The Coalition of Cancer Cooperative Groups—the voice for cancer clinical trials—was established in 1997 with the sole mission of improving the quality of life and survival of cancer patients by increasing participation in cancer clinical trials.
With a distinguished Board of Directors comprised of the Chairs of 10 NCI-sponsored Cooperative Groups, and thousands of oncologists and cancer research specialists among our members, we are uniquely positioned as a go-to source of clinical trial information for clinicians, patients, advocates and the public alike. We also want to provide our members with a forum for discussion of issues and questions related to current cancer research and clinical trials.
Toward that goal, we are delighted to introduce a new series of quarterly newsletters dedicated to highlighting the results of select cancer research and clinical trials. As the newsletter was developed for you—our members and the cancer community—we welcome comments and feedback as well as suggestions for topics that should be covered in the newsletter.
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Although the incidence of colorectal cancer is declining, it remains the third most common cancer in adults in the US, with 150,000 new cases diagnosed in the US in 2008 alone. For patients with localized disease, surgical removal of tumor tissue can be curative. But despite the efficacy of surgery, disease recurs in roughly sixty percent of patients. For those with advanced disease, the benefits of standard chemotherapy are modest at best, and the 5-year survival rate for these patients is only 5% (1).
The development of new, targeted drugs like cetuximab (Erbitux) and panitumumab (Vectibix) promises patients with advanced disease more of a fighting chance. These drugs deprive the tumor of essential survival signals by interfering with a protein called EGFR (epidermal growth factor receptor) that is often expressed at high levels on colorectal tumors (2). In recent studies of patients with metastatic, treatment-refractory disease, those treated with cetuximab or panitumumab survived longer than those given supportive care alone (3, 4).
But not all patients with EGFR-expressing tumors benefit from these drugs, prompting researcher to search for potential genetic markers that could predict responsiveness. These studies revealed that patients with mutations in a protein called KRAS, which occur in 30-40% of colorectal cancer patients, do not benefit from the addition of cetuximab or panitumumab to standard chemotherapy regimens (FOLFIRI or FOLFOX ) (4, 5, & 6). KRAS transmits growth signals from EGFR to the inside of the tumor cell; when KRAS is mutated, the EGFR pathway becomes perpetually activated. Mutations in KRAS are also associated with failure to benefit from the small molecule EGFR-inhibitors gefitinib (Iressa) and erlotinib (Tarceva) in patients with advanced non-small cell lung cancer (NSCLC) (7).
EGFR inhibitors are generally given to patients with advanced, treatment-refractory disease. But new data shows that cetuximab in combination with chemotherapy is also effective as a first-line treatment (8, 9), and ongoing studies are evaluating it its benefits in post-operative adjuvant regimens in patients with stage II and III disease. Despite the availability of laboratory tests, patients are not routinely evaluated for KRAS status prior to treatment. However, the American Society of Clinical Oncology (ASCO) now recommends that potential candidates for EGFR-targeted drugs should be tested for KRAS mutation status, and patients with a mutated form should be excluded from treatment.
Routine KRAS testing could spare patients the expense of treatment with costly drugs that are unlikely to work; a recent analysis estimated the cost of treatment with cetuximab (weekly) and panitumumab (bi-weekly) at $10,000 per month. Testing would also spare patients the side effects of these drugs, which can sometimes be severe. Ultimately, tailoring treatment with EGFR inhibitors based on KRAS status will allow unresponsive patients to avoid ineffective therapies during the crucial early stages when anticancer treatment should be initiated while eliminating associated side effects and expense.
References
1. www.nci.gov
2. Perez-Soler, R, and L. Saltz. 2005. Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? J. Clin. Oncol. 23: 5235-5246.
3. Jonker, D.J. et al. 2007. Cetuximab for the treatment of colorectal cancer. New Engl. J. Med. 357: 2040-2048.
4. Amado R.G. et al. 2008. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol. 26: 1626-1634.
5. Lievre A. et al. 2006. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 66:3992-3995.
6. Di Fiore F. et al. 2007. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. Brit. J. Cancer 96: 1166-1169.
7. Bonomi P.D. et al. 2007. Selecting patients for treatment with epidermal growth factor tyrosine kinase inhibitors. Clin Cancer Res. 13: 4606s-4612s.
8. Van Cutsam, E. et al. 2008. KRAS status 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: May 20 Suppl; abstract 2.
9. Bokemeyer, C. 2008. KRAS 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: May 20 Suppl; abstract 4000.
10. Eberhard, D.A. et al. 2005. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J. Clin. Oncol. 23: 5900-5909.
11. Tsao M. et al. 2006. An analysis of the prognostic and predictive importance of K-ras mutation status in the National Cancer Institute of Canada Clinical Trials Group BR.21 study of erlotinib versus placebo in the treatment of non-small-cell lung cancer. J. Clin. Oncol. 24: 365s.
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TrialCheck®, developed by the Coalition, is an information and technology cancer clinical trial software system for eligibility matching. TrialCheck®’s navigation service provides precise screening to match patients to trials near their homes by capturing disease subtype, age, prior treatment history, performance state and stage. Trials can also be search by drug, protocol ID, performance site and anatomical site.
Winner of the 2008 Consumer Health World award and NCI’s Bronze-level certified Biomedical Informatics Grid, TrialCheck® is used by the American Cancer Society, American Society of Clinical Oncology, Web MD and others because it provides the most up-to-date trial listings that is completely unbiased. TrialCheck® includes all federally (U.S.) registered cancer studies, whether publicly or privately funded.
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HIMSS, April 5-7, Chicago, IL, Booth 2779
ONS, April 29-May 2, San Antonio, TX, Booth 250
ASCO, May 20-June 1, Orlando, FL, Booth 713
ECOG Spring Meeting, June 12-14, Philadelphia, PA
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