to those treated with the AC-T (doxorubicin and cyclophosphamide followed by paclitaxel) regimen. Of the 108 women in the previous analysis, 83 (77%) were treated with AC-T; 25, 46 and 12 women in the three groups, respectively. The geometric mean AMH recoveries for these new groups were 3.2%, 4.7% and 1.3%. When the BRCA mutation positive group was compared with other two groups, the former had significantly worse recovery of serum AMH levels (ANOVA, p=0.044, F=4.2).
Conclusions: These data show that women with breast cancer and pathogenic BRCA mutations have striking liability to chemotherapy-induced ovarian reserve loss and may have to be preferentially counselled on fertility preservation methods. In addition, taken together with the previous data showing that women with BRCA mutations may have accelerated ovarian aging, even unaffected reproductive age individuals may have to be proactive about family building or early preservation of their fertility (Supported by NIH R01HD053112).
Citation Format: Oktay K, Bedoschi G, Goldfarb SB, Taylan E, Titus S, Palomaki GE, Cigler T, Robson M, Dickler MN. Impact of BRCA mutations on chemotherapy-induced loss of ovarian reserve: A prospective longitudinal study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD6-06.