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Deciphering Metastatic Colorectal CarcinomaBy Maude Veech
Metastatic colorectal carcinoma (MCRC), the second leading cause of cancer-related death in the United States, has represented a treatment quandary. Although half a dozen therapeutic agents are available, oncologists have had no reliable markers to guide the administration of those drugs. Rather, the best results have been obtained by giving all available therapies in various combinations and sequences as tolerated by the patient. However, recent developments in MCRC have finally brought clinicians to the cusp of individualized therapy. The latest step toward tailored care is the discovery of a molecular marker that predicts a lack of response or, in some cases, inferior response to monoclonal antibodies (MAbs) that inhibit the epidermal growth factor receptor (EGFR). Researchers at The University of Texas M. D. Anderson Cancer Center considered the discovery so important that earlier this year, they temporarily halted all MCRC clinical trials involving EGFR MAbs at this institution; similar amendments occurred worldwide. M. D. Anderson’s trials are expected to restart in September, after the participants have had their tumors tested for the molecular marker and, if necessary, been removed from protocols involving EGFR MAbs. “For the first time, we have a clinically proven predictive marker for MCRC that tells us when EGFR inhibitors may not be effective,” said Cathy Eng, M.D., an associate professor in Gastrointestinal Medical Oncology and the principal investigator for many of M. D. Anderson’s MCRC trials. “EGFR MAbs have improved outcomes for many MCRC patients in recent years, but we did not understand why some patients derived no benefit. Now we have a universally accepted marker to help guide our therapy, and that is significant because we can limit unnecessary patient exposure and expense by not giving EGFR MAbs to patients whose cancers are not likely to respond.” Consider the case of a Cancer and Leukemia Group B/Southwest Oncology Group phase III trial (CALGB/SWOG 80405). Dr. Eng describes the trial as the first “head-to-head comparison” of the EGFR inhibitor cetuximab (Erbitux) and the vascular endothelial growth factor (VEGF) inhibitor bevacizumab (Avastin) in combination with cytotoxic chemotherapy; a third arm involves both biologic therapies combined with chemotherapy. With the introduction of molecular marker testing, patients whose molecular marker status suggests they will likely not benefit from anti-EGFR therapy will be recommended to withdraw from the cetuximab-containing arms—and perhaps may be referred for another experimental trial or be treated off-protocol with a standard chemotherapy regimen. Greater molecular understanding The recently identified molecular marker is a mutation of the tumor suppressor gene KRAS. Studies have reported that the KRAS mutation exists in 30%–45% of MCRCs. In MCRC with a KRAS mutation, treatment with a single-agent EGFR MAb has been shown to be no more effective than best supportive care and might even worsen outcomes.
“A study in the United Kingdom that tested panitumumab (Vectibix, a fully human EGFR MAb) versus best supportive care found that the presence of a KRAS mutation in tumors rendered the drug as effective as best supportive care,” said Dr. Eng, who spoke on KRAS at this year’s meeting of the American Society of Clinical Oncology. However, if the mutation was not present, panitumumab conferred an improvement in progression-free survival of 5 weeks. The importance of the KRAS mutation for therapies combining EGFR MAbs with cytotoxic chemotherapeutic agents was further verified by the CRYSTAL trial, which compared the standard chemotherapy combination FOLFIRI (leucovorin, 5-FU, and irinotecan [Camptosar]) with or without cetuximab in previously untreated patients. When FOLFIRI with cetuximab was given to patients with the KRAS mutation, the response rate and progression-free survival duration were inferior to those of patients whose tumors did not have the mutation. This understanding of MCRC on the molecular level came years after the development of EGFR-targeted drugs. EGFR promotes cell division and enhances cell survival, and EGFR is overexpressed in many cancers, including those of the colon, breast, lung, prostate, brain, kidney, and ovary. EGFR MAbs inhibit cell growth and cause apoptosis. A variety of EGFR inhibitors are effective in different types of EGFR-associated cancers, but in MCRC and several others, cetuximab has been an important advance. Cetuximab, a chimeric murine monoclonal antibody against EGFR, was developed by M. D. Anderson President John Mendelsohn, M.D., and his research colleagues in the early 1980s. After nearly 2 decades of clinical investigation, the agent was approved for the treatment of MCRC in 2004 by the U.S. Food and Drug Administration (FDA). Cetuximab is used with or without cytotoxic chemotherapy to treat relapsed or refractory MCRC. Unfortunately, some MCRC patients receive no benefit from cetuximab or other EGFR inhibitors. For a while, it was thought that testing MCRCs for their degree of EGFR overexpression would help identify those patients who would respond to EGFR-targeted therapies; however, studies have shown that such testing does not predict response. Lee Ellis, M.D., a professor in Surgical Oncology and Cancer Biology and chair, ad interim, of the Department of Cancer Biology, believes the reason is that all colon cancers overexpress EGFR, and a failure to detect overexpression by a test represents a failure of the test, not a lack of overexpression. As Dr. Ellis noted, “Biology is not linear—things aren’t always as you expect.” Dr. Eng agreed. “It took several years to determine that EGFR expression had no bearing on drug efficacy,” she said. Avoiding unnecessary treatment
The KRAS test, though, is expected to be very helpful in deciding when to use an EGFR MAb. One reason to avoid giving EGFR MAbs when a KRAS mutation is present is to avoid unnecessary side effects. “About 85% of patients using EGFR inhibitors develop a significant rash,” said Dr. Eng. While treatable with topical and oral antibiotic therapies, the rash represents a quality-of-life issue; it can be painful and pruritic and can cause a patient to be self-conscious about his or her appearance. A more dangerous side effect to be avoided is a severe allergic reaction. This occurs rarely in most patient groups—usually less than 5% of patients are affected. But for reasons still being researched, up to 30% of patients in some Appalachian states, such as Tennessee and North Carolina, are severely allergic to EFGR MAbs. Panitumumab, a second-generation EGFR inhibitor under FDA review, should reduce the chance of allergic reaction in all patients to less than 1%. Still, the rash is expected to remain a problem with panitumumab, as it occurs with all EGFR inhibitors. The high cost of anti-EGFR therapy—about $10,000 a month—also makes it important to avoid treating patients who would derive no benefit. But perhaps most important of all, the time wasted on such therapy could be better used treating patients with therapies that have a possibility of producing a tumor response, such as FOLFOX (a combination of folinic acid [leucovorin], 5-fluorouracil [5-FU], and oxaliplatin) with bevacizumab; FOLFIRI with bevacizumab; or investigational VEGF inhibitors. Researchers expect the KRAS test to be approved by the FDA soon. It has been used at M. D. Anderson since January, and the National Cancer Institute recently required its use in all clinical studies in MCRC. Miles to go Despite needing many more answers, researchers are confident that therapy for MCRC will become more effective. “Hopefully, we will increasingly be able to characterize patients by the presence or absence of molecular markers,” Dr. Eng said. “This characterization of patients’ tumors would allow truly personalized medicine rather than the handful of standardized chemotherapy regimens available until now.”
For more information, call Dr. Eng at 713-792-2828. Other articles in OncoLog, September 2008 issue:
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