Impaired Tamoxifen Metabolism Reduces Survival in Familial Breast Cancer Patients

Abstract

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 reduced CYP2D6 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 and were also considered poor metabolizer. Time to tumor recurrence, disease-free survival, and overall survival were reduced in the patient group with 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 platinum-versus taxane-based chemotherapy are under way in patients with metastatic BRCA1-and 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 w...

Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen

“…The 115 enrolled patients were genotyped for the CYP2D6 *wt, *3, *4, *5 and *41 alleles. Poor metabolizers showed a significantly worse overall survival, a condition that was also observed in the subset analysis considering only CYP2D6*4, especially in BRCA2 carriers [16] . Karle et al [17] analysed the effect of the CYP2D6 genotyping in a palliative setting, enrolling 88 patients with ER positive advanced breast cancer.…”

“…In five of them the investigation focused exclusively on allele*4, while in the study of Newmann et al [16] performed in patients with familiar breast cancer, a subanalysis for *4 alone has also been performed [7,8,11,13,15] . In six other, the analysis included a larger pool of intermediate/poor metabolizers based on a combined basis of common non-functional alleles, including allele*4 [6,7,9,11,14,16] . All of them were unique regarding the worse clinical course of ER+ breast cancer under tamoxifen therapy in non-extensive metabolizers.…”

“…Many of all existing studies analyse cohorts that include a number of patients with ER-negative disease [15,16,20,23,24] , while two other provide no sufficient data regarding the hormonal status of the enclosed population [11,13] . This condition represents a strong limitation in the interpretation of the published results.…”

“…August 10, 2014|Volume 5|Issue 3| WJCO|www.wjgnet.com Goetz et al [8] RFS DFS OS NS (P = 0.075) NS (P = 0.097) NS Worse (P = 0.005) Worse (P = 0.008) NS Scroth et al [9,10] RR MR [12] DFS 118 mo 114 mo 98 mo Bijl et al [13] RBCM NS Increased (P = 0.041) Newman et al [16] OS Worse Karle et al [17] PFS 14 mo 9 mo Abraham et al [20] BCSS NS Nowell [23] BCR, OS NS NS Rae et al [25] RR NS NS Regan et al [26] BCE prospective multicenter randomised trial (Austrian Breast and Colorectal Study 8 -ABCSG trial 8) have been newly published. In this cohort 3901 postmenopausal patients with resected ER+ early cancer were randomised to receive either five years tamoxifen or two years tamoxifen followed by anastrazole administration over three more years.…”

Antidepressant use and risk of central nervous system metastasis

“…Reasons for this inconsistency in previous studies include differences in SSRI inhibition ability, genomic differences, differences in data collection, limited information on tamoxifen compliance, and small sample size [274]. Research on genotype and concomitant antidepressant use is also limited by small sample size [280][281][282], with sample sizes in some studies ranging from n=4 to n=13, too small to draw any conclusion [281,282]. More research must be conducted to determine if this interaction truly exists.…”