Cancer biomarkers--a good start.

Cancer researchers and the pharmaceutical industry have invested trillions of dollars and millions of man years in the search for drugs that will cure cancer; but despite this gargantuan effort, success to date has been patchy. In 2009, there is a sense of "could do better" rather than the conclusive triumph over cancer that everyone would hope for. Why is this, and how can the situation be improved?

Perhaps part of the problem is the remarkable power of cancer cells to evolve in response to their environment. The pharmaceutical industry is incredibly good at developing new drugs with the ability to kill cancer cells; but, often, when these are daministered to a patient, there is an initially positive response until the cancer mutates and evolves in an effort to establish a way to overcome the effects of the therapy.

The plasticity of the cancer genome means that it is not sufficient to kill a cancer as it exists at one point in time--there is a need for a dynamic approach that follows the cancer as it twists and turns to escape the effect of the therapy, and to hunt it down until every last cell is destroyed. This, of course, is easier said than done.

There are, however, grounds for optimism. The Human Genome Project is complete, the Cancer Genome Project is underway, and our understanding of how cancer works has never been better. At a basic level there are three types of genetic change responsible for a normal cell turning into a tumor:

* activation of oncogenes--genes which tell the new cancer to grow;

* loss of tumor suppressors--genes which would have told the cancer to stop growing; and

* loss of DNA repair genes--genes normally work to maintain the integrity of the genome; without them, the other changes are much more likely to occur.

A common analogy is to liken the cell to an automobile. The accelerator pedal represents the oncogenes, which, when activated, is like locking the pedal in the "fully on" position. The brake pedal is likened to the tumor suppressors; the loss of these means that the car cannot stop. Perhaps it is stretching the analogy a little, but an incompetent car mechanic would represent the loss of DNA repair genes like that having an inept individual working on the car would cause an increase in the likelihood of brake or accelerator problems.

It follows then, that to truly wipe out cancer cell within the body, it is not enough to have effective drugs that target some of the cancer-growth pathways--it is also essential to have a way of monitoring the cancer itself, so the drug therapy can be adjusted to match the tumor as it evolves. In this way, it might be possible to use a sequence of treatments to allow a better outcome for the patient.

The tools to allow this are now emerging in the form of cancer biomarkers. The word "biomarker" has a very broad definition and is essentially anything associated with drug response that can be measured. This includes predictive biomarkers--which can be used to select patients--and response biomarkers which (as their name suggests) indicates whether a drug is working or not. There are many classes of biological molecules which can be tested as biomarkers. The most fundamental for cancer are genetic biomarkers, because cancer is essentially a genetic disease in that it is caused by somatic gene changes. Somatic gene changes are the underlying alterations which can predict how an individual tumor will respond to treatment and include mutations, methylation changes, gene rearrangements, and gene-expression changes. All of these genetic changes cause a plethora of other variations to the cell, its immediate environment, and to the whole body; so, as a result, other biomarkers include proteins, peptides, carbohydrates, and metabolites.

For a biomarker to be successful in guiding future drug treatments, there are two key requirements. The first is obviously that the marker, whatever it is, must be associated with drug response. In the language of diagnostics, it must show clinical utility; or, in common parlance, it must answer the "so what" question. If there is no clearly defined treatment decision based on the use of the bio-marker, then it was probably not worth testing for in the first place.

The second requirement has much more to do with the practicality of implementing a biomarker-driven drug selection strategy. Normally at the start of treatment, there will be a tumor biopsy available--this is excellent material for the measurement of many types of biomarkers and is probably the ideal sample. There is, however, a major problem with the tumor biopsy. Earlier in this article, it was pointed out that it would be essential to have a way of monitoring the tumor as it evolved. Unfortunately, for most cancers, there is no practical and safe way to take repeated primary biopsies, so it becomes essential to be able to use a different source of tumor material or even a surrogate for the tumor itself.

There is currently a great deal of interest in the detection of circulating tumor cells(1) or circulating nucleic acid which has been shed from the cancer. These methods can be technically demanding and suffer from a lack of sensitivity, but they do have the huge advantage that regular sampling is both feasible and practical. If these methods can be honed to a workable level, the door can be opened to biomarker monitoring and therapy adjustment.

There is also the possibility of using a surrogate biomarker. For example, hair follicles have the same epithelial origins as many cancers and can be used to indicate whether or not a drug is having the expected effect within the body.

The use of biomarkers to guide therapy is still in its infancy; and although there have been a number of notable recent successes such as the use of KRAS mutation status(2) to guide the use of the colorectal-cancer drugs Erbitux (cetuximab) (3), (4, (5), (6) and Vectibix (panitumumab),(7) and the association between EGFR mutations and response to Iressa (gefitinib) (8), (9), (10) and Tarceva (erlontinib) (11), there is still a long way to go before biomarkers become part of the complete cancer-treatment regime. A greater use of cancer biomarkers is not the only innovation needed to improve outcomes with cancer drugs; but, perhaps, with their increasing adoption, we will soon be able to report that cancer treatment has improved from "could do better" to "a good start."

Note per the author. Erbitux--trademark of Merck KGaA/lmclone Systems; Vectibix--trademark of Amgen Inc.; Iressa--trademark of AstraZeneca group of companies; and Tarceva--trademark of OSI Pharmaceuticals.

References

(1.) Horiike A, Kimura H, Nishio K, Ohyanagi F, et al. Detection of Epidermal Growth Factor Receptor Mutation in Transbronchial Needle Aspirates of Non-Small Cell Lung Cancer. Chest. 2007;131(6):1628-1634.

(2.) Jimeno A, Messersmith WA, Hirsch FR, Franklin WA, Eckhardt SG. KRAS Mutations and Sensitivity to Epidermal Growth Factor Receptor Inhibitors in Colorectal Cancer: Practical Application of Patient Selection. J Clin Oncol. 2009;27(7):1130-1136.

(3.) Bokemeyer C, et al. K-RAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience. J Clin Oncol. 26:2008. (May 20 suppl; abstr 4000)

(4.) Van Cutsem E, et al. K-RAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. J Clin Oncol. 26:2008. (May 20 suppl; abstr 2)

(5.) Tol J, Koopman M, Rodenburg CJ, Punt CJ, et al. A randomised phase III study on capecitabine, oxaliplatin and bevacizumab with or without cetuximab in first-line advanced colorectal cancer, the CAIR02 study of the Dutch Colorectal Cancer Group (DCCG). Annals of Oncology. April 2008.

(6.) Tejpar S, et al., Relationship of efficacy with K-RAS status (wild type versus mutant) in patients with irinotecan-refractory metastatic colorectal cancer (mCRC), treated with irinotecan (q2w) and escalating doses of cetuximab (q1w):The EVEREST experience (preliminary data). J Clin Oncol. 26: 2008. (May 20 suppl; abstr 4001)

(7.) Amado RG, et al. Analysis of K-RAS mutations in patients with metastatic colorectal cancer receiving panitumumab monotherapy. Paper presented at: European Cancer Organization (ECCO), May 24-26, 2007, Limassol, Cypress.

(8.) Kimura H, Kasahara K, Kawaishi M, et al. Detection of Epidermal Growth Factor Receptor Mutations in Serum as a Predictor of the Response to Gefitinib in Patients with Non Small-Cell Lung Cancer. Clin Cancer Res. 2006;12(13).

(9.) Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129-2139.

(10.) Guillermo Paez J, Pasi A, Janne, Jeffrey C.Lee, et al. EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy. Originally published in Science Express, 1-10. 4 AD. Science. 2004;304(5676): 1497-1500.

(11.) Mack P, Holland W, Burich R, Davies A, Gandara D, et al. Predictive value of EGFR and KRAS mutations detected in plasma from non-small cell lung cancer (NSCLC) patients treated with docetaxel and intermittent erlotinib. In: Proceedings from the American Society of Clinical Oncology; May 30-June 2, 2008; Chicago, IL. Abstract 8062.

By Stephen Little, PhD

Stephen Little, PhD, is the CEO of DxS Limited (www.dxsdiagnostics.com), Manchester, UK.