Abstract
More than 10% of women diagnosed with breast cancer during reproductive age carry hereditary germline pathogenic variants in high-penetrance BRCA genes or in others genes involved in DNA repair mechanisms such as PALB2, BRIP or ATM. Anticancer treatments may have an additional negative impact on the ovarian reserve and subsequently on the fertility of young patients carrying such mutations. Recently, the combination of carboplatin and paclitaxel is being recommended to these BRCA-mutated patients as neoadjuvant therapy. However, the impact on the ovary is unknown. Here, we investigated their effect of on the ovarian reserve using mice carriers of BRCA1-interacting protein C-terminal helicase-1 (BRIP1) mutation that plays an important role in BRCA1-dependent DNA repair. Results revealed that the administration of carboplatin or paclitaxel did not affect the ovarian reserve although increased DNA double-strand breaks were observed with carboplatin alone. Co-administration of carboplatin and paclitaxel resulted in a significant reduction of the ovarian reserve leading to a lower IVF performance, and an activation of the PI3K-Pten pathway, irrespective of the genetic background. This study suggests that co-administration of carboplatin and paclitaxel induces cumulative ovarian damage and infertility but a heterozygote genetic predisposition for DNA damage related to BRCA1 gene function does not increase this risk.
Highlights
More than 10% of women diagnosed with breast cancer during reproductive age carry hereditary germline pathogenic variants in high-penetrance BRCA genes or in others genes involved in DNA repair mechanisms such as PALB2, BRIP or ATM
BRCA is known to be involved in homologous DNA recombination, and plays an essential role in DNA double-strand breaks (DSBs) repair protecting the integrity of the genome in proliferating cells
The gonadotoxicity of combined regimen including both carboplatin and paclitaxel is unknown, in the cases of mutations involved in DNA repair mechanisms such as BRCA1, BRIP, RADF51
Summary
More than 10% of women diagnosed with breast cancer during reproductive age carry hereditary germline pathogenic variants in high-penetrance BRCA genes or in others genes involved in DNA repair mechanisms such as PALB2, BRIP or ATM. Other germline mutations in genes involved in DNA repair such as RAD51, PALB2 or BRIP confer cancer susceptibility, highlighting their crucial role in maintaining genome integrity For these patients, fertility issues may be of particular concern as previous studies suggested a possible negative impact of BRCApathogenic variants on ovarian reserve and fertility[3,4]. Major advances in anticancer therapies have contributed to increase the survival rate over the last years These treatments may have some long-term side effects including a negative impact on ovarian germ cells that may lead to premature ovarian insufficiency (POI) and subsequent infertility[7,8]. The gonadotoxicity of combined regimen including both carboplatin and paclitaxel is unknown, in the cases of mutations involved in DNA repair mechanisms such as BRCA1, BRIP, RADF51
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