BMC cancer · 2021
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.
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Cordova-Delgado Miguel, Bravo María Loreto, Cumsille Elisa, Hill Charlotte N, Muñoz-Medel Matías, Pinto Mauricio P, Retamal Ignacio N, Lavanderos María A, Miquel Juan Francisco, Rodriguez-Fernandez Maria, Liao Yuwei, Li Zhiguang, Corvalán Alejandro H, Armisén Ricardo, Garrido Marcelo, Quiñones Luis A, Owen Gareth I
Аннотация
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.
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.
Предметные рубрики MeSH
AgedAntineoplastic Combined Chemotherapy ProtocolsCapecitabineCase-Control StudiesConfidence IntervalsDNA-Binding ProteinsDihydrouracil Dehydrogenase (NADP)EndonucleasesFemaleFluorouracilGene FrequencyGenes, p53GenotypeGlutathione S-Transferase piGlycine HydroxymethyltransferaseHumansLeucovorinLogistic ModelsMaleMethylenetetrahydrofolate Reductase (NADPH2)Middle AgedMultidrug Resistance-Associated Protein 2ATP-Binding Cassette, Sub-Family C ProteinsMultienzyme ComplexesNomogramsOdds RatioOrganoplatinum CompoundsOrotate PhosphoribosyltransferaseOrotidine-5'-Phosphate DecarboxylasePlatinum CompoundsPolymorphism, Single NucleotidePyrimidinesQuality of LifeRetrospective StudiesStomach NeoplasmsXeroderma Pigmentosum Group D Protein