Abstract A032: The EGFR polymorphism R497K compromises the pathological response of breast tumors to neoadjuvant chemotherapy

Abstract

Abstract Introduction:The degree of pathological response of breast tumors to neoadjuvant chemotherapy presents great interindividual variability, and new biomarkers are searched as an attempt to improve outcome prediction, and minimize treatment failure. The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor, which plays an essential role in organ development and growth by regulating the differentiation of cells and tissues. The R497K polymorphism (rs11543848), located in the exon 13 of the EGFR gene, has attenuated functions in ligand binding, tyrosine kinase activation and growth stimulation. Other EGFR polymorphism is a (CA)n dinucleotide repeat sequence in intron 1 (rs72554021), ranging from 14 to 25 repeats. Shorter sequences of this (CA)n dinucleotide repeat sequence are associated with increased gene expression of EGFR in breast tumors. Aim: The aim of the present study was to evaluate the impact of EGFR polymorphisms, in combination with clinicopathological variables, on the degree of response to breast cancer neoadjuvant chemotherapy. Methods: The study protocol was approved by the Ethics Committee of the Brazilian National Cancer Institute (129/08). A cohort of Brazilian women (≥ 18 years old) with unilateral non-metastatic breast cancer undergoing neoadjuvant chemotherapy with cyclophosphamide, doxorubicin, 5-fluoruracil and docetaxel (CAF-T protocol) was evaluated. Genomic DNA was extracted from blood samples and the polymorphism R497K was identified by PCR-RFLP, whereas the fragment length of the intron 1 was determined by capillary electrophoresis. Complete tumor response (cTR) was defined by the absence of remaining tumor in the breast, whereas complete pathological response (cPR) was defined by no residual tumor both in the breast and in axillary lymph nodes. The association between EGFR genotypes and histopathological features or pathological outcomes was evaluated by the Chi-square method. Results: A cohort of 298 patients was analyzed. The rate of cTR was 8.3%, with 6% of patients reaching cPR. The evaluation of (CA)n lengths indicated a range of 14 to 24 repeats, with the major allele being (CA)16 (0.419, 95%CI = 0.380–0.459). The R497K genotypes were in Hardy-Weinberg equilibrium, and the frequency of the Lys allele was 0.197 (95%CI = 0.167–0.230). Patients with the Lys allele had lower chance of achieving cTR (OR = 0.147, 95%CI 0.033-0.664), after adjustment for other independent prognostic factors (tumor grade and molecular classification) Conclusion: Our data suggest that the characterization of the EGFR R497K polymorphism in breast cancer patients may help predicting the pathological response to neoadjuvant chemotherapy. Financial support: MS/FAF, CNPQ, FAPERJ, CAPES. Citation Format: Marcelo Sobral Leite, Letícia Carlos Giacomin, Rodrigo Soares Mora-Neto, Rosane Vianna-Jorge. The EGFR polymorphism R497K compromises the pathological response of breast tumors to neoadjuvant chemotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A032.