Abstract A26: The distribution pattern of ERα expression, VEGFR2 expression level and its genetic variation as potential biomarkers for tamoxifen resistance
Authors: Babyshkina Nataliya , Vtorushin Sergey , Patalyak Stanislav , Dronova Tatyana , Slonimskaya Elena , Cherdyntseva Nadejda 
Published: May 2016

Background. The crosstalk between estrogen receptor alpha (ERα) and growth factor receptors is an essential part of tamoxifen resistance and the vascular endothelial growth factor/ tyrosine kinase domain receptor (VEGF/KDR) signaling pathway is clinically significant in the mechanisms of this resistance. The aim of the present study was to analyze the association of distribution pattern of ERα expression, VEGFR2 expression level, ESR1 and KDR single nucleotide polymorphisms (SNPs) with tamoxifen response in hormone receptor-positive primary breast cancer.

Material and methods. Formalin-fixed paraffin-embedded and fresh frozen breast cancer tissue of the primary tumor was obtained from 97 hormone receptor-positive breast cancer patients treated with adjuvant tamoxifen at the Tomsk Cancer Research Institute. The distribution patterns of ERα expression and Ki-67 protein expression were determined by immunohistochemistry. The quantitative expression levels of VEGFR2 (CD309) and p-Akt473 was measured using a flow cytometry. TaqMan SNP assays were used for genotyping ESR1+30T&gt;C (rs2077647), ESR1 2014G&gt;A (rs2228480), KDR-604T&gt;C (rs2071559) and KDR 1192G&gt;A (rs2305948) polymorphisms. Progression-free survival (PFS) was used as end-point for survival analyses.

Results. Patients who did not benefit from tamoxifen treatment (tamoxifen resistance group -TR) showed significantly higher heterogeneous ERα expression than tamoxifen sensitive patients (TS; 81.1% and 58.3% respectively, P = 0.021). We found that ESR12014A mutant allele carriers were more prevalent in TR patients than in TS group (26.3% vs. 8.0%, respectively, P = 0.009). Similarly, the KDR -604T allele of rs2071559 was statistically significant related with tamoxifen resistance (P = 0.034). However, the KDR 1192G allele of rs2305948 were significantly less common in the tamoxifen progressive group compared to the tamoxifen sensitive patients (38.0% vs. 90.0%, respectively, P = 0.035). In addition, the variant homozygote KDR 1192GG (vs. AA) of rs2305948 was associated with VEGFR2 expression (r = -0.524, p = 0.012). VEGFR2 expression levels also showed borderline significant correlation with p-Akt473 expression (r = 0.368, p = 0.070). The Kaplan-Meier survival analysis demonstrated a significant relationship of heterogeneous distribution of ERα expression with poor survival of tamoxifen treated patients (log-rank P = 0.009). Moreover, the PFS for the patients with the KDR -604TT genotypes of rs2071559 were worse than for the patients with the CC genotype (log-rank P = 0.123).

Conclusion. The distribution pattern of ERα expression, VEGFR2 expression level and its genetic variation can serve as potential predictors for hormone receptor-positive breast cancer patients treated with adjuvant tamoxifen and thus provide more information for optimizing patient's selection to tamoxifen adjuvant therapy.

Citation Format: Nataliya Babyshkina, Sergey Vtorushin, Stanislav Patalyak, Tatyana Dronova, Elena Slonimskaya, Nadejda Cherdyntseva. The distribution pattern of ERα expression, VEGFR2 expression level and its genetic variation as potential biomarkers for tamoxifen resistance. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A26.