Monday, November 19, 2012

Why all the buzz about biomarkers?

Why all the buzz about biomarkers and what might they mean for personalized medicine? The short answer is that they can be used to diagnose disease, predict outcomes, suggest treatments and save lives. Biomarkers are substances that can be detected on the surface of, or inside cells. They are made using instructions written within corresponding genes. Cells do not use all of their genes all of the time, so the presence of biomarkers tells us something about which genes are currently active in which cells. Mutations in genes can cause differences between the biomarkers of individuals, or even between the biomarkers of different cells in the same individual, and these differences can profoundly affect the behavior and life-cycle of certain cells. Most mutations are neutral or result in damaged cells that die or are destroyed by the organism's natural defenses, but some types of mutation cause the cell to begin to divide rapidly while evading or confusing the body's ability to detect and destroy them. Essentially, natural selection run amok and the cellular level is the basis of cancer.

The processes that lead to cancer can happen in many different ways, which is why there are many different kinds of cancer indication. The study of this process is called oncology, and the genes involved are often referred to as oncogenes. The study of oncogenes, the biomarkers they encode, and the correlations between different types of cancer tumor and likely patient outcomes have all received a tremendous boost from advances in molecular biology.  Sensitive new techniques allow large numbers of resected, remnant, archived, FFPE preserved tissue samples and biopsies to be analyzed at the molecular level. These lab studies of surgically removed biosamples have revealed much about the different ways that cancer can arise, and have helped to suggest powerful diagnostic tests to distinguish between different categories.

Treating cancer is difficult for a number of reasons, but four big ones are 1) cancer cells and normal cells are genetically similar and physically intermingled, therefore it is hard to specifically attack only the cancer cells. 2) There is great potential for rapid spread of cancer cells throughout the body through a process known as metastasis. In some cases, surgical disruption of a tumor can actually accelerate this process. 3) Evolution acts very effectively on rapidly dividing cells to cause them to adapt to any attempt to selectively destroy them. 4) The molecular basis for cancer is highly variable. Many different genes are involved, and the nature of the mutations that cause the cancer as well as the interaction of mutated and normal genes is complex, leading to unique problems for each patient. Additionally, variations in the ways that different patients respond to different treatments can make it very difficult to use a one-size-fits-all treatment approach.

My boss (a former biomedical scientist) recently surprised me when he said something like: "As a scientist, I am embarrassed and ashamed by the slow progress made in the fight against cancer, especially given the millions that have been spent." At first I thought that seemed a bit harsh given the amazing growth in understanding of cancer as a disease at the molecular level over the last 10 years. But then, when I think about friends, relatives and acquaintances who have succumbed during that time, I started to think that my boss might be right. Honestly, clinical approaches to cancer are still pretty primitive, and for most patients, limited to resection and / or chemotherapy. Chemotherapy in particular sometimes seems like a desperate act. The chemicals involved are often horribly toxic, not especially selective, and in many cases, they are as likely to kill the patient as they are to cure them. The overall success rates are unimpressive, the side effects can be awful. Worse yet, in some cases, tests for specific biomarkers already exist that could predict whether a particular chemotherapy agent is probably either futile, dangerous or even fatal for a specific patient. Medicine's embarrassing secret is that this information is all too often not reaching the frontline doctors, and even when it does, the financial and regulatory difficulties involved with creating a personalized diagnostic and treatment plan mean that so far, personalized cancer treatment based on biomarkers has not really lived up to its promise.

Let's look at some specific examples from oncology research. The following links all point at publications that describe how the presence of specific biomarkers can be used to predict aspects of patient response to various chemicals used in chemotherapy:

To remedy the disconnect between biomarker research and patient care, a number of companies such as Foundation Medicine have begun to specialize in ways to connect cancer patients with cutting edge information and appropriate treatments or clinical trials, but despite these intermediates, fiscal and regulatory barriers continue to stymy efforts to convert laboratory knowledge into personalized clinical practice. Furthermore, no obvious solution to this problem is in sight. If anything with the "1000 dollar genome" looming and only 3000 trained genetic councilors in the US, it seems likely that the embarrassing gap between the availability of information about our own biomarkers and our ability to understand the meaning of this knowledge and create appropriate personalized remedies based upon that information is likely to grow very quickly in the coming years.

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