ABCB1 C3435T gene polymorphism as a potential biomarker of clinical outcomes in HER2-positive breast cancer patients.

HER2-positive breast cancer patients treated with trastuzumab schemes have good initial clinical outcomes. Despite this beneficial effect, many patients experiment resistance to these drugs. Several gene polymorphisms in ABCB1, HER2, and CCND1 have been proposed as potential predictors of clinical outcomes of trastuzumab schemes. The aim of this study was to evaluate the association between 4 gene polymorphisms potentially responsible for bad prognosis (HER2-Ile655Val, CCND1-A870G and ABCB1C1236T, C3435T) and clinical outcomes in HER2-positive BC patients. A retrospective cohorts study was performed. Eighty-four HER2-positive BC patients treated with trastuzumab schemes were included. The four gene polymorphisms were analyzed by PCR Real-Time with Taqman® probes. Genotypes were investigated for their association with tumor response, survival and resistance. Patients with CC genotype of ABCB1-C3435T presented higher risk of resistance to chemotherapy/trastuzumab schemes, compared to those carrying the T-allele (RR: 2.71; CI95%:1.29-5.68; p=0.013888), progression (RR: 1.89; p=0.017964); and exitus (RR: 2.09; p=0.03276). Multivariate logistic regression analysis considering clinical variables and ABCB1-C3435T revealed that the only independent factor associated to resistance to therapy was ABCB1-C3435T gene polymorphism (ORCT/CC: 0.25; p=0.0123; ORTT/CC: 0.09; p=0.0348. The protective effect of ABCB1-C3435T T-allele was confirmed in the multivariate Cox regression analysis for PFS (HRCT/CC: 0.41; p=0.00806; HRTT/CC: 0.22; p=0.01982) and OS (HRCT/CC: 0.49; p=0.0555; HRTT/CC: 0.12; p=0.0398). ABCB1-C1236T, CCND1-A870G and HER2-Ile655Val polymorphisms were not associated to resistance, PFS or OS (p>0.05). The A-allele for CCND1-rs9344 was associated with higher response rates (RR: 3.44; uncorrected p-value: 0.03816) in the bivariate analysis, but no statically association was found after Bonferroni correction (p=0.15264). ABCB1-C3435T, ABCB1-C1236T and HER2-Ile655Val gene polymorphisms were not associated with response. Although this study demonstrates a prognostic value of ABCB1-C3435T gene polymorphism to predict clinical outcomes, further studies with a larger sample will be necessary to validate this result.

Association of ABCB1 and VEGFA gene polymorphisms with breast cancer susceptibility and prognosis.

Breast cancer (BC) is the most common cause of cancer-related death in women worldwide. Several ABCB1 and VEGFA gene polymorphisms, such as ABCB1-G1199 T/A (rs2229109), VEGFA -634 G > C (rs2010963), VEGFA 2578 C > A (rs699947) and VEGFA 7 C > T (rs25648) have been associated with risk of BC and clinical outcomes. The purpose of this study was to evaluate the association between these gene polymorphisms and BC risk and prognosis. A retrospective case-control study was conducted, including 84 BC cases and 119 controls of Spanish (European, Caucasian) origin. ABCB1-G1199 T/A (rs2229109), VEGFA -634 G > C (rs2010963), VEGFA 2578 C > A (rs699947) and VEGFA 7 C > T (rs25648) gene polymorphisms were analysed by TaqMan®. The genotypic logistic regression model adjusted by aged revealed no association with any of the polymorphisms and BC risk, although the C-allele of VEGFA 2578 C > A showed a trend to higher BC risk in the allelic and recessive models (p = 0.055 and 0.054, respectively). There was no influence of these gene polymorphisms on overall survival (OS). The univariate Cox model showed that carriers of the A-allele for VEGFA 2578 C > A tended to have longer OS compared to CC patients (CC vs A-allele Hazard ratio (HR): 2.08; CI95 % = 0.96-4.49; p = 0.0587). There was no association between the gene polymorphisms analysed and disease-free survival (DFS). The univariate Cox model showed a trend toward a longer DFS in patients carrying ABCB1-G1199 T/A GG genotype compared to those with A-allele (GG vs A-allele HR: 0.43; CI95 % = 0.18-1.03; p = 0.0612). No influence of ABCB1-G1199 T/A (rs2229109), VEGFA -634 G > C (rs2010963), VEGFA 2578 C > A (rs699947) and VEGFA 7 C > T (rs25648) gene polymorphisms on risk of developing BC was found in our study. There was no association between the polymorphisms studied and DFS and OS.