Drug metabolising enzyme polymorphisms and chemotherapy-related ovarian failure in young breast cancer survivors.

Cyclophosphamide is associated with chemotherapy-related ovarian failure (CROF) in breast cancer survivors, however little is known about predicting individual risks. We sought to identify genetic alleles as biomarkers for risk of CROF after cyclophosphamide treatment. One hundred fifteen premenopausal women with newly diagnosed breast cancer were genotyped for single nucleotide polymorphisms (SNPs) in genes involved in cyclophosphamide activation ( and and detoxification ( and ). Patients prospectively completed menstrual diaries. With median follow up of 808 days, 28% experienced CROF. Survivors homozygous for the minor allele had lower hazards for developing CROF (HR 0.22 [95% CI 0.05-0.94], =.04), while survivors homozygous for the minor allele had higher hazards for developing CROF (HR 4.5 [95% CI 1.5-13.4], =.007) compared to patients with at least one major allele. In separate multivariable models adjusting for age and tamoxifen use, the associations were no longer statistically significant ( HR 0.24 [95% CI 0.06-1.0], =.05; HR 2.5 [0.8-7.6], =.11). and SNPs were not significantly related to CROF. In younger breast cancer survivors undergoing cyclophosphamide-based chemotherapy, genetic variation in and merits further study to determine its relationship with CROF.IMPACT STATEMENT Young breast cancer survivors face important potential implications of chemotherapy-related ovarian failure (CROF). Little is known about individual risk for CROF. Cyclophosphamide, a particularly gonadotoxic drug commonly used in breast cancer treatment, is metabolised by various cytochrome p450 enzymes. Studies have shown genetic variation in p450 enzymes is associated with differential clinical outcomes after cyclophosphamide treatment: breast cancer patients homozygous for minor allele had improved overall survival; lupus patients homozygous for minor allele had increased risk for CROF; and was associated with decreased risk for CROF. We show a surprising opposite trend for the risk of CROF in breast cancer patients with and variants, while we did not show a significant risk for genetic variation in (which had previously been shown to have a protective effect) or . This study shows the complexity of genetic variation in predicting outcomes to treatment. We advocate for future replicative studies to potentially validate and and definitively negate and as biomarkers for risk of CROF after cyclophosphamide treatment. Understanding genetic variation in chemotherapy metabolism has the potential to individualise treatment regimens to maximise efficacy and minimise toxicity.