New Science of Toxgnostics

Systematic, agnostic study of genetic predictors of toxicity from anti-cancer therapy

The burden of chemotherapy-associated toxicity is well known, but there are relatively few tools that increase the precision of anti-cancer drug prescription. A group of researchers from the University of Oxford, UK proposed in an article published online on 15 May 2014 in the Nature Reviews Cancer, a shift in emphasis from the focussed study of polymorphisms in drug metabolic pathways in small sets of patients to broader agnostic analyses to systematically correlate germline genetic variants with adverse events in large, well-defined cancer populations.

The authors advocate that, whenever possible, randomised trials of novel antineoplastic agents should function as vehicles for a genome-wide exploration of germline determinants of toxicity. The use of a blood sample should also enable all patients to be analysed, rather than a subset.

A systematic and agnostic approach to discovering toxicity-associated single nucleotid polymorphisms (SNPs), which goes beyond the relatively rigid constructs of genes encoding determinants of drug absorption, distribution, metabolism and excretion, embedded in well designed and adequately powered trials might lead to the discovery of high-performing molecular toxgnostics with sufficient clinical usefulness to change practice and improve chemotherapy safety, thereby saving money and substantially reducing morbidity and mortality, wrote the UK researchers.

Of the thousands of putative toxgnostic markers reported in the literature, only a few are currently used in clinical practice

Thiopurine methyltransferase (TPMT)

Determination of thiopurine methyltransferase (TPMT) activity is recommended prior to treatment of patients with 6-mercaptopurine and 6-thoiguanine in the UK.

An association of TPMT variants with cisplatin-induced ototoxicity in children prompted the US Food and Drug Administration (FDA) to list TPMT as a biomarker for adverse drug reactions to cisplatin. However, a subsequent study failed to replicate this finding, and it has been argued that the FDA decision was premature.

Despite high levels of cytochrome P450 polymorphism, the only P450 assay that is currently recommended for routine clinical use is for the optimisation of the prescription of warfarin, despite the fact that drugs such as tamoxifen and potentially paclitaxel are metabolised by P450 enzymes that are known to be polymorphic.

UDP glucuronosyl transferase 1A1 polymorphism (UGT1A1*28)

Initial data linking the occurrence of severe neutropenia to homozygosity for the UDP glucuronosyl transferase 1A1 polymorphism (UGT1A1*28) were sufficiently compelling that the FDA changed the package insert for irinotecan to include this as a risk factor. However, a subsequent meta-analysis has indicated that this phenomenon is dose-dependent, as the correlation with genotype could not be found when lower doses of irinotecan were used.

Dihydropyrimidine dehydrogenase (DPYD)

Dihydropyrimidine dehydrogenase (DPYD) degrades 5-FU to dihydrofluorouracil - an essential first step in the catabolism of the active form of the drug to inactive metabolites. Several rare variants in DPYD, which are collectively present in approximately 1% of the Caucasian population, alter the activity of the enzyme, resulting in an increase in the plasma concentrations of the active drug and increased toxicity, which typically manifest as stomatitis, diarrhoea and myelosuppression. Although the use of 5-FU in patients with DPYD deficiency can result in fatal toxicity, the low frequency of the causal variants means that routine screening pre-treatment is relatively rare.

Thymidylate synthetase (TS)

Similarly, although variants in TYMS (encoding thymidylate synthetase (TS) - the principal target of the main active metabolite of 5-FU) have been reported to predict 5-FU benefit, testing for these is not widely used in practice.

In a recent analysis, capecitabine toxicity was associated with the rare, functional DPYD alleles 2846T>A and *2A, as well as with the common TYMS polymorphisms 5′VNTR 2R/3R and 3′UTR 6bp ins-del. There was weaker evidence for these polymorphisms predicting toxicity from bolus and infusional 5-FU monotherapy. No good evidence of association with toxicity was found for the remaining polymorphisms, including several that are currently included in predictive kits. No polymorphisms were associated with toxicity in combination regimens, perhaps reflecting the lower dose of drugs when used in combination.

Regarding association of SNP in SLCO1B1 and clearance of methotrexate in children with acute lymphoblastic leukaemia (ALL), it has been suggested that this SNP could be used to identify patients with ALL who have reduced drug clearance and therefore an increased risk of toxicity.

Variation in FGD4

A well-performed recent analysis used a toxgnostic approach to attempt to define variants associated with paclitaxel neuropathy in patients with breast cancer. The embedding of the study within a large phase III clinical trial permitted the investigators to analyse both the severity and the timing of onset of dysfunction, using a standardised grading system. Although no polymorphisms reached genome-wide significance, a variant in FGD4 of marginal significance was validated in an independent replication set. FGD4 is a gene with a proven role in hereditary Charcot-Marie-Tooth neuropathy. Using a time to event model, the authors were able to generate risk plots for the development of grade 2 neuropathy according to the cumulative paclitaxel dose for patients lacking, heterozygous for or homozygous for the risk allele.

The authors advocate in their article that it is time to integrate prognostic biomarkers, companion diagnostics and toxgnostics into treatment protocols for cancers, accordingly with development of algorithms that embrace the totality of precision medicine and allow optimal patient stratification, drug and dose selection to improve the risk/benefit ratio to favour the patient as much as possible.

The full article is available to ESMO members through the ESMO Scientific Journal Access Programme.

Reference

Church D, Kerr R, Domingo E, et al. Toxgnostics': an unmet need in cancer medicine. Nature Reviews Cancer 2014; Published online 15 May. doi:10.1038/nrc3729