Association of cyclophosphamide drug-metabolizing enzyme polymorphisms and chemotherapy-related ovarian failure in breast cancer survivors.
OBJECTIVE
To determine if genetic variation in chemotherapy metabolism are associated with risk of ovarian failure in breast cancer patients after adjuvant chemotherapy.


METHODS
Prospective cohort study.


METHODS
Comprehensive cancer center.


METHODS
Early-stage breast cancer patients who were premenopausal at cancer diagnosis and treatment.


METHODS
None.


METHODS
Chemotherapy-related ovarian failure (CROF).


RESULTS
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.


CONCLUSIONS
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.
Su
H Irene
HI
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, PA 19146, USA. isu@obgyn.upenn.edu
Sammel
Mary D
MD
Velders
Luke
L
Horn
Michelle
M
Stankiewicz
Corrie
C
Matro
Jennifer
J
Gracia
Clarisa R
CR
Green
Jamie
J
DeMichele
Angela
A
D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics*; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004798:Enzymes / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D015999:Multivariate Analysis; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D016649:Primary Ovarian Insufficiency / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics*; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors
D018906:Antineoplastic Agents, Alkylating; D001189:Aryl Hydrocarbon Hydroxylases; D003520:Cyclophosphamide; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; D004798:Enzymes; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D010089:Oxidoreductases, N-Demethylating; C585599:CYP2B6 protein, human; C510164:CYP3A5 protein, human; C510163:CYP3A4 protein, human; C413545:glutathione S-transferase T1; C484555:GSTA1 protein, human; C496556:GSTP1 protein, human