Genetic variants and clinical determinants affecting the response to 5-Fluorouracil-based treatment in Chilean patients with advanced colorectal cancer

Leslie Carol Cerpa¹Christopher Sandoval²Paula Escalante¹Juan Pablo Cayun Pellizaris¹Maria Alejandra Lavanderos¹Claudio Alarcón-Concha¹Guillermo Kaempfe¹Diego Moreno-Tapia¹Camilo Salvador Quiroz¹Carolina Gutierrez-Cáceres¹Olga Barajas³Bettina Müller⁴Alicia Colombo⁵Gerardo Donoso⁵Angie Nuñez⁶Nelson M Varela¹Luis Abel Quiñones^1*

• ¹Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic and Clinical Oncology, Faculty of Medicine, University of Chile, Santiago de Chile, Santiago Metropolitan Region (RM), Chile
• ²Felix Bulnes Hospital, Santiago, Santiago Metropolitan Region (RM), Chile
• ³Clinical Hospital of the University of Chile, Santiago, Santiago Metropolitan Region (RM), Chile
• ⁴National Cancer Institute, Santiago, Chile
• ⁵Biobank of Fluids and Tissues of the University of Chile, Santiago, Chile
• ⁶Faculty of Pharmacy, University of Costa Rica, San José, San Jose, Costa Rica

Background: Colorectal cancer is the second most prevalent cancer in Chile, affecting both sexes. Late-stage diagnosis occurs in approximately 25% of cases, with a five-year survival rate of only 14%. Standard treatment involves surgical resection followed by 5-fluorouracil-based chemotherapy, often combined with oxaliplatin or irinotecan. However, patient responses vary significantly due to genetic polymorphisms affecting drug metabolism, including variants in TYMS, DPYD, GSTs, and DNA repair enzymes. While genetic factors influencing chemotherapy outcomes have been studied, their impact remains unclear and varies across populations. No predictive model integrating genetic and clinical variables for chemotherapy safety in Chilean colorectal cancer patients has been established. Objective: This study aimed to identify relevant genetic variants in TYMS, TYMP, DPYD, GSTP1, MTHFR, ERCC2, ABCB1, ABCC2, ABCC4, and ABCG2 genes, which, combined with clinical factors, could contribute to a predictive model for 5-FU-based chemotherapy safety in advanced colorectal cancer patients. Methods: A retrospective nested case-control study was conducted on 82 advanced colorectal cancer patients. Sixteen genetic variants were analyzed to assess their association with adverse reactions and their severity using logistic regression. Multivariate models were developed to predict chemotherapy safety. Results: Among the 16 variants analyzed in 82 patients, key findings included: The G allele of GSTP1 (rs1695) was protective against neuropathy (OR = 0.147; p = 0.012) but increased mucositis risk (OR = 2.27; p = 0.036). The C allele of DPYD (rs1801265) was linked to a higher neuropathy risk (OR = 4.58; p = 0.05). The TYMS deletion genotype (rs11280056) conferred protection against hematological adverse reactions (OR = 0.029; p = 0.001). On the other hand, the 3R genotype of TYMS 5'UTR (rs45445694) is associated as a risk factor for skin and subcutaneous tissue disorders (OR = 6.40; p = 0.029). Two multivariate models were developed to predict anemia (p = 0.027) and pain (p = 0.01) development.This study provides a foundation for developing pharmacogenetic-based predictive models for adverse reactions associated with 5-FU, including neuropathy, mucositis, and hematological and skin toxicities. Future research may refine these models to enable personalized dose adjustments, improving chemotherapy safety in Chilean colorectal patients.