Vascular Endothelial Growth Factor (VEGF) mediates angiogenesis, which is crucial for tumor development and progression. The present study aimed to evaluate the impact of VEGFA gene polymorphisms rs699947, rs833061, rs1570360, rs2010963 and rs3025039 on breast cancer features and prognosis. A cohort of Brazilian women (N D 1038) with unilateral non-metastatic breast cancer was evaluated. The association between VEGFA polymorphisms and histopathological features or pathological complete response (pCR) to neoadjuvant chemotherapy was evaluated by the Chi-square test, with calculation of the respective odds ratio (OR) and 95% confidence intervals (95% CI). The impact of individual categories on disease-free survival was evaluated using Kaplan-Meier curves and multivariate Cox proportional hazards regression models for calculation of adjusted hazard ratios (HR adjusted ). Variant genotypes of rs699947 (CA C AA) were significantly associated with high-grade (G2 C G3) tumors (OR D 1.82; 95% CI D 1.15 -2.89), and with shorter diseasefree survival among patients treated with neoadjuvant chemotherapy followed by mastectomy (HR adjusted D 1.82; 95% CI D 1.16 -2.86). Variant genotypes of rs833061 (TC C CC) were significantly associated with highgrade (G2 C G3) tumors (OR D 1.79; 95% CI D 1.12 -2.84) and with positive lymph node status (OR D 1.34; 95% CI D 1.01 -1.77), but showed no independent effect on disease-free survival. Variant haplotypes ( à 2 to à 5) appear to favor pCR (OR D 7.1; 95% CI D 1.7 -30.1). VEGFA genotyping may add to prognostic evaluation of breast cancer, with rs699947 being the most likely to contribute.

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.

Breast cancer is the leading cancer among women, and its increasing incidence is a challenge worldwide. Estrogen exposure is the main risk factor, but obesity among postmenopausal women has been shown to favor disease onset and progression. The link between obesity and mammary carcinogenesis involves elevated estrogen production and proinflammatory stimuli within the adipose tissue, with activation of the cyclooxygenase-2 pathway. Here, we evaluate the impact of the four most common cyclooxygenase-2 gene polymorphisms (rs689465, rs689466, rs20417 and rs20417), in combination with obesity, on the risk of breast cancer progression in a cohort of Brazilian breast cancer patients ( = 1038). Disease-free survival was evaluated using Kaplan-Meier curves, with multivariate Cox proportional hazards regression models for calculation of adjusted hazard ratios (HR). Obesity did not affect disease progression, whereas rs689466 variant genotypes increased the recurrence risk among obese patients (HR = 2.5; 95% CI = 1.4-4.3), either for luminal (HR = 2.2; 95% CI = 1.1-4.2) or HER2-like and triple-negative tumors (HR = 3.2; 95% CI = 1.2-8.5). Likewise, the haplotype *4, which contains variant rs689466, was associated with shorter disease-free survival among obese patients (HR = 3.3; 95% CI = 1.8-6.0), either in luminal (HR = 3.5; 95% CI = 1.6-7.3) or HER2-like and triple-negative (HR = 3.1; 95% CI = 1.1-8.9) tumors. Such deleterious impact of variant rs689466 on disease-free survival of obese breast cancer patients was restricted to postmenopausal women. In conclusion, cyclooxygenase-2 genotyping may add to the prognostic evaluation of obese breast cancer patients.