AUTHOR=Cerpa Leslie C. , Sandoval Christopher , Escalante Paula , Cayún Juan P. , Lavanderos María A. , Alarcón-Concha Claudio , Kaempfe Guillermo , Moreno-Tapia Diego , Quiroz Camilo S. , Gutierrez-Cáceres Carolina , Barajas Olga , Müller Bettina , Colombo Alicia , Donoso Gerardo , Nuñez Angie , Varela Nelson M. , Quiñones Luis A. 

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

JOURNAL=Frontiers in Oncology

VOLUME=Volume 15 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2025.1589724

DOI=10.3389/fonc.2025.1589724

ISSN=2234-943X

ABSTRACT=BackgroundColorectal 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.ObjectiveThis 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.MethodsA 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.ResultsAmong 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.ConclusionsThis 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.