In terms of pathologic review, testing patients with metastatic colon cancer for the oncogenic BRAF gene mutation is now "optional" as part of the clinical workup, said Paul Engstrom, MD, here at the NCCN 15th Annual Conference.
"BRAF testing is now permitted but not mandatory," Dr. Engstrom, from Fox Chase Cancer Center in Philadelphia, Pennsylvania, told Medscape Oncology. The question is: "Should it be mandatory?"
BRAF testing can help identify which individual patients with metastatic disease will benefit from targeted therapy with antiepidermal growth-factor-receptor (EGFR) monoclonal antibodies.
Only about 15% of patients with metastatic colorectal cancer are responders to targeted therapy with the anti-EGFR therapies panitumumab (Vectibix, Amgen) and cetuximab (Erbitux, Bristol-Myers Squibb), noted Dr. Engstrom.
Currently, only KRAS testing is required by the NCCN guideline to help identify which metastatic colon cancer patients are candidates for anti-EGFR treatment. "If a patient has mutant KRAS, there is no advantage with the treatment," said Dr. Engstrom, adding that BRAF status is not needed when KRAS is mutated.
BRAF testing should take place only after KRAS testing, and only when the testing indicates wildtype KRAS, noted Dr. Engstrom, explaining that, in such cases, the BRAF results might further identify likely responders.
According to the new guideline, patients with a BRAF mutation "appear unlikely to benefit from anti-[EGFR] monoclonal antibodies."
Dr. Engstrom cited recent results from the phase 3 CRYSTAL trial as evidence that BRAF mutations are prognostic indicators of worse outcomes in KRAS wildtype patients.
In that analysis, treatment with fluorouracil and irinotecan (FOLFIRI) plus cetuximab in KRAS wildtype patients provided a median overall survival of 23.5 months, and of 25.1 months for patients with both KRAS and BRAF wild-type status, but just 14.1 months for KRAS wildtype patients who had BRAF mutations. These and other results from the CRYSTAL study were covered by Medscape Oncology earlier this year.
BRAF is one of a number of additional markers that has been identified as potentially useful in refining patient selection for the treatment of metastatic colorectal cancer. One expert previously told Medscape Oncology that BRAF was the best candidate for clinical use.
"It is clear. BRAF will eventually be used because all of the data are consistent. Anywhere from 3% to 12% of metastatic colorectal cancer patients have a mutated form of BRAF, and all those patients do poorly," said Wells Messersmith, MD, a gastrointestinal oncologist from the University of Colorado Cancer Center in Boulder.
Dr. Messersmith, who made his comments before the release of the CRYSTAL results, also said that the only hold-up to incorporating BRAF testing into clinical practice was definitive clinical trial data. "Practice-changing data must come from large prospective randomized clinical trials," he said.
The NCCN feels that more data than those from the CRYSTAL trial, which is a large prospective randomized trial, are needed before BRAF testing becomes a required part of clinical workups. "Some of the data are inconsistent" in these patients, according to the NCCN guideline.
Adjuvant Therapy Update
In terms of the use of adjuvant therapy in colon cancer, the new NCCN guideline has a number of new recommendations.
Bevacizumab (Avastin, Roche), panitumumab, cetuximab, and irinotecan (Camptosar, Pfizer) "should not be used in the adjuvant setting for stage II or III patients outside the setting of a clinical trial," the guideline now reads. Dr. Engstrom emphasized that the agents are particularly "inappropriate for stage III disease."
These drugs have shown effectiveness in the metastatic setting, but not in earlier stages of disease, he suggested.
The guideline indicates that there are no data to support any kind of adjuvant therapy, either chemotherapy or targeted therapy, in stage I disease.
Furthermore, the use of adjuvant chemotherapy in stage II disease is also largely ineffective, said Dr. Engstrom, citing a recent retrospective analysis by John Marshall, MD, from Georgetown University in Washington, DC. "The difference between chemotherapy and observation was minimal," said Dr. Engstrom about the analysis.
Nevertheless, "certain high-risk stage II patients," such as those with lymphovascular invasion, poorly differentiated histology, and inadequate lymph node sample, may be considered for chemotherapy, said Dr. Engstrom, citing the guideline.
Recommended adjuvant chemotherapy in these high-risk patients includes infusional fluorouracil (5-FU), leucovorin, and oxaliplatin (FOLFOX) and 5-FU, folinic acid, and oxaliplatin (FLOX), states the guideline.
However, the guideline also now recommends that testing for mismatch repair proteins be "considered" for all patients younger than 50 years to help guide chemotherapy decisions. Patients with stage II low-frequency microsatellite instability might have a good prognosis, and they do not benefit from 5-FU adjuvant therapy, said Dr. Engstrom, citing earlier studies.
The Oncotype DX colon cancer test (Genomic Health), a multigene expression test that is approved by the US Food and Drug Administration and available for use, can help clinicians identify stage II patients at higher risk for recurrence and, thus, potentially in need of adjuvant chemotherapy, suggested Dr. Engstrom. "There is a definite correlation between recurrence score and recurrence," he said.
"Our committee does not recommend the Oncotype DX currently, but with more data, it might play a role," he said.
Dr. Engstrom reports being a consultant to or being on the advisory board or speaker's bureau of Novartis.
National Comprehensive Cancer Network (NCCN) 15th Annual Conference. Presented March 11, 2010.
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