Association of cyclophosphamide drug–metabolizing enzyme polymorphisms and chemotherapy-related ovarian failure in breast cancer survivors

ObjectiveTo determine if genetic variation in chemotherapy metabolism are associated with risk of ovarian failure in breast cancer patients after adjuvant chemotherapy.DesignProspective cohort study.SettingComprehensive cancer center.Patient(s)Early-stage breast cancer patients who were premenopausal at cancer diagnosis and treatment.Intervention(s)None.Main Outcomes Measure(s)Chemotherapy-related ovarian failure (CROF).Result(s)A total of 127 breast cancer subjects who were premenopausal at cancer diagnosis and underwent cyclophosphamide-based chemotherapy were genotyped for nine single-nucleotide polymorphisms (SNPs) in enzymes involved in cyclophosphamide activation (CYP3A4, CYP2B6, CYP3A5) and detoxification (GSTA1, GSTM1, GSTP1, GSTT1). Median age at chemotherapy was 43.2 years. Median follow-up after chemotherapy was 5.2 years. For the entire cohort, there was no significant association between CROF and SNPs. However, the association between CROF and SNPs was modified by age at chemotherapy. In subjects younger than 45 years old at chemotherapy, CYP3A4∗1B variants had significantly longer time to CROF than CYP3A4∗1A homozygotes in an adjusted multivariable Cox model. Age and tamoxifen use were also independently associated with CROF.Conclusion(s)A common SNP in a cyclophosphamide drug–metabolizing enzyme appears to be related to ovarian failure after cyclophosphamide-based chemotherapy in young women with breast cancer. Larger prospective studies to validate these results should be directed toward women younger than 45 years of age at chemotherapy.