Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity.

BACKGROUND: Fluoropyrimidine drugs are extensively used for the treatment of solid cancers. However, adverse drug reactions are a major clinical problem, often necessitating treatment discontinuation. The aim of this study was to identify pharmacogenetic markers predicting fluoropyrimidine toxicity. METHODS: Toxicity in the first four cycles of 5-fluorouracil or capecitabine-based chemotherapy were recorded for a series of 430 patients. The association between demographic variables, DPYD, DPYS, TYMS, MTHFR, CDA genotypes, and toxicity were analysed using logistic regression models. RESULTS: Four DPYD sequence variants (c.1905+1G>A, c.2846A>T, c.1601G>A and c.1679T>G) were found in 6% of the cohort and were significantly associated with grade 3-4 toxicity (P<0.0001). The TYMS 3'-untranslated region del/del genotype substantially increased the risk of severe toxicity (P=0.0123, odds ratio (OR)=3.08, 95% confidence interval (CI): 1.38-6.87). For patients treated with capecitabine, a MTHFR c.1298CC homozygous variant genotype predicted hand-foot syndrome (P=4.1 × 10⁻6, OR=9.99, 95% CI: 3.84-27.8). The linked CDA c.-92A>G and CDA c.-451C>T variants predicted grade 2-4 diarrhoea (P=0.0055, OR=2.3, 95% CI: 1.3-4.2 and P=0.0082, OR=2.3, 95% CI: 1.3-4.2, respectively). CONCLUSION: We have identified a panel of clinically useful pharmacogenetic markers predicting toxicity to fluoropyrimidine therapy. Dose reduction should be considered in patients carrying these sequence variants.

Faecal screening of colorectal cancer.

AIMS: Screening and prevention of colorectal cancer (CRC) is a public health priority. Recent progress in understanding the biology of CRC has lead to possible new approaches to screening. In particular, assay of faecal molecular markers represents a promising non-invasive approach to screening, with improved safety, accuracy and patient compliance. METHODS: MEDLINE/PubMed searches were used to identify key articles relating to faecal-based screening with secondary review of cited publications. RESULTS: Faecal markers of CRC can be broadly divided into DNA based and non-DNA based. CONCLUSIONS: Faecal occult blood testing for CRC screening has been advocated for decades for its non-invasiveness and low cost. It has exhibited a 15-33% decrease in mortality, despite drawbacks with sensitivity and compliance. Other non-DNA markers have the adequate sensitivity for inflammatory lesions but do not have the required specificity for screening average-risk populations. Faecal DNA testing has the potential to enhance the performance characteristics of stool testing. Because of molecular heterogeneity of cancer, no single DNA marker has yielded adequate sensitivity. Analysis of several combinations of markers in studies have produced high detection rates of both CRC and advanced adenomas in selected patient groups. However, the currently available markers, both non-DNA and DNA, have not yet been validated in large-scale studies screening average -risk population nor have they so far shown the necessary sensitivity and specificity required for large-scale screening programmes. Another major drawback with the DNA-based markers is the cost-effectiveness. Issues regarding implementation and compliance remain unanswered. These critical problems have to be rectified before these techniques can be recommended for large-scale CRC screening.