Increased chemotherapy-induced ovarian reserve loss in women with germline BRCA mutations due to oocyte deoxyribonucleic acid double strand break repair deficiency.
Adult
Animals
Anti-Mullerian Hormone
/ blood
Antineoplastic Agents
/ adverse effects
BRCA1 Protein
/ genetics
BRCA2 Protein
/ genetics
Biomarkers
/ blood
Breast Neoplasms
/ drug therapy
DNA Breaks, Double-Stranded
DNA Repair
Female
Germ-Line Mutation
Humans
Longitudinal Studies
Mice
Oocytes
/ drug effects
Ovarian Reserve
/ drug effects
Primary Ovarian Insufficiency
/ blood
Prospective Studies
Time Factors
Treatment Outcome
BRCA
chemotherapy
fertility preservation
ovarian insufficiency
ovarian reserve
Journal
Fertility and sterility
ISSN: 1556-5653
Titre abrégé: Fertil Steril
Pays: United States
ID NLM: 0372772
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
21
08
2019
revised:
23
01
2020
accepted:
24
01
2020
pubmed:
26
4
2020
medline:
17
2
2021
entrez:
26
4
2020
Statut:
ppublish
Résumé
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. 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. Sera were longitudinally obtained before and 12-24 months after chemotherapy treatment, assayed for antimüllerian hormone (AMH), and adjusted for age at sample collection. Ovarian recovery, defined as the geometric mean of the after chemotherapy age-adjusted AMH levels compared with baseline levels. 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. 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.
Identifiants
pubmed: 32331767
pii: S0015-0282(20)30036-4
doi: 10.1016/j.fertnstert.2020.01.033
pmc: PMC7339936
mid: NIHMS1586734
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
BRCA1 Protein
0
BRCA1 protein, human
0
BRCA2 Protein
0
BRCA2 protein, human
0
Biomarkers
0
Anti-Mullerian Hormone
80497-65-0
Banques de données
ClinicalTrials.gov
['NCT00823654']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1251-1260.e1Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD053112
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
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