Common variants in genes coding for chemotherapy metabolizing enzymes, transporters, and targets: a case–control study of contralateral breast cancer risk in the WECARE Study

Abstract

PurposeWomen who receive chemotherapy for a first primary breast cancer have been observed to have a reduced risk of contralateral breast cancer (CBC), however, whether the genetic profile of a patient modifies this protective effect is currently not understood. The purpose of this study is to investigate the impact of germline genetic variation in genes coding for drug metabolizing enzymes, transporters, and targets on the association between chemotherapy and risk of CBC.MethodsFrom the population-based Women’s Environment Cancer and Radiation Epidemiology (WECARE) Study, we included 636 Caucasian women with CBC (cases) and 1,224 women with unilateral breast cancer (controls). The association between common chemotherapeutic regimens, CMF and FAC/FEC, and risk of CBC stratified by genotype of 180 single nucleotide polymorphisms in 14 genes selected for their known involvement in metabolism, action, and transport of breast cancer chemotherapeutic agents, were determined using conditional logistic regression.ResultsCMF (RR = 0.5, 95 % CI 0.4, 0.7) and FAC/FEC (RR = 0.7, 95 % CI 0.4, 1.0) are associated with lower CBC risk relative to no chemotherapy in multivariable-adjusted models. Here we show that genotype of selected genes involved in the metabolism and uptake of these therapeutic agents does not significantly alter the protective effect of either CMF or FAC/FEC on risk of CBC.ConclusionThe results of this study show that germline genetic variation in selected gene does not significantly alter the protective effect of CMF, FAC, and FEC on risk of CBC.Electronic supplementary materialThe online version of this article (doi:10.1007/s10552-013-0237-6) contains supplementary material, which is available to authorized users.

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

“…ditional chemotherapy. This observation was also issued among CYP2D6*4 carriers [24] . The Arimidex, Tamoxifen Alone or in Combination (ATAC) study was a doubleblind randomized clinical trial in which postmenopausal women with early-stage breast cancer were randomly assigned to receive anastrozole alone, tamoxifen alone, or a combination of both agents in a double-blind fashion.…”

“…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.…”

Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci

“…Six additional variants were reported for several phenotypes (Table 2) in previous candidate gene, patent filing or GWAS studies, but their P values were not specified or did not reach the genome-wide significance level 31–36 . By contrast, the remaining eight variants were missense SNPs that have not been reported in the NHGRI GWAS Catalog for any trait (Table 2).…”

Association of CYP3A4/5, ABCB1 and ABCC2 polymorphisms and clinical outcomes of Thai breast cancer patients treated with tamoxifen

“…Tamoxifen is extensively metabolized by cytochrome P450 (CYP) enzyme 2D6 in the liver to produce pharmacologically active metabolites such as endoxifen and 4-hydroxytamoxifen 2. It is well documented that CYP2D6 polymorphisms play an important role in tamoxifen effectiveness;3 however, some findings have been inconsistent 4–7. To date, there is no consensus whether CYP2D6 genotyping is definitely essential before receiving the drug regimen.…”