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The Promise of Molecular Profiling

VBCC - February 2012, Volume 3, No 1 - VBCC Perspectives
Caroline Helwick

At the 2012 Gastrointestinal Cancers Symposium, Value-Based Cancer Care (VBCC) asked Al B. Benson, III, MD, FACP, Professor of Medicine, Associ­ate Director for Clinical Investi­gations, Robert H. Lurie Compre­hensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Immediate Past President, ACCC, and editorial board member of VBCC, to discuss the growing importance of molecular profiling in cancer care.

VBCC: Where is the field of molecular profiling at this point, and where is it heading?

Dr Benson: Comprehensive molecular profiling of a tumor will help us distinguish subtypes within cancers. We have been doing this with breast cancer for some time now, and at this meeting we heard more about several distinct types of gastric cancer including those that express HER2.

In colon cancer, for example, oncologists are now ordering tests for the KRAS mutation, if they are considering anti-EGFR (epidermal growth factor receptor) therapy. But there are other potential markers, such as BRAF. Recently, the drug vemurafenib, an inhibitor of BRAF kinase, was ap­proved by the US Food and Drug Administration for the treatment of patients with unresectable or meta­static melanoma with the BRAF V600E mutation.

Although BRAF mutations are also seen in colon cancer, it is unclear whether a drug with the same target that works in melanoma will also have efficacy for patients with colorectal cancer. So we cannot assume that an observation in one tumor type will apply to another. We will have to investigate mutations across tumor types, particularly if we are to more precisely develop treatments linked to biologic profiles within a disease spectrum.

We are also learning that the biologic profile of the primary tumor may be very different from the metastatic tumor. As mutations develop over time, we need to be able to track these. This should help inform drug development, telling us which strategies we need for which disease setting. This is a complex endeavor. Most of us who are involved in cancer care believe that a patient will not have a single mutation (or marker), but a collection of markers. It may, therefore, take a combination of different types of drugs to address these markers.

VBCC: How do you envision molecular profiling will improve the clinical trial process?

Dr Benson: Currently, in our clinical trials, we typically identify 1 biomarker (to be targeted by a specific drug) that will be the focus of the trial. What we have to do is independently screen a number of patients, until we obtain that particular subset of trial participants that test positive for that mark­er. Perhaps in the future we will need a subset of patients with 3 or more, not 1, mutations.

What will help this whole process is for our clinical trial candidates to have a molecular profile already available as part of routine assessment. This will make screening for clinical trials much more efficient, because a diagnostic profile or panel, such as a gene profile, would already be available from which patients could be selected for a specific molecularly driven trial.

VBCC: Will molecular profiling aid in drug development?

Dr Benson: One of the goals is to enhance drug development. Histor­ically, our conventional approach to study relatively unselected patients with a given disease has worked to a certain extent. However, under our current methods, many patients are not being treated optimally. To create a tighter link between a particular biologic characteristic and a targeted drug that addresses this characteristic will be much more beneficial to the individual patient. That is why there is so much emphasis on biomarkers in drug development.

VBCC: When do you expect that mole­cular profiling will become advanced enough to reach these goals?

Dr Benson: We are getting closer. Companies are developing mutation panels. But some of these cannot fully be utilized now. Although they are increasingly identifying larger numbers of mutations, currently we are not able to use them for treatment decisions. If these continue to evolve, however, and they prove to be economical as commercial diagnostic tests, it will certainly help speed up the process of developing molecularly based treatments based on specific gene profiles as an example.

What is exciting about gene signature work is that it represents what will become a continuum. It will allow researchers to build on a body of work and move us closer to where we want to be—which is not only to identify patients who are most likely to have a recurrence, but to identify those who will be most likely to benefit from a particular intervention.

The message we need to get out is that the development of molecular principles that guide cancer therapy is massively complex. It is going to be very expensive. And we need everyone on board: the insurers, regulators, funding agencies, diagnostic and pharmaceutical industries, and patients, who will be asked, for example, to undergo repeat biopsies.

This is very exciting, because we are beginning to have the tools that can actually do this work. But there is a high level of complexity involved, and the challenge is to identify these biologic profiles for individual pa­tients. Being able to segregate out the various mutations and treatment strategies would revolutionalize cancer care. It is hard to predict just when we will get there. There is huge promise that it could occur within the next 5 years, but it is difficult to know for sure.

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