PTGS2 polymorphism rs689466 favors breast cancer recurrence in obese patients

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 (HR_adj). Obesity did not affect disease progression, whereas rs689466 variant genotypes increased the recurrence risk among obese patients (HR_adj = 2.5; 95% CI = 1.4-4.3), either for luminal (HR_adj = 2.2; 95% CI = 1.1-4.2) or HER2-like and triple-negative tumors (HR_adj = 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_adj = 3.3; 95% CI = 1.8-6.0), either in luminal (HR_adj = 3.5; 95% CI = 1.6-7.3) or HER2-like and triple-negative (HR_adj = 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.