Scanning the human genome and the horizon: the potential and pitfalls of pharmacogenetics and stratified medicine

TAILORING TREATMENT FOR PATIENTS WITH CANCER

Cancer is viewed as a genetic disease and pharmacogenetics is already being applied to its management. Its pathogenesis is a multistep process associated with inherited risk factors but most importantly with the accumulation of somatic mutations that alter key signalling pathways. Much of the process is stochastic and so marked by heterogeneity between individuals; tumours of apparently similar histological classifications can differ markedly in genotype. The Cancer Genome Project (https://www.sanger.ac.uk/research/projects/cancergenome/) is underway, systematically identifying all mutated cancer genes and their associated biochemical pathways. This is leading to new paradigms of disease classification that are based on perturbed pathways, and for which rational drug design is leading to targeted therapeutics.⁸ It has been proposed that signatures of somatic oncogene mutations that cut across traditional tissue-specific classifications could result in personalised treatment regimens.⁸ The clinical utility of a genetic approach to stratify treatment protocols is yet to be determined through clinical trials but there is most scope for the application of pharmacogenetics to prevent adverse events when treatments have a narrow therapeutic index, which is a characteristic of most cancer therapy.

There are two distinct forms of treatment stratification that are already embedded within management protocols for the oncology clinic. First, through the use of ‘companion diagnostics’ for actionable driver mutations, before prescribing the targeted drug. The rationale being to use therapeutics only when there is proven clinical utility. The classic example is the detection of over-expression of the ERBB2 oncogene in breast cancer before prescribing the monoclonal antibody therapy, trastuzumab. However, it must be recognised that stratifying the patient group could result in some patients, who could derive some benefit from an expensive drug, but would not benefit from it as much as another group of patients, being refused access to it. Where a new drug is perceived by the public to be an effective and hence desirable treatment for cancer, denial of treatment might lead to individual distress and to adverse publicity, unless communication is managed extremely carefully. Another related risk is that people categorised as ‘non-responders’ or ‘difficult to treat’ may be stigmatised or discriminated against, for example in insurance-based healthcare systems.⁹

The second form of stratification is to avoid severe adverse events with tests for inherited variants of pharmacokinetics and pharmacodynamics. For example, the fluoropyrimidine 5-FU is an anti-metabolite that has been used as a chemotherapeutic agent for more than five decades for many common cancers. Rare variants for the rate-limiting enzyme of 5-FU catabolism, dihydropyrimidine dehydrogenase, have recently been recommended as pharmacogenetic markers to guide fluoropyrimidine dosing because carriers can have life-threatening adverse events with standard protocols.¹⁰

The rapid progress in the field of human genomics has been contingent on the emergence of key technologies exploiting the chemistry of DNA synthesis. The most relevant today being high-throughput DNA sequencing¹¹ referred to as next generation sequencing. If we scan the horizon it seems likely that further stratification will occur through the increasing use of sequencing to analyse cancer genomes, which is one of the aims for Genomics England. The advances in our understanding of cancer biology, coupled with rapid and cheap whole-genome sequencing is even permitting the non-invasive analysis of cancers as they evolve through treatment regimens, and so cancer management could become truly personalised and depend on fewer surgical investigations.¹²