A prospective longitudinal analysis of the predictors of amenorrhea after breast cancer chemotherapy: Impact of BRCA pathogenic variants

Abstract

BackgroundBetter tools for post‐chemotherapy amenorrhea risk assessment are needed for fertility preservation decision‐making. Our aim was to determine the predictors of amenorrhea risk at 12 and 18 months post‐chemotherapy in women with breast cancer.Methods142 women with breast cancer were longitudinally followed for their menstrual changes at 6, 12, and 18 months after the completion of adjuvant chemotherapy with an Anthracycline‐Cyclophosphamide‐based (AC‐based) or Cyclophosphamide‐Methotrexate +5‐Fluorouracil regimen. Pre‐ and/or post‐chemo AMH levels, age, BMI, tamoxifen use, regimen type, and germline BRCA pathogenic variant (gBRCApv) status were evaluated for the prediction of amenorrhea at 6–18 months.ResultsIn multivariable‐adjusted logistic regression, age (p = 0.03) and AMH (p = 0.03) at 12 months, and gBRCApv status (p = 0.03) at 18 months were significant predictors of amenorrhea (areas under the ROC curve of 0.77 and 0.76, for 12 and 18 months, respectively) among 102 evaluable subjects. An undetectable AMH immediately post‐chemotherapy was predictive of amenorrhea with <18 month follow‐up. In longitudinal analysis estimating time trends, baseline AMH and gBRCApv status was associated with the risk of amenorrhea over 6–18 months; the AMH >2.0 ng/mL group showed attenuated time‐trend risk of amenorrhea versus AMH ≤2.0 group (ratio of ORs = 0.91, 95% CI = 0.86–0.97, p = 0.002), while the gBRCApv + showed a steeper time trend, versus the controls (ratio of ORs = 1.12, 95% CI = 1.04–1.20, p = 0.003).ConclusionsIn addition to the pre‐ and post‐treatment AMH levels, gBRCApv status is a novel potential predictor of amenorrhea at 12 and 18 months after chemotherapy. The higher likelihood of amenorrhea in women gBRCApv suggests that they are more prone to losing their fertility post‐chemotherapy.

Onset and resolution of ovarian toxicity with nirogacestat treatment in females with desmoid tumors: Updated safety analyses from the DeFi phase 3 study

“…19,30 years, or more. 32,33 Although DeFi OT resolution data suggest that the impact of nirogacestat on the ovary does not persist, the long-term effects of nirogacestat on fertility are currently unknown, and further data collection may be warranted. ASCO and European guidelines support fertility preservation methods with treatments known to or that could potentially impact ovarian function [34][35][36] ; therefore, health care providers should initiate discussions with their patients to address any fertility concerns before DT treatment.…”

Fertility and Pregnancy-Related Issues in Young BRCA Carriers With Breast Cancer

“…The author concluded that, despite the small simple size of g BRCA1/2 carriers with breast cancer included in the study, g BRCA1/2 PVs carriers may have a higher risk of chemotherapy-induced amenorrhea. 34 …”

The role of declining ataxia-telangiectasia-mutated (ATM) function in oocyte aging

“…We also showed in single human and mouse oocytes that the gene and protein expression of key ATM-Pathway members decline with age, suggesting that the age-induced DNA DSB accumulation is due to declining DNA DSB repair efficiency. Moreover, we found that women with BRCA mutations experience larger ovarian reserve loss and a higher risk of amenorrhea compared to controls in response to genotoxic stressors such as chemotherapy [ 13 , 14 ]. Cumulatively, these original findings established a central role for BRCA1 function and the ATM-Pathway in the maintenance of primordial follicle reserve, and generated a novel hypothesis that an age-induced decline in the ATM-Pathway function may contribute and explain the hallmarks of oocyte aging under a single mechanism [ 2 ].…”