Onco-fertility and personalized testing for potential for loss of ovarian reserve in patients undergoing chemotherapy: proposed next steps for development of genetic testing to predict changes in ovarian reserve

Abstract

Women of reproductive age undergoing chemotherapy face the risk of irreversible ovarian insufficiency. Current methods of ovarian reserve testing do not accurately predict future reproductive potential for patients undergoing chemotherapy. Genetic markers that more accurately predict the reproductive potential of each patient undergoing chemotherapy would be critical tools that would be useful for evidence-based fertility preservation counselling. To assess the possible approaches to take to develop personalized genetic testing for these patients, we review current literature regarding mechanisms of ovarian damage due to chemotherapy and genetic variants associated with both the damage mechanisms and primary ovarian insufficiency. The medical literature point to a number of genetic variants associated with mechanisms of ovarian damage and primary ovarian insufficiency. Those variants that appear at a higher frequency, with known pathways, may be considered as potential genetic markers for predictive ovarian reserve testing. We propose developing personalized testing of the potential for loss of ovarian function for patients with cancer, prior to chemotherapy treatment. There are advantages of using genetic markers complementary to the current ovarian reserve markers of AMH, antral follicle count and day 3 FSH as predictors of preservation of fertility after chemotherapy. Genetic markers will help identify upstream pathways leading to high risk of ovarian failure not detected by present clinical markers. Their predictive value is mechanism-based and will encourage research towards understanding the multiple pathways contributing to ovarian failure after chemotherapy.

Female Oncofertility: Current Understandings, Therapeutic Approaches, Controversies, and Future Perspectives

“…Advances in genomic science that could facilitate oncofertility are also encouraging achievements. Some works have tried to develop a system of genetic markers to predict the susceptibility to chemotherapy-induced damage [ 19 ]. Genetic mutations involving the DNA repairing system are supposed factors increasing ovarian susceptibility to chemotherapy-induced damage [ 19 ].…”

“…Some works have tried to develop a system of genetic markers to predict the susceptibility to chemotherapy-induced damage [ 19 ]. Genetic mutations involving the DNA repairing system are supposed factors increasing ovarian susceptibility to chemotherapy-induced damage [ 19 ]. Several genetic defects in BRCA1/2 [ 224 , 225 ], minichromosome maintenance complex component 8/9 [ 226 ], helicase for meiosis 1 [ 227 ], nucleoporin 107 [ 228 ], and synaptonemal complex central element protein 1 [ 229 ] are suggested to be implicated in ovarian insufficiency.…”

“…This fertility-compromised status has been well-documented to cause emotional distress and poor quality of life [ 15 , 16 , 17 , 18 ]. It was reported that there will be approximately 100 million women at risk of chemotherapy-induced ovarian impairment in 2025 [ 19 ]. In this context, preserving the fertility and quality of life of CCS has received considerable concerns.…”

Genomic Consideration in Chemotherapy-Induced Ovarian Damage and Fertility Preservation

“…Fmr1 and Brca testing can be performed easily in genetic clinics. Patients with mutations in these genes are at a higher genetic risk at baseline [95]. Evaluation of other frequent genetic variants, including Nobox, Figla, Bnc1, Sohlh1, Sohlh2, Foxo3, and Hfm1, could help identify individuals with increased genetic risk of ovarian damage due to chemotherapy.…”

A Warning Call for Fertility Preservation Methods for Women Undergoing Gonadotoxic Cancer Treatment

“…It can impair disease recovery, social reinsertion, personal and family life, as well as a great decrease in quality of life. Women tend to report a better acceptance of procreation issues when prior informed by the medical team, rising the importance of proper medical care before the treatment onset [9,12].…”