Genetic polymorphism and toxicity of adjuvant FOLFOX-4 chemotherapy in Korean colon cancer patients.

Abstract

3617 Background: Adjuvant chemotherapy using 5-FU/leucovorin/oxaliplatin (FOLFOX-4) is the standard of care in curatively resected high-risk stage II and stage III colon cancer. Previous reports suggest that genetic polymorphisms can influence the efficacy and toxicity of chemotherapy. We have analyzed the association between genetic polymorphism and toxicity of adjuvant FOLFOX-4 in Korean colon cancer patients. Methods: Patients who underwent curative resection of colon cancer with pathological stage II and III received 12 cycles of adjuvant FOLFOX-4. Each cycle consisted of oxaliplatin (85 mg/m2) on day 1, folinic acid (200 mg/m2) and bolus of 5-FU (400 mg/m2) followed by 22 hour infusion of 5-FU (600 mg/m2) on days 1 and 2 repeated every 2 weeks. Clinical data and peripheral blood samples were prospectively collected. Twenty polymorphisms in 10 genes (TS, MTHFR, ERCC1, XPD, XRCC1, ABCC2, AGXT, GSTP1, GSTT1 and GSTM1) were analyzed by PCR-RFLP, SNaPshot or direct sequencing using genomic DNA from peripheral blood mononuclear cells. Results: A total of 292 patients were included in this study. The frequencies of grade 3/4 neutropenia, thrombocytopenia, anemia and febrile neutropenia were 60.5%, 3.5%, 0.4% and 1.1%, respectively. Grade 3/4 nonhematologic toxicities were diarrhea (5.7%), vomiting (2.4%), nausea (1.7%), sensory neuropathy (1.7%) and hypersensitivity (1.4%). In hematologic toxicity, grade 3/4 neutropenia was significantly associated with ERCC1 19007T/T (p = 0.020) and MTHFR 677T/T (p = 0.027). ABCC2 3972C/C (p = 0.022) and ABCC2-24C/C genotypes (p = 0.047) were associated with grade 3/4 thrombocytopenia. In nonhematologic toxicity, sensory neuropathy was significantly associated with MTHFR 1298A/C or C/C (p = 0.005) and AGXT 1142A/A (p = 0.001) genotypes. XRCC1 2746A/A (p = 0.006) and XPD 156C/C (p = 0.004) genotypes were significantly associated with grade 3/4 diarrhea. Conclusions: This largest pharmacogenetic study of adjuvant FOLFOX-4 in colon cancer shows that the genetic polymorphisms of ERCC1 19007C>T, XPD 156C>A, MTHFR 677C>T, MTHFR 1298A>C, XRCC1 2746G>A, ABCC2 3972C>T, ABCC2 -24C>T, and AGXT 1142A>G may be useful in predicting toxicity of adjuvant FOLFOX-4. No significant financial relationships to disclose.