Impaired TamoxifenMetabolism Reduces Survival in Familial Breast Cancer Patients

Purpose: Tamoxifen has been the mainstay adjuvant hormonal treatment for breast cancer for many years. Conversion of tamoxifen to its active metabolite, endoxifen, is reduced by low activity of the cytochrome P450 enzyme, CYP2D6.We examined the effect of reducedCYP2D6 activity on the response to tamoxifen in patients with familial early-onset breast cancer. Experimental Design:We conducted a case note review and genotyping for the CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*41 alleles in 115 patients (47 BRCA1, 68 BRCA2) with familial breast cancer who had been treated with 20-mg tamoxifen following surgery. Results: Eight (7%) individuals had genotypes consistent with poor metabolizer status, and 4 (3.5%) individuals took CYP2D6 inhibitor drugs concomitant with their tamoxifen andwere also considered poor metabolizer.Time to tumor recurrence, disease-free survival, and overall survival were reduced in the patient groupwith poor metabolizer CYP2D6 activity. However, a significant effect was confined to patients with BRCA2 mutations with a worse overall survival (median survival, 7 versus 28 years; P = 0.008; adjusted hazard ratio, 9.7). Conclusions: Poor metabolizer status for CYP2D6 predicts worse overall survival in patients with familial breast cancer. Therefore, CYP2D6 inhibitor drugs should not be prescribed concomitantly with tamoxifen. Prospective studies should be undertaken to establish the effect of CYP2D6 status on outcome in familial breast cancer patients treated with tamoxifen. Breast cancer is the most common cancer in females, with more than 1 million women worldwide diagnosed every year (1). In the United States, f170,000 new diagnoses of invasive breast cancer are expected in 2007 (2). Familial susceptibility to breast cancer accounts for f10% to 25% of all breast cancer cases, with the majority of high risk familial breast cancer cases due to mutations in the BRCA1 and BRCA2 genes (3, 4). The lifetime risks for developing breast cancer are 65% to 85% and 45% to 85% for BRCA1 and BRCA2 mutation carriers, respectively (5). In addition, BRCA1 and BRCA2 mutation carriers have increased lifetime risks of ovarian cancer of 37% to 62% and 11% to 23%, respectively (6). Importantly, breast cancer due to BRCA1 and BRCA2 mutations accounts for a disproportionately high number of life-years lost because of the early onset of disease. Currently, the treatment of breast cancer in women with BRCA1 or BRCA2 mutations does not differ from the treatment in women with sporadic breast cancer (7). However, trials of poly(ADP-ribose) polymerase inhibitors and platinumversus taxane-based chemotherapy are under way in patients with metastatic BRCA1and BRCA2-related breast cancer, aiming to exploit impaired DNA damage response pathways (8). Often, the presence of a BRCA1 or BRCA2 mutation is unknown at the time of primary treatment and so is unavailable to guide treatment decisions (9). In the majority of studies, ipsilateral and contralateral breast cancer rates of recurrence have been increased in women with BRCA1 or BRCA2 mutations compared with women with sporadic breast cancer (10, 11). Histopathologic analyses have shown important differences between BRCA1and BRCA2-related breast tumors (12). Notably, sporadic and BRCA2-related breast cancers are more likely to be estrogen receptor (ER) positive than those with BRCA1 mutations (13). Tamoxifen is a selective ER modulator and its antagonist properties predominate in breast tissue. It remains the standard adjuvant therapy for premenopausal women and a significant proportion of postmenopausal women with ER-positive breast cancer. Multiple trials have shown its positive influence on disease-free survival and overall survival from breast cancer (14, 15). Specifically, tamoxifen is associated with a 50% reduction in the incidence of contralateral breast cancer in both BRCA1 and BRCA2 mutation carriers, independent of the ER status of the primary tumor (16, 17). A number of studies have considered the role of pharmacogenetics in breast cancer treatment (18) and recent focus has Cancer Therapy: Clinical Authors’Affiliations: Department of Medical Genetics, St. Mary’s Hospital, and Health ResearchMethodologyGroup, University ofManchester; and Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, United Kingdom Received12/20/07; revised 4/28/08; accepted 5/15/08. Grant support: Genesis UK. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Requests for reprints:William G. Newman, Department of Medical Genetics, St. Mary’s Hospital, University of Manchester, Manchester M13 0JH, United Kingdom. Phone: 44-161-276-6264; Fax: 44-161-276-6145; E-mail: William.newman@ manchester.ac. uk. F2008 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-5235 www.aacrjournals. org Clin Cancer Res 2008;14(18) September15, 2008 5913 Research. on May 2, 2017. © 2008 American Association for Cancer clincancerres.aacrjournals. org Downloaded from been directed at tamoxifen metabolism. Importantly, pharmacokinetic analyses have indicated that the cytochrome P450 enzyme CYP2D6 is the rate-limiting step in the conversion of tamoxifen to its active metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen; ref. 19). Endoxifen is up to 100 times more potent than the parent drug in suppressing estrogendependent cell proliferation (20). Reduction in CYP2D6 activity due to polymorphisms in the CYP2D6 gene or to drug inhibitors, including some selective serotonin reuptake inhibitors including fluoxetine and paroxetine, has been shown to reduce endoxifen levels and be associated with poorer outcome in women with breast cancer who have been treated with tamoxifen (21–24). Therefore, we undertook to establish the effect of variation in CYP2D6 and concomitant medication on the outcome of a cohort of patients with familial breast cancer, due to BRCA1 and BRCA2 mutations, treated with tamoxifen. Materials andMethods Of our entire cohort of 456 probands with pathogenic BRCA1 or BRCA2 mutations at a single U.K. cancer genetics center, we ascertained 125 unrelated White Caucasian women (7.8% of Ashkenazi Jewish ethnicity) on whom we had complete clinical data with a range of pathogenic BRCA1 (51) or BRCA2 (74) mutations with breast cancer and who had been treated with tamoxifen following surgery. Germ-line DNA samples extracted from lymphocytes were available from 115 patients (47 BRCA1 and 68 BRCA2 mutations). We genotyped the patient cohort and a healthy ethnically matched control population without cancer (90 individuals) for the common CYP2D6 null alleles, CYP2D6*3 (c.2549delA), and CYP2D6*4 (c.1934G>A+1), and the intermediate allele CYP2D6*41 (c. 2988G>A) by TaqMan allelic discrimination methods (Applied Biosciences). Quality assurance was ensured by sequence analysis of 10% of samples. In addition, the CYP2D6 gene deletion CYP2D6*5 was genotyped by a TaqMan dosage