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Background: The 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., Methods: The 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., Conclusions: The 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.

Cyclooxygenase-2 (COX-2) overexpression is associated with worse prognosis in breast cancer. COX-2 is encoded by a polymorphic gene, called PTGS2, and its expression may be genetically influenced. In this article, we investigate the association between PTGS2 haplotypes and histopathological parameters with prognostic value on the clinical outcome of breast cancer. The study involved 606 women under current treatment for non-metastatic breast cancer. Patients were genotyped for rs689465, rs689466, rs20417, and rs5275, and their haplotypes were inferred. The distribution of PTGS2 genotypes and haplotypes was evaluated according to histopathological categorical groups used for prognostic determination of low/intermediate versus high risk of tumor recurrence. Our results indicate positive associations between variant genotypes of rs689465 and estrogen receptor negativity (OR: 1.59, 95% CI: 1.04-2.44, P: 0.02) or HER2 positivity (OR: 1.79, 95% CI: 1.00-3.18, P: 0.03), and between variant genotypes of rs20417 and estrogen receptor negativity (OR: 1.75, 95% CI: 1.15-2.57, P: 0.005), progesterone receptor negativity (OR: 1.56, 95% CI: 1.09-2.22, P: 0.01) or HER2 positivity (OR: 1.80, 95% CI: 1.04-3.13, P: 0.02). In contrast, variant genotypes of rs689466 are negatively associated with estrogen receptor negativity (OR: 0.57, 95% CI: 0.33-0.98, P: 0.03). A total of eight haplotypes were inferred, and there was a significant difference in their distribution as a function of tumor size (P: 0.011), estrogen receptor status (P: 0.018), and HER2 status (P: 0.025). PTGS2 haplotype *7 (formed by rs689465G, rs689466A, rs20417C, and rs5275T) is positively associated with higher tumor size (OR: 3.72, 95% CI: 1.19-11.22, P: 0.006), estrogen receptor negativity (OR: 2.43, 95% CI: 0.97-5.98, P: 0.032), progesterone receptor negativity (OR: 2.58, 95% CI: 1.05-6.39, P: 0.02), and HER2 positivity (OR: 4.17, 95% CI: 1.19-14.44, P: 0.007). Our results suggest that PTGS2 haplotype *7 may contribute to higher growth of untreated breast cancer and that PTGS2 haplotypes need to be considered in the characterization of breast cancer prognosis.