Evaluation of the EGFR polymorphism R497K in two cohorts of neoadjuvantly treated breast cancer patients.

Marcelo Sobral-Leite,Letícia Carlos Giacomin,Daniely Regina Freitas-Alves,Esther H Lips,Lennart Mulder,Jelle Wesseling,Hayra De Andrade Vieira-Monteiro,Rosane Vianna-Jorge,Marjanka K Schmidt,Sten Cornelissen,William B Coleman

doi:10.1371/journal.pone.0189750

Abstract

Pathological response of breast cancer to neoadjuvant chemotherapy (NAC) presents great variability, and new prognostic biomarkers are needed. Our aim was to evaluate the association of the epidermal growth factor receptor gene (EGFR) polymorphism R497K (rs2227983) with prognostic features and clinical outcomes of breast cancer, including the pathological response to NAC and the recurrence-free survival (RFS). Tumoral complete response (tCR) was defined by no remaining invasive cancer in the excised breast, whereas pathological complete response (pCR) was defined by no remaining invasive cancer both in the excised breast and lymph nodes. Two independent cohorts were analyzed: one from Brazil (INCA, n = 288) and one from The Netherlands (NKI-AVL, n = 255). In the INCA cohort, the variant (Lys-containing) genotypes were significantly associated with lower proportion of tCR (ORadj = 0.92; 95%CI = 0.85–0.99), whereas in the NKI-AVL cohort they were associated with tumor grade 3 (p = 0.035) and with triple-negative subtype (p = 0.032), but not with clinical outcomes. Such distinct prognostic associations may have arisen due to different neoadjuvant protocols (p < 0.001), or to lower age at diagnosis (p < 0.001) and higher proportion of tumor grade 3 (p = 0.018) at the NKI-AVL cohort. Moreover, NKI-AVL patients achieved better proportion of pCR (21.2% vs 8.3%, p < 0.001) and better RFS (HRadj = 0.48; 95% adjCI = 0.26–0.86) than patients from INCA. In conclusion, large scale studies comprehending different populations are needed to evaluate the impact of genome variants on breast cancer outcomes.

Highlights

Breast cancer (BC) is the most frequent type of cancer in women both in the developed and the developing world [1]
The current study was conducted with patients who were submitted to surgery after neoadjuvant chemotherapy (NAC) and had genotyping data (n = 288 for INCA and 255 for the NKI-AVL cohort)
Regarding R497K, the variant Lys allele was more frequent at the NKI-AVL (0.25; 95% confidence intervals (95%confidence interval (CI)) = 0.21–0.28) than at the INCA cohort (0.19; 95%CI = 0.16–0.23, p = 0.044), and the frequency of combined variant genotypes was slightly, yet significantly, higher in the NKI-AVL cohort (Table 1)

Summary

Introduction

Breast cancer (BC) is the most frequent type of cancer in women both in the developed and the developing world [1]. It is a very heterogeneous disease with regards to its morphology, molecular profile, and clinical course [2], and new prognostic biomarkers are needed to improve treatment selection [3]. The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor of the ErbB family, whose activation leads to mitogenic signaling (4). Moriai et al showed an attenuated tyrosine kinase activity associated with the variant 'A' allele, with consequent reductions in ligand binding, growth stimulation, and induction of proto-oncogenes MYC, FOS, and JUN [10]. The R497K-Lys variant seems to have no impact on the risk of developing cancer [13], it has been associated with better clinical outcomes in different cancer populations [14,15,16,17,18,19,20,21,22]

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