By Ian Olver AM for oncologynews.com.au
The term translational research is broad but most often refers to the translation of basic research findings into policy or practice. To achieve this the research question must be one that can be translated. An example would be in applying the discovery of a druggable target, resulting from the application of the technological advance of high throughput sequencing demonstrating the molecular profile of a tumour, into clinical trials of a targeted drug and then into clinical practice.
In most clinical trials you try not to restrict the patient population because it reduces the population to which the results apply. In trials of targeted therapies, however, the population should be restricted to those who have the target of the drug being tested. This was illustrated by the initial trials of the EGFR (epidermal growth factor receptor) antagonists in colorectal cancer which showed they were of little benefit. A selected population with wild type KRAS and therefore the target, showed a survival advantage. We need to know the tumour molecular characteristics and be able to measure the biomarkers which will show which treatment is likely to be effective.
The broad definition of a biomarker is a molecule either generated by the cancer or by the body in response to the cancer which can be measured in blood or other body fluids or in the tissues. Biomarkers can be used across the spectrum of treatment.
Genomics demonstrates the variation in DNA which can predict the susceptibility to cancer. Biomarkers can also be used to help diagnose cancer.
Particularly useful would be prognostic biomarkers which, measured prior to treatment could predict the long-term outcome, irrespective of treatment. They would be used in the clinic to determine whether a cancer could be watched or treated, or whether there was a need for additional (adjuvant) therapy after surgical removal. There are many potential candidates for these biomarkers including histopathological or molecular characteristics, altered methylation of DNA or production of micro RNA or even circulating cancer cells. However, any such candidate needs to undergo rigorous trials to assess its validity.
Predictive biomarkers predict the response to treatment. Again, candidate markers need to be validated in clinical trials. An example would be HER 2 and the response to Trastuzumab or EGFR gene copy number and increased survival in non-small cell lung cancer.
Currently the greatest use of biomarkers is to select treatment on the basis of showing that its target is present. The early use was the identification of oestrogen receptors to determine the use of tamoxifen but now there are many companion diagnostic tests for monoclonal antibodies and small molecules and the choice of therapy is becoming personalised. Pharmacogenomic markers may indicate the rate of metabolism of a drug and therefore be helpful in determining drug doses.
Pharmacodynamic markers reveal the likely impact of the drug on the tumour and the patient. They can be very useful in early phase drug studies and can be measured in tumour samples but also in normal tissues like skin or blood cells.
Biomarkers must be part of new therapy development to aid translation into practice
Some biomarkers can be used to monitor treatment. A good example is alpha FP (fetoprotein) and beta HCG (human chorionic gonadotrophin) that can be used to follow the progress of the treatment of testicular cancers and may be the first signal of relapse.
In testing a new drug, the substantive endpoint is usually an increase in overall survival for the new drug compared to the previous standard of care. However, this can often take several years to reach and so there is an interest in finding earlier endpoints that are a surrogate for survival. Progression free survival is one such candidate but does not always predict survival. Biomarkers may also be considered, but need extensive investigation to determine whether they are true surrogates for overall survival. If so, drugs could be made available to the public much earlier than waiting for a survival endpoint.
Early phase drug trials should incorporate new biomarkers in order to validate them. Incorporating them into later phase trials allows the identification of subsets of patients that respond better.
We polled a sample of Australian oncologists, pathologists and researchers about biomarkers. The number of respondents who used biomarkers was 73% but only 53% said that they could access them easily. When asked about their reliability, 43% rated them as reliable, 20% ineffective and 27% were unsure. The greatest use of biomarker tests was in screening, treatment selection (HER2 in breast, BRAF and PD-1 in melanoma, KRAS in bowel) and treatment monitoring. The top priorities for the future development of biomarkers were stated to be for screening for ovarian, prostate, pancreatic and lung cancer.
Biomarkers must be part of new therapy development to aid translation into practice.