Genetic variants in oxidative stress-related genes predict chemoresistance in primary breast cancer: a prospective observational study and validation
Menée à partir d'échantillons tumoraux prélevés sur deux cohortes de 806 et 339 patientes atteintes d'un cancer primitif du sein, cette étude observationnelle montre une association entre des polymorphismes de gènes impliqués dans le stress oxydant et la résistance des cellules tumorales à la chimiothérapie
Chemotherapy response in patients with primary breast cancer is difficult to predict and the role of host genetic factors has not been thoroughly investigated. We hypothesized that polymorphisms in oxidative stress (OS)-related genes, including estrogen-quinone metabolizing enzymes NQO2 and GSTM1-5, may influence disease progression and treatment response. In this prospective observational study, nineteen polymorphisms tagging known variations in candidate genes were genotyped and analyzed in 806 patients with primary breast cancer. Three functional polymorphisms, which were demonstrated to affect genes expression levels in experiments in vitro and ex vivo, modified the effect of chemotherapy on disease-free survival (DFS). There were significant interactions between chemotherapy and individual polymorphisms or combined genotypes (designated as Genetic-Score). Patients harboring high Genetic-Score had a 75% reduction in the hazard of disease progression compared to patients with low Genetic-Score when no chemotherapy was administered (hazard ratio [HR]=0.25, 95%CI: 0.10-0.63, P=0.005); however, they received much less survival benefit from adjuvant chemotherapy compared to patients with low Genetic-Score when chemotherapy was administered (HR=4.60 for interaction, 95%CI: 1.63-13.3, P=0.004). These findings were validated in another population (n=339). In conclusion, germ-line polymorphisms in OS-related genes affect chemotherapy sensitivity in breast cancer patients. Although reduced OS levels might prevent breast cancer progression, they probably compromise the effectiveness of adjuvant chemotherapy. Our findings also indicate that host-related factors must be considered for individualized chemotherapy.
Cancer Research , résumé, 2011