Genetic Polymorphisms of DNA Repair Genes and their Influence on Paclitaxel based Chemotherapy Induced Toxicity Reactions in Breast Cancer Patients.

Background: Systemic chemotherapy constitutes an indispensable component of breast cancer (BC) management, where therapeutic drug combinations such as anthracyclines, platinum compounds, and taxanes form the cornerstone of standard treatment protocols. Although DNA repair genes are pivotal in cancer susceptibility, their specific roles in mediating acute or chronic toxicity outcomes induced by chemotherapy remain undetermined. Consequently, this study was planned  to elucidate the impact of polymorphisms in base excision repair (BER) genes, including XRCC1, XRCC2, XRCC3, APE1, and hOGG1, on treatment response and toxicity outcomes in BC patients undergoing paclitaxel and doxorubicin-based chemotherapy within an Indian population.

Methods: One hundred and four (104) BC patients receiving combined paclitaxel and doxorubicin chemotherapy were enrolled with documentation of both hematological and non-hematological toxicity reactions induced by the treatment. Genetic polymorphism of XRCC1, XRCC2, XRCC3, APE1, and hOGG1 genes was investigated using Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) analysis.

Results: Analysis of the demographic characteristics of BC patients revealed a significant association between mucositis and peripheral neuropathy with advancing age. An increased body mass index was also significantly correlated with hematological toxicities, such as neutropenia (p=0.022) and febrile neutropenia (p=0.048), as well as with peripheral neuropathy (p=0.001). Univariate logistic regression analysis demonstrated a significant association between the XRCC3 (Ser241Cys) polymorphism and peripheral neuropathy (OR=3.00, 95% CI: 1.29-6.95; p=0.010). Similarly, regression analysis indicated a significant association of APE-1 (Asp148Glu) polymorphism with febrile neutropenia (OR=3.55, 95% CI: 1.03-12.21; p=0.044) and chemotherapy-induced nausea and vomiting (CINV) (OR=4.19, 95% CI: 1.61-10.94; p=0.003) in BC patients treated with paclitaxel and Doxorubicin regimen.

Conclusion: The findings from this study underscore the significant influence of genetic polymorphisms in XRCC3 (Ser241Cys) and APE-1 (Asp148Glu) on the acute toxicity effects induced by paclitaxel in BC patients.