Individualized therapies in colorectal cancer: KRAS as a marker for response to EGFR-targeted therapy

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Date: Apr. 22, 2009
Publisher: BioMed Central Ltd.
Document Type: Report
Length: 5,733 words

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Authors: David Z Chang (corresponding author) [1]; Vikas Kumar [1]; Ying Ma [1]; Kuiyuan Li [2]; Scott Kopetz [1]

Introduction

Over the past decade, we have witnessed an important development in the field of cancer treatment: therapy that is targeted to specific pathways involved in tumor growth and progression. This mechanistic, target-based approach is adding to the treatment options for cancer, and these treatments should be less toxic to normal cells and thus improve the therapeutic index.

To date, however, the overall effectiveness of targeted therapy in solid tumors has not been as robust as that achieved, for example, by Gleevec (imatinib) in the treatment of chronic myelogenous leukemia (CML). The difference in targeted therapy effectiveness in CML compared with solid tumors can be explained in part by the genetic etiology of the diseases. CML is caused by a single genetic alteration that results in a BCR/ABL fusion gene. This gene produces a chimeric protein with strong tyrosine kinase activity that can be effectively blocked by Gleevec. For most solid tumors, on the other hand, although they may appear to be morphologically similar on microscopic examination, molecular studies can identify different genetic alterations in tumors from different patients. Due to this heterogeneity, an agent targeting one particular pathway is unlikely to be effective in all patients. Clearly, there is a need to identify those patients who are most likely to respond to a specific therapy.

The identification of specific subgroups of patients who may benefit from a particular targeted therapy has been most successful in patients with breast cancer. Anti-estrogen treatment, an early type of targeted therapy, mainly benefits patients with estrogen receptor-positive breast cancer. Trastuzumab, a HER2-targeting monoclonal antibody, is most beneficial in patients with tumors that overexpress HER2. Recent data also suggest that genetic profiling can predict which patients may benefit from adjuvant therapy after resection of their breast cancers (e.g., Genomic Health's Oncotype DX[R] test, which profiles the expression of 21 genes and makes a prediction about the likelihood of disease recurrence). These findings show great promise for identifying patients eligible for treatment with specific targeted therapies, as well as for making decisions about dosage and length of treatment.

Individualized therapies that are tailored to a patient's genetic composition and tests that can predict which therapy he/she will respond to will be of tremendous value for colorectal carcinoma (CRC). Despite significant progress in the development of new therapies over the last decade, CRC remains one of the top three causes of cancer death in the United States, where it is estimated that 148,810 patients will be newly diagnosed with CRC in 2008, with 49,960 deaths from this disease [1]. Many of these patients will receive one or more lines of chemotherapy, but not everyone responds to each regimen. For example, the targeted agent cetuximab as a single agent has a response rate of only about 10% in patients with irinotecan-refractory CRC [2, 3]. In other words, the majority of people receiving cetuximab may not benefit from...

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Gale Document Number: GALE|A200630514