Association of Molecular Markers With Toxicity Outcomes in a Randomized Trial of Chemotherapy for Advanced Colorectal Cancer: The FOCUS Trial

• Published in: Journal of clinical oncology Vol. 27; no. 33; pp. 5519 - 5528
• Main Authors: BRAUN, Michael S, RICHMAN, Susan D, THOMPSON, Lindsay, DALY, Catherine L, MEADE, Angela M, ADLARD, Julian W, ALLAN, James M, PARMAR, Mahesh K. B, QUIRKE, Philip, SEYMOUR, Matthew T
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 20.11.2009
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Biological and medical sciences; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; Camptothecin - administration & dosage; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Dihydrouracil Dehydrogenase (NADP) - genetics; Dihydrouracil Dehydrogenase (NADP) - metabolism; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; Follow-Up Studies; Gastroenterology. Liver. Pancreas. Abdomen; Glutathione Transferase - genetics; Glutathione Transferase - metabolism; Humans; Leucovorin - administration & dosage; Leucovorin - adverse effects; Male; Medical sciences; Methylenetetrahydrofolate Reductase (NADPH2) - genetics; Methylenetetrahydrofolate Reductase (NADPH2) - metabolism; Middle Aged; Neoplasm Invasiveness - pathology; Neoplasm Staging; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - adverse effects; Polymorphism, Genetic; Predictive Value of Tests; Probability; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Survival Analysis; Thymidylate Synthase - genetics; Thymidylate Synthase - metabolism; Time Factors; Treatment Outcome; Tumors; Rectal disease; Prognosis; Genetic marker; Toxicity; Colorectal cancer; Malignant tumor; Molecular marker; Colonic disease; Chemotherapy; Randomization; Treatment; Cancerology; Digestive diseases; Intestinal disease; Clinical trial; Advanced stage; Cancer
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2008.21.6283

Predicting efficacy and toxicity could potentially allow individualization of cancer therapy. We investigated putative pharmacogenetic markers of chemotherapy toxicity in a large randomized trial. Patients were randomly assigned to different sequences of chemotherapy for advanced colorectal cancer. First-line therapy was fluorouracil (FU), irinotecan/FU (IrFU) or oxaliplatin/FU (OxFU). Patients allocated first-line FU had planned second-line irinotecan alone, IrFU, or OxFU. The primary toxicity outcome measure was toxicity-induced delay or dose reduction; the secondary outcome was Common Terminology Criteria of Adverse Events grade >or= 3 toxicity. DNA was analyzed in 1,188 patients; 1,036 were assessable for the primary outcome, including 688 treated with FU, 270 with IrFU (first or second line), 280 with OxFU (first or second line), 184 with irinotecan alone, and 454 with any irinotecan-containing regimen. Ten polymorphisms were assessed: thymidylate synthase-enhancer region (TYMS-ER), thymidylate synthase 1494 (TYMS-1494), dihydropyrimidine dehydrogenase (DPYD), methylenetetrahydrofolate reductase (MTHFR), mutL homolog 1 (MLH1), UDP glucuronyltransferase (UGT1A1), ATP-binding cassette group B gene 1 (ABCB1), x-ray cross-complementing group 1 (XRCC1), glutathione-S-transferase P1 (GSTP1), and excision repair cross-complementing gene 2 (ERCC2). Results Using the primary outcome measure, no polymorphism was significantly associated (P < .01) with the toxicity of any regimen or with the difference in toxicity of IrFU or OxFU versus FU alone. Trends (of doubtful significance) were seen for associations of XRCC1, ERCC2, and GSTP1 with toxicity during irinotecan regimens: XRCC1, primary end point, any irinotecan-containing regimen (P = .045); ERCC2, secondary end point, irinotecan alone (P = .003); GSTP1, secondary end point; IrFU (P = .039); and irinotecan alone (P = .05). There was no evidence of association of UGT1A1*28 with irinotecan toxicity. These results do not support the routine clinical use of the evaluated polymorphisms, including UGT1A1*28. Further investigation of XRCC1, ERCC2, and GSTP1 as potential predictors of irinotecan toxicity is warranted.