From Patient Outcomes to Drug Development, biomarkers hold promise for improved care. But are there any caveats?
Biomarkers (or, biological molecules) indicate processes taking place within the body which may serve as data signals for a variety of conditions and diseases. Also known as signature molecules or molecular markers, biomarkers can be found in array in bodily tissues and fluids including blood, DNA, stool, urine, and tumor tissue. For instance, while blood pressure may be conceived of as a biomarker, other biomarkers might measure the number of immune cells in a biopsy sample, or the level of a particular protein. While exact definitions of biomarkers remain somewhat contingent on the publication or organization invoking them, broadly speaking, biomarkers refer to any biological characteristic which can be tested for or measured in a patient. In other words, they refer to a broad subcategory of medical signs which offer objective indications of a patient’s medical state inasmuch as they are quantifiable and empirical —that is, able to be measured accurately and reproducibly. In medical parlance, biomarkers are distinct from medical symptoms as medical symptoms are limited to signals of illness and health which are observed by patients themselves. Moreover, biomarkers might indicate whether a patient is likely to develop an illness, how far an illness has progressed, or give an indication as to whether a patient is likely to benefit from a given drug. There are dozens of biomarkers which are presently utilized to monitor and identify diseases such as multiple sclerosis, diabetes, cardiovascular disease, and cancer.
Within the realm of cancer research and medicine, biomarkers are primarily used as prognostic, diagnostic, and predictive tools, but hold further potential applications in the areas of risk assessment and screening. As indicators of prognosis, biomarkers can help forecast how aggressive a disease or condition is. As a prognostic indicator, for instance, biomarkers may portend how a patient may fare in the absence of treatment. In diagnostic usage, biomarkers may help diagnose disease and identify cancers within their early stages. Biomarkers are especially promising for their potential predictive applications in assessing how well a patient might respond to treatment, to monitor the progression of disease, as well as to predict potential instances of recurrence.
In oncology, biomarkers are identified in three primary ways:
The first, genetic testing, refers to the process in which clinical teams examine a patient’s genetic make-up to assess abnormal changes and mutations which may include missing, extra, or “misplaced” genes. For breast cancer, one prominent example of biomarkers are mutations in the BRCA gene which are potentially indicative of a heightened risk of developing breast cancer. In addition, genetic profiling of the genes associated with HER2 positive breast cancer can be important in differentiating what treatment might be most suitable and effective for a patient.
Other emerging genomic biomarkers are not associated with a single gene. To illustrate, tumor mutation burden (TMB) is a biomarker that examines the number of mutations across the whole genome in a tumor. This has been shown to be helpful in assessing whether a patient might benefit from immunotherapy. Jacob Bradley, a PhD student conducting research on TMB at University of Edinburgh’s School of Mathematics and Institute for Genetic and Molecular Medicine explains:
“Here, as is often the case with genomic biomarkers, the biomarker itself is not directly what makes the tumor more or less susceptible to treatment, but rather serves as a proxy for some other molecular feature of tumor cells which is much harder to measure (in this case neoantigen burden- the number of foreign proteins in a cell that can be recognized by the patient’s immune system).”
Another method of identifying biomarkers includes biochemical tests to determine if a patient has a particular protein (an over-active protein) present. Lastly, clinical teams may perform chromosomal tests to assess whether a patient exhibits abnormal chromosomal changes. Still, there are other tests performed to understand a patient’s biomarkers including those designed to measure the number of immune cells in a biopsy sample.
Notably, many medical researchers believe that the continuing discovery of new and increasingly sensitive biomarkers magnifies the potential to usher in a new standard of personalized medical care. As biomarkers in oncology attempt to further trace and determine patients’ individual, unique biomedical characteristics, clinical teams may be empowered to deliver an improved standard of care for patients. Many healthcare professionals and researchers share the hope that in the future biomarkers will constitute improved bases for cancer prevention and diagnosis, offering patients the most optimal treatments for the particular characteristics of their cancer, and determining the likelihood of recurrence.
Many medical researchers also consider biomarkers to be integral to the future of drug development. In conducting clinical trials, researchers must be able to accurately and effectively measure the effects of investigational drugs on patients. As such, biomarkers may have a fundamental role to play in measuring these effects. Dr. Janet Woodcock, Director of the FDA’s Center for Drug Evaluation and Research enumerates the promise that biomarkers hold for drug development in these terms:
“Drug development today has many problems. The major problem is the failure rate…even for drugs that have gone through the whole pre-clinical process, all sorts of animal testing, and all sorts of types of assays. Once they get into people they have a less than 1 in 10 chance of actually getting to market; 9 out 10 may fail in that development. We have to do better than that if we are going to accelerate treatment availability; if we are going to lower the cost of drug development and not have it continue to escalate and if we are going to let a lot of innovators into this space of participating in drug development. To improve the success rate and efficiency of drug development, we need a whole new generation of biomarkers that are more informative. They can tell developers earlier whether or not their drug may have toxicity or may not work at all — to get that early read on what is going to be successful… those biomarkers are ones that have yet to be developed.”
In the realm of genomics, much of the research surrounding biomarkers, including recent studies undertaken by Guardant and Foundation Medicine, focuses on single gene biomarkers. Dr. Nirmesh Patel, Chief Scientific Officer of Cambridge Cancer Genomics insists improving cancer care necessitates the discovery and development of complex biomarkers. Dr. Patel contends:
“single gene biomarkers only give us a fraction of the total picture, if we want to understand how to best treat cancer we need to incorporate more of its complexity into companion diagnostics.”
According to Dr. Patel this might involve incorporating pathway analysis, neoantigens, mutation trajectory, signaling cascades, protein-protein interactions, clonal reconstruction, and multigene signatures, among other factors.
Moreover, medical researchers N. Lynn Henry and Daniel Hayes assert that given:
“the critical role that biomarkers play at all stages of disease, it is important that they undergo rigorous evaluation, including analytical validation, clinical validation, and assessment of clinical utility, prior to incorporation into routine clinical care.”
Jacob Bradley raises parallel issues of consideration:
“Biomarkers are rarely 100% accurate or predictive. There can be all sorts of difficulties in accurate measurement (often through small availability of appropriate biopsy tissue) and due to the complexity and uniqueness of an individual’s illness, two patients with the same biomarker will not progress in the same way all the time. Biomarkers will always be used in the context of the other information a clinician has available. That said, more and more new therapies are being approved by drug administrations such as the FDA for patients with accompanying biomarkers. This is seen as being a step towards ‘precision medicine’, where patients are stratified according to the specifics of their disease rather than all being treated in the same manner. Another complication with genomic biomarkers in particular are the associated costs. This is particularly relevant for biomarkers that require sequencing a large section of DNA, such as TMB. Whole genome sequencing is not yet standard of care for typical cancer patients, and in practice still costs several thousands of pounds. There are efforts are underway to see whether biomarkers like TMB can be estimated by looking at smaller, indicative sections of the genome. My research revolves around understanding what patterns of genomic mutation correspond to different levels of TMB, and whether it will be possible to produce more efficient, cost-effective genomic testing.”
Overwhelmingly, the patients I have interviewed have expressed hope and enthusiasm for biomarkers’ potential to increase the efficacy of current cancer therapies and improve survival rates. Nevertheless, patients I have spoken to who are familiar with biomarkers have expressed a few common concerns regarding the current cost accrued in testing for biomarkers (sometimes directly as in the cases of several US patients I interviewed) and patients’ general lack of access to such tests; as well as the dearth of precise and efficacious biomarkers that currently exist for myriad cancers. Moreover, many patient advocates decried the lack of education that many patients currently possess regarding how biomarker testing might be relevant and beneficial for them as they seek treatment. As research moves forward into the realms of tumor mutational burden (TMB) and complex biomarkers, it is imperative to consider how the use of biomarkers might not just aid medical researchers conducting clinical trials but the lives and health of millions of cancer patients. Crucial attention and resources must be brought to bear on increasing the access and affordability of biomarker testing; its diversity across a range of cancers; and how patients might be educated in the benefits, nuances, and potential drawbacks of biomarker testing.
References Consulted and Further Reading: