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Association of molecular markers with toxicity outcomes in a randomized trial of chemotherapy for advanced colorectal cancer: The FOCUS Trial
Journal of Clinical Oncology, 10/30/09

AuthorLastNameFI et al. – Predicting efficacy and toxicity could potentially allow individualization of cancer therapy. We investigated putative pharmacogenetic markers of chemotherapy toxicity in a large randomized trial. The results of this trial do not support the routine clinical use of the evaluated polymorphisms, including UGT1A1*28.

Methods

Patients randomly assigned to different sequences of chemotherapy for advanced colorectal cancer
First-line therapy 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 ≥ 3 toxicity
DNA analyzed in 1,188 patients; 1,036 assessable for 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 primary outcome measure, no polymorphism significantly associated with toxicity of regimen or with difference in toxicity of IrFU or OxFU versus FU alone
Trends (of doubtful significance) seen for associations of XRCC1, ERCC2, and GSTP1 with toxicity during irinotecan regimens: XRCC1, primary end point, any irinotecan-containing regimen ; ERCC2, secondary end point, irinotecan alone ; GSTP1, secondary end point; IrFU ; and irinotecan alone
No evidence of association of UGT1A1*28 with irinotecan toxicity

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