Molecular Diagnostics
fluid diagnostic markers. The issues therefore remain fundamentally unchanged; those are the issues of specificity and sensitivity. What are we measuring and how little of it can we detect? While immunodiagnostic approaches continue to represent the largest proportion of FDA- approved cancer diagnostics, rapid developments in the use of mass spectroscopy have brought new power to the search for rare molecules or frag- ments of molecules in fluids. However; this tech- nology suffers from questions around reproducibil- ity and standardisation.
Next generation sequencing (NGS), owing to its massively ‘parallel’ nature, allows the simulta- neous sequencing of many millions of individual DNA molecules. This provides scientists and cli- nicians with both exquisite sensitivity and speci- ficity for the detection of abnormal DNA in solid tissues and in body fluids. To this end, several large pharma companies are investigating the fea- sibility of using NGS to detect somatic mutations in genes such as TP53, KRAS and EGFR in DNA in the circulation, as surrogate markers for the presence of a tumour. In addition, the sheer capacity of this technique allows multiplexing, so that many gene hotspots can be sequenced simul- taneously. While NGS is economically and practi- cally unsuited to routine application as a strictly ‘diagnostic’ tool, it is now in use in at least one centre in the UK for the routine screening for mutations in the BRCA 1 and 2 genes in breast/ovarian cancer family members. The standardisation and miniaturisation of tech- nologies such as mass spectroscopy and next gen- eration sequencing will probably make these the technologies of choice for the identification in the first instance, and then routine detection of, diag- nostic markers in fluids. Indeed, through miniatur- isation, these could ultimately become point-of- care technologies.
Prognostics
The value of more robust and sensitive ‘diagnostic’ tests, able to detect pre-malignant lesions or can- cers at increasingly early stage is clear. Yet it has been argued that there is currently insufficient resource being given to early detection by, for example, imaging at the expense of new targeted drug development, ie treatment (more on this later). Between diagnostic and predictive tests, sit prognostic tests, the value of which is slightly less clear. Once the presence of a tumour is diagnosed and the disease is staged using standard clinico- pathological criteria, the oncologist or surgeon will have a reasonable idea of the prognosis without
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resorting to molecular tests. How important this information is to the patient depends very much on the individual.
Nevertheless there is an argument for molecular prognostic tests in cancer, where routine staging fails to provide clear guidance as to the nature or intensity of any further treatment. The OncotypeDx™ test, based upon the analysis of expression of 21 genes, quantifies the likelihood of disease recurrence in women with early-stage hor- mone receptor-positive breast cancer, and as such is prognostic. This clinical situation is not uncom- mon, where it is unclear whether to offer chemotherapy, with its unpleasant side-effects. The evidence is that clinical practice in this situation varies significantly internationally, and nationally in the UK. A similar problem occurs with Stage 2b colorectal cancer, where there is often uncertainty as to whether to treat with adjuvant chemotherapy following surgery, and multiplexed molecular tests are under development to address this. One would think that the availability of objec- tive tests that offer an individualised risk assess- ment in these situations would be attractive. Unfortunately such tests remain problematic for the UK and many other national health services, primarily due to their cost. Against a somewhat bleak economic background, there is also an inherent conservatism about the need for rock- solid evidence bases, and perhaps a degree of com- placency concerning the adequacy of current clin- ico-pathological evaluation. Interestingly, the OncotypeDx test, in addition to providing an individualised probability of dis- ease recurrence, has also been shown to be useful in assessing the likely benefit of chemotherapy, which makes it both ‘prognostic’ and ‘predictive’ (see below).
Predictives
Perhaps the most exciting advances in diagnostics are those around ‘predictives’: finding biological markers that predict likely response to a drug or treatment. There are a number of drivers con- tributing to these advances.
Several years ago the FDA and EU, in separate reports, highlighted the need for better “product evaluation tools” in the drug development process, tools which would produce safer and more effec- tive drugs, and in turn lead to improved patient outcome1,2. Behind this lay two uncomfortable facts: the first was that the cost to pharmas of tak- ing a single, new anti-cancer agents from discovery to licensing had grown to unsupportable levels (currently estimated to be in excess of $1 billion);
Drug Discovery World Spring 2011
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