BackgroundThe epidermal growth factor receptor (EGFR) is differently expressed in breast cancer, and its presence may favor cancer progression. We hypothesized that two EGFR functional polymorphisms, a (CA)n repeat in intron 1, and a single nucleotide polymorphism, R497K, may affect EGFR expression and breast cancer clinical profile.MethodsThe study population consisted of 508 Brazilian women with unilateral breast cancer, and no distant metastases. Patients were genotyped for the (CA)n and R497K polymorphisms, and the associations between (CA)n polymorphism and EGFR transcript levels (n = 129), or between either polymorphism and histopathological features (n = 505) were evaluated. The REMARK criteria of tumor marker evaluation were followed.Results(CA)n lengths ranged from 14 to 24 repeats, comprehending 11 alleles and 37 genotypes. The most frequent allele was (CA)16 (0.43; 95% CI = 0.40–0.46), which was set as the cut-off length to define the Short allele. Variant (CA)n genotypes had no significant effect in tumoral EGFR mRNA levels, but patients with two (CA)n Long alleles showed lower chances of being negative for progesterone receptor (ORadjusted = 0.42; 95% CI = 0.19–0.91). The evaluation of R497K polymorphism indicated a frequency of 0.21 (95% CI = 0.19 – 0.24) for the variant (Lys) allele. Patients with variant R497K genotypes presented lower proportion of worse lymph node status (pN2 or pN3) when compared to the reference genotype Arg/Arg (ORadjusted = 0.32; 95% CI = 0.17–0.59), which resulted in lower tumor staging (ORadjusted = 0.34; 95% CI = 0.19-0.63), and lower estimated recurrence risk (OR = 0.50; 95% CI = 0.30-0.81). The combined presence of both EGFR polymorphisms (Lys allele of R497K and Long/Long (CA)n) resulted in lower TNM status (ORadjusted = 0.22; 95% CI = 0.07-0.75) and lower ERR (OR = 0.25; 95% CI = 0.09-0.71). When tumors were stratified according to biological classification, the favorable effects of variant EGFR polymorphisms were preserved for luminal A tumors, but not for other subtypes.ConclusionsThe data suggest that the presence of the variant forms of EGFR polymorphisms may lead to better prognosis in breast cancer, especially in patients with luminal A tumors.
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.
Introdução: A quimioterapia neoadjuvante do câncer de mama visa a redução da extensão tumoral e da área cirúrgica, favorecendo a conservação da mama e a sobrevida pós-mastectomia. O grau de resposta patológica, baseado no tamanho do tumor residual e no grau de acometimento linfonodal após ressecção tumoral, tem sido proposto como desfecho primário da eficácia antineoplásica, auxiliando a identificação de causas de falha terapêutica. Objetivo: Avaliar o impacto de fatores clinicopatológicos sobre o grau de resposta à quimioterapia neoadjuvante do câncer de mama. Método: Uma coorte de mulheres com câncer de mama unilateral não metastático, submetidas à quimioterapia neoadjuvante com doxorrubicina e docetaxel, foi avaliada quanto ao grau de resposta patológica. Resultados: Foram avaliadas 227 pacientes com desfecho clínico definido após tratamento quimioterápico neoadjuvante, entre as quais, 4,8% tiveram resposta patológica completa (ausência de remanescentes tumorais na mama e nos linfonodos axilares) e 5,7% apresentaram progressão de doença. As variáveis associadas a maior risco de falha terapêutica foram: comprometimento linfonodal em qualquer grau (OR=15,25; IC95%=2,11-110,01) e positividade para receptor de estrogênio (OR=14,62; IC95%=3,05-70,01). Como consequência, houve melhor perfil de resposta para pacientes com tumores do subtipo molecular HER2 (OR=0,04; IC95%=0,00-0,40) ou triplo-negativo (OR=0,08; IC95%=0,00-0,60) em comparação ao tipo luminal A. Conclusão: A resposta tumoral à quimioterapia neoadjuvante não foi afetada por comorbidades sistêmicas, mas e influenciada pela expressão de receptores de estrogênio.
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.
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