RESUMO
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 (N = 1038). Disease-free survival was evaluated using Kaplan-Meier curves, with multivariate Cox proportional hazards regression models for calculation of adjusted hazard ratios (HRadj). Obesity did not affect disease progression, whereas rs689466 variant genotypes increased the recurrence risk among obese patients (HRadj = 2.5; 95% CI = 1.4-4.3), either for luminal (HRadj = 2.2; 95% CI = 1.1-4.2) or HER2-like and triple-negative tumors (HRadj = 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 (HRadj = 3.3; 95% CI = 1.8-6.0), either in luminal (HRadj = 3.5; 95% CI = 1.6-7.3) or HER2-like and triple-negative (HRadj = 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.
Assuntos
Neoplasias da Mama/genética , Ciclo-Oxigenase 2/genética , Recidiva Local de Neoplasia/genética , Obesidade/genética , Idoso , Neoplasias da Mama/patologia , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Obesidade/patologia , Polimorfismo de Nucleotídeo Único , Prognóstico , Modelos de Riscos ProporcionaisRESUMO
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 = 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 (HRadjusted). Variant genotypes of rs699947 (CA + AA) were significantly associated with high-grade (G2 + G3) tumors (OR = 1.82; 95% CI = 1.15 - 2.89), and with shorter disease-free survival among patients treated with neoadjuvant chemotherapy followed by mastectomy (HRadjusted = 1.82; 95% CI = 1.16 - 2.86). Variant genotypes of rs833061 (TC + CC) were significantly associated with high-grade (G2 + G3) tumors (OR = 1.79; 95% CI = 1.12 - 2.84) and with positive lymph node status (OR = 1.34; 95% CI = 1.01 - 1.77), but showed no independent effect on disease-free survival. Variant haplotypes (*2 to *5) appear to favor pCR (OR = 7.1; 95% CI = 1.7 - 30.1). VEGFA genotyping may add to prognostic evaluation of breast cancer, with rs699947 being the most likely to contribute.