BACKGROUND:In late reproductive-aged breast cancer survivors, there is a need for real-time biomarkers of postchemotherapy ovarian function. The objective was to determine whether antimullerian hormone (AMH) and inhibin B are such biomarkers. The authors tested whether AMH and inhibin B were impacted by breast cancer treatment by comparing cancer survivors to age-matched control women and determined the association between these hormones and postchemotherapy menstrual pattern. METHODS: Breast cancer patients (n ¼ 127) with American Joint Committee on Cancer stage I to III disease who were premenopausal at diagnosis were enrolled postchemotherapy and observed. The primary endpoint was chemotherapy-related amenorrhea (CRA) (!12 months of amenorrhea after chemotherapy). Matched pair analyses compared AMH, inhibin B, and follicle-stimulating hormone (FSH) levels between cancer and age-matched control subjects. Associations between hormones, CRA status, and change in CRA status over time were assessed. RESULTS: The median age of the patients at chemotherapy was 43.2 years (range, 26.7-57.8 years). At enrollment, median follow-up since chemotherapy was 2.1 years, and 55% of subjects had CRA. Compared with age-matched controls, cancer subjects had significantly lower AMH (P ¼ .004) and inhibin B (P < .001) and higher FSH (P < .001). AMH (P ¼ .002) and inhibin B (P ¼ .001) were found to be significantly associated with risk of CRA, even after controlling for FSH. AMH was significantly lower (P ¼ .03) and FSH was significantly higher (P ¼ .04) in menstruating subjects who developed subsequent CRA. CONCLUSIONS: AMH and inhibin B are 2 additional measures of postchemotherapy ovarian function in late reproductive-aged breast cancer survivors. With further research and validation, these hormones may supplement limited current tools for assessing and predicting postchemotherapy ovarian function. Cancer 2010;116:592-9.

STRUCTURED ABSTRACTObjective-To determine if genetic variation in chemotherapy metabolism are associated with risk of ovarian failure in breast cancer patients after adjuvant chemotherapy. Design-Prospective cohort study. Setting-Comprehensive cancer center.Patients-Early stage breast cancer patients who were premenopausal at cancer diagnosis and treatment. Interventions-None. Main outcomes measures-Chemotherapy related ovarian failure (CROF)Results-127 breast cancer subjects who were premenopausal at cancer diagnosis and underwent cyclophosphamide-based chemotherapy were genotyped for 9 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 years of follow up since chemotherapy were 5.2 years. For the entire cohort, there was no significant association between CROF and SNPs. However, the association between CROF and SNPs CONFLICTS OF INTEREST: None CAPSULE:A common single nucleotide polymorphism in a cyclophosphamide drug metabolizing enzyme is associated with ovarian failure after cyclophosphamide-based chemotherapy in young breast cancer patients. Genetic variation in chemotherapy metabolism may contribute to inter-individual differences in risk of chemotherapy related ovarian failure. NIH Public Access Author ManuscriptFertil Steril. Author manuscript; available in PMC 2011 July 1. Published in final edited form as:Fertil Steril. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript was modified by age at chemotherapy. In subjects younger than 45 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 less than 45 years of age at chemotherapy. KeywordsOvarian failure; chemotherapy metabolism; genetic polymorphisms; breast cancer IntroductionMore than two million American women are breast cancer survivors (1). One-third of these women are less than 54 years old, and 10 percent of the total are between ages 35 and 45 (2). While chemotherapy has decreased recurrences and improved survival, these medications also induce ovarian damage and aging, resulting in premature ovarian failure and early menopause in a large proportion of women (3-5).Predicting ovarian failure after chemotherapy is important to this large population of reproductive-aged breast cancer survivors. The degree of ovarian function affects breast cancer prognosis, choice of cancer adjuvant therapy, need for contraception, fertility potential and menopausal concerns (6-8). Thus, the ability to predict ovarian function after cancer therapy would impa...