Abstract
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 shown to affect gene expression levels in experiments in vitro and ex vivo, modified the effect of chemotherapy on disease-free survival. 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 with patients with low genetic score when no chemotherapy was administered (HR = 0.25, 95% CI: 0.10-0.63, P = 0.005); however, they received much less survival benefit from adjuvant chemotherapy compared with 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, germline 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.
Highlights
It is well established that estrogens and their metabolites play critical roles in breast carcinogenesis
We investigate whether women harboring genetic variations in estrogen–quinone metabolizing genes involved in oxidative stress (OS) experience different disease progression, and we explore the effect of these variations on chemotherapy response, which is determined by the survival after diagnosis of breast cancer in the adjuvant setting
In this prospective observational study, we noted that associations between disease-free survival (DFS) and germline polymorphisms in the estrogen–quinone metabolizing genes involved in OS were modified by adjuvant chemotherapy
Summary
It is well established that estrogens and their metabolites play critical roles in breast carcinogenesis. The estrogen–quinone metabolizing enzymes are involved in breast carcinogenesis but are related to the detoxification of reactive oxygen species The role of NQO2 in breast cancer prognosis, as well as in chemotherapy response, is still unclear. Our previous studies concluded that genetic variants in NQO2 and GSTM1-5 are related to breast cancer risk to different extents [6, 7]. The influence of variations in OS-related genes on breast cancer progression and prognosis might depend on whether a patient underwent chemotherapy or not. We investigate whether women harboring genetic variations in estrogen–quinone metabolizing genes involved in OS experience different disease progression, and we explore the effect of these variations on chemotherapy response, which is determined by the survival after diagnosis of breast cancer in the adjuvant setting
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
