The objective of prospective cohort study was to test if candidate single nucleotide polymorphisms ( SNPs ) in enzymes involved in Cyclophosphamide activation or detoxification are associated with time to ovarian failure after chemotherapy in young breast cancer survivors.
Premenopausal breast cancer survivors ( n ¼ 116 ) with stages 0 to III disease and planned Cyclophosphamide-based chemotherapy were enrolled at diagnosis from three academic breast programs and followed longitudinally for menstrual pattern.
Participants were genotyped for SNPs in genes involved in Cyclophosphamide activation ( CYP3A4 [ rs1067910 ] and CYP2C19 [ rs42244285 ] ) and detoxification ( GSTP1 [ rs1695 ] and GSTA1 [ rs4715332 ] ).
The primary endpoint was time to chemotherapy-related amenorrhea ( CRA ), defined as more than 12 months of amenorrhea after the end of chemotherapy.
Using the time-to-event method, the association between single nucleotide polymorphisms and chemotherapy-related amenorrhea were assessed using Cox proportional hazard regression models. A priori sample size calculations estimated 80% power to detect relative risks of 1.7-2.6.
The cohort had a median age of 39.7 years ( range 20.8-46.1 ) at end of chemotherapy and median follow up of 594.5 days ( range 23-2119 ).
28% experienced chemotherapy-related amenorrhea. Survivors with at least one major allele of GSTA1 had significantly lower hazards of developing chemotherapy-related amenorrhea compared to survivors who were homozygous for the minor allele ( hazard ratio, HR=0.22 [ 95% CI 0.61-0.91 ] ).
Survivors with at least one major allele of CYP2C19 had significantly higher hazards of developing chemotherapy-related amenorrhea compared to survivors who were homozygous for the minor allele ( HR=4.56 [ 95% CI 1.54-13.57 ] ).
CYP3A4 and GSTP1 SNPs were not related to chemotherapy-related amenorrhea.
Increased age was also associated with chemotherapy-related amenorrhea.
In separate multivariable models adjusting for age and body mass index ( BMI ), GSTA1 remained significantly associated with chemotherapy-related amenorrhea ( HR=0.23 [ 95% CI 0.06-0.96 ], p¼0.04 ) while CYP2C19 was attenuated ( HR=2.75 [ 0.89-8.49 ] ).
In conclusion, in younger breast cancer patients undergoing Cyclophosphamide-based chemotherapy, the presence of one or more major alleles of GSTA1 was found to have lower risk of developing chemotherapy-related amenorrhea.
Inter-individual variation in enzymes involved in chemotherapy metabolism is related to post-treatment ovarian function. ( Xagena )
Source: American Society for Reproductive Medicine ( ASRM ) Annual Meeting, 2015