Only Small Number of Genetic Markers Show Association With Capecitabine Toxicity in Colorectal Cancer
In a study reported in the Journal of Clinical Oncology, Rosmarin et al assessed the association of reported fluorouracil (5-FU) toxicity genetic markers with occurrence of capecitabine toxicity of grade ≥ 3 in the QUASAR2 trial in colorectal cancer and with occurrence of capecitabine and 5-FU toxicity in meta-analyses of other trials of capecitabine or 5-FU. Of all polymorphisms examined, only four variants were found to be associated with capecitabine monotherapy toxicity in this analysis, and there was less evidence of strong effects of examined variants on bolus or infusional 5-FU monotherapy.
Study Details
In the study, 36 polymorphisms associated with 5-FU toxicity were identified in a systematic literature search. These variants were evaluated for associations with global capecitabine toxicity (grades 0–2 vs ≥ 3) in 927 patients in the QUASAR2 trial. Meta-analyses of QUASAR2 and 16 additional published studies (n = 4,855) were performed to examine associations of the polymorphisms with capecitabine and 5-FU toxicity in various 5-FU monotherapy and combination therapy regimens. Significance was set at P < .0065 for the QUASAR2 analysis, P < .0033 for capecitabine meta-analysis, and P < .0048 for 5-FU meta-analysis.
Capecitabine Toxicity
Of all polymorphisms examined, capecitabine toxicity of grade ≥ 3 was significantly associated only with the rare functional DPYD alleles 2846T>A and *2A (combined odds ratio [OR] = 5.51, P = .0013) and with the common TYMS polymorphisms 5’VNTR2R/3R and 3’UTR 6bp ins-del (combined OR = 1.31, P = 9.4 × 10-6). In a meta-analysis including QUASAR2 and four additional studies (n = 382), there was no evidence that any additional variants among 15 examined were associated with capecitabine toxicity. The TYMS polymorphisms appeared to have similar effect on risks for hand-foot syndrome (OR = 1.30, P = .00052) and diarrhea (OR = 1.24, P =.038), whereas DPYD2846A appeared to have a more marked effect for diarrhea (OR = 3.14, P = .093) than for hand-foot syndrome (OR = 1.31, P = .69).
5-FU Toxicity
Of 15 variants analyzed in meta-analysis of infusional 5-FU monotherapy, only TYMS 5’VNTR2R was significant (OR = 1.45, P = .0035), and it remained significant after adjustment for the 3’UTR6bp ins-del variant (OR = 1.53, P = .0040). The variant appeared to be primarily associated with increased risk of diarrhea (OR = 1.45, P = .042). Although it did not reach the threshold for significance, the DPYD*2A polymorphism was associated with increased risk of global toxicity (OR= 6.71, P = .0075), primarily reflecting increased risk of diarrhea (OR = 7.71, P = .011).
In meta-analysis of bolus 5-FU monotherapy, only the TYMS 3’UTR6bp ins allele was associated with increased risk (OR = 1.98, P = .00038), mainly reflecting increased risk of mucositis (OR = 2.03, P =.00086). However, the association was not significant after adjusting for 5’VNTR alleles. The DPYD*2A variant did not meet criteria for formal significance for global toxicity, but was associated with a significant increase in risk for grade ≥ 3 neutropenia (OR = 12.9, P = .0004).
None of the polymorphisms was associated with global or specific toxicity in 5-FU combination therapy regimens.
Prediction of Capecitabine Toxicity
It was estimated that use of a DPYD combined rare functional alleles test and TYMS score test could provide 26% sensitivity, 86% specificity, 49% positive predictive value, and 70% negative predictive value for capecitabine global toxicity of grade ≥ 3.
The investigators concluded: “A panel of genetic biomarkers for capecitabine monotherapy toxicity would currently comprise only the four DPYD and TYMS variants…. We estimate this test could provide 26% sensitivity, 86% specificity, and 49% positive predictive value—better than most available commercial kits, but suboptimal for clinical use. The test panel might be extended to include additional, rare DPYD variants functionally equivalent to *2A and 2846A, though insufficient evidence supports its use in bolus, infusional, or combination [5-FU]. There remains a need to identify further markers of [5-FU] toxicity for all regimens.”
Ian Tomlinson, MD, of Wellcome Trust Centre for Human Genetics, Oxford, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by the Oxford National Institute for Health Research Comprehensive Biomedical Research Centre, Wellcome Trust (UK), Swedish Cancer Society, Robert-Bosch-Foundation, Federal Ministry for Education and Research, Germany, Keasbey Memorial Foundation, and Hoffman La Roche. For full disclosures of the study authors, visit jco.ascopubs.org.
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