ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2022) 19 9.14 | DOI: 10.1530/ey.19.9.14

On Behalf Of The PanCareLIFE Consortium. Cancers (Basel). 2021; 13: 4598. PMID: 34572825.

Brief Summary: This cohort study of female childhood cancer survivors (CCS) identified associations between specific nucleotide polymorphisms (SNP) in cytochrome P450 (CYP450) enzymes, which metabolize alkylating agents (AA), and variability in AA-induced ovarian damage.

Chemotherapy with alkylating agents (AA) is a well-recognized risk factor of gonadal failure in female childhood cancer survivors (CCS). However, significant inter-individual variability in ovarian damage is reported and polymorphisms in the genes encoding these enzymes may explain this variability.

Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function in a discovery group of adult female CCS, from the pan-European PanCareLIFE cohort (discovery cohort). The results were validated, and meta-analysis performed, using the USA-based St. Jude Lifetime Cohort (replication cohort). Eligible participants were women diagnosed with cancer before the age of 25 years and treated with chemotherapy. They had survived at least 5 years after diagnosis and were >18 years of age at evaluation. Nine genetic variants in three CYP450 enzymes were analyzed in relation to cyclophosphamide equivalent dose (CED) and its impact on AMH levels.

The polymorphism CYP3A4*3 was associated with lower AMH levels in both the discovery and replication cohort. Meta-analysis showed a deleterious effect of CYP3A4*3 on AMH levels. Conversely, the polymorphism CYP2B6*2 showed a protective effect on AMH levels in CCS receiving a CED >8000 mg/m2.

Single nucleotide polymorphisms (SNPs) in CYP genes have been associated with cyclophosphamide toxic effects on ovaries in exposed adult women (1). This is the first study to evaluate the effect of SNPs in CYP450 enzymes on gonadotoxicity due to AA exposure during childhood. The results may improve clinical practice by identifying patients at high risk of ovarian impairment who may benefit from early referral and counseling about fertility preservation options. For young girls at high risk of infertility, preservation measures involve the surgical removal of an ovary (or part of it) with ovarian tissue cryopreservation. Cryopreservation of oocytes is only possible in some older adolescent patients, who can postpone cancer treatment. Pharmacogenetic is increasingly used to personalize therapy and minimize side effects. In the near future, evidence-based knowledge of genetic predisposition to AA toxicity may optimize the delivery of tailored therapy and fertility counselling. Future prospective research is important to define the clinical relevance of polymorphisms in determining the gonadotoxic effect of cancer treatment. Moreover, differences in pharmacokinetics between children and adults may be potentially involved and require further study.

References: 1. Su HI; Sammel, M.D.; Velders, L.; Horn, M.; Stankiewicz, C.; Matro, J.; Gracia, C.R.; Green, J.; De Michele, A. Association of cyclophosphamide drug–metabolizing enzyme polymorphisms and chemotherapy-related ovarian failure in breast cancer survivors. Fertil. Steril. 2010, 94, 645–654.

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