A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer.

Juan Francisco Miquel, Gareth I Owen, Luis A Quiñones, Marcelo Garrido, Ricardo Armisén, Alejandro H Corvalán, Zhiguang Li, Yuwei Liao, Maria Rodriguez-Fernandez, Miguel Cordova-Delgado, María A Lavanderos, Ignacio N Retamal, Mauricio P Pinto, Matías Muñoz-Medel, Charlotte N Hill, Elisa Cumsille, María Loreto Bravo

Journal: BMC cancer 2021;21(1):1030

PMID: 34525956

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Abstract

BACKGROUND

Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3-4 toxicity.

METHODS

Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms.

RESULTS

Reported grade ≤ 2 and 3-4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70-10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19-1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity.

CONCLUSION

Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.

Address: Faculty of Chemical and Pharmaceutical Sciences, Universidad de Chile, 8380494, Santiago, Chile.; Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, 8331150, Santiago, Chile.; Department of Hematology and Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, 8330032, Santiago, Chile.; Millennium Institute on Immunology and Immunotherapy, 8331150, Santiago, Chile.; Faculty of Dentistry, Universidad de Los Andes, 7620001, Santiago, Chile.; Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic and Clinical Oncology, Faculty of Medicine, Universidad de Chile, 8380494, Santiago, Chile.; Latin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Madrid, Spain.; Escuela de Química y Farmacia, Facultad de Ciencias Médicas, Universidad Bernardo O'Higgins, Santiago, Chile.; Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, 8330032, Santiago, Chile.; Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.; Central Laboratory, Yangjiang People's Hospital, GuangDong Province, Yangjiang, China.; Center of Genome and Personalized Medicine, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.; National Institute on Aging, National Institute of Health, Baltimore, USA.; Advanced Center for Chronic Diseases (ACCDiS), 8330034, Santiago, Chile.; Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina, Clínica Alemana, Universidad del Desarrollo, 7590943, Santiago, Chile.; Laboratory of Chemical Carcinogenesis and Pharmacogenetics, Department of Basic and Clinical Oncology, Faculty of Medicine, Universidad de Chile, 8380494, Santiago, Chile. [email protected].; Latin American Network for Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Madrid, Spain. [email protected].; Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, 8331150, Santiago, Chile. [email protected].; Department of Hematology and Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, 8330032, Santiago, Chile. [email protected].; Millennium Institute on Immunology and Immunotherapy, 8331150, Santiago, Chile. [email protected].; Advanced Center for Chronic Diseases (ACCDiS), 8330034, Santiago, Chile. [email protected].

DOI: 10.1186/s12885-021-08745-0

Link outs

Free resources

Full Text Sources:

Medical:

https://medlineplus.gov/stomachcancer.html

Miscellaneous:

https://assays.cancer.gov/CPTAC-212

Research Materials:

https://antibodies.cancer.gov/detail/CPTC-GSTP1-1

MeSH Terms: Aged, Antineoplastic Combined Chemotherapy Protocols, Capecitabine, Case-Control Studies, Confidence Intervals, DNA-Binding Proteins, Dihydrouracil Dehydrogenase (NADP), Endonucleases, Female, Fluorouracil, Gene Frequency, Genes, p53, Genotype, Glutathione S-Transferase pi, Glycine Hydroxymethyltransferase, Humans, Leucovorin, Logistic Models, Male, Methylenetetrahydrofolate Reductase (NADPH2), Middle Aged, Multidrug Resistance-Associated Protein 2, Multidrug Resistance-Associated Proteins, Multienzyme Complexes, Nomograms, Odds Ratio, Organoplatinum Compounds, Orotate Phosphoribosyltransferase, Orotidine-5'-Phosphate Decarboxylase, Platinum Compounds, Polymorphism, Single Nucleotide, Pyrimidines, Quality of Life, Retrospective Studies, Stomach Neoplasms, Xeroderma Pigmentosum Group D Protein