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BRAF V600E mutations linked to worse survival in metastatic colorectal cancer
Harboring a BRAF V600E mutation appeared associated with a poorer prognosis and greater risk for recurrence after curative-intent resection compared with KRAS mutations among patients with colorectal cancer and liver metastasis, according to study results.
Researchers did not observe this association among patients with non-V600E BRAF mutations.
“BRAF mutations affect the same signaling pathway as KRAS mutations, the most important difference being that the genetic product of a BRAF-mutated gene exerts its influence downstream from KRAS,” Georgios Antonios Margonis, MD, PhD, surgical oncology fellow at Johns Hopkins University School of Medicine, and colleagues wrote. “Although these similarities suggest a possible role for BRAF as a prognostic indicator of colorectal liver metastasis, this hypothesis has not been well studied because of the low (2%-4%) incidence of BRAF mutations in resected colorectal liver metastasis compared with the 30% to 40% incidence of KRAS mutations.”
Margonis and colleagues assessed 853 patients (59.8% men; mean age, 60.2 years) with colorectal cancer and liver metastasis who underwent resection with curative intent.
All patients had data on BRAF and KRAS mutational status. Researchers observed:
- 5.1% had mutated BRAF and wild-type KRAS (V600E and non-V600E);
- 38.4% had wild-type BRAF and mutated KRAS; and
- 56.5% had wild-type BRAF and wild-type KRAS.
A greater proportion of patients with mutated BRAF and wild-type KRAS were female (62.8% vs. 35.2%), aged 65 years or older (51.2% vs. 36.9%), had right-sided primary tumors (64.3% vs. 46.8%) and presented with a metachronous liver metastasis (64.3% vs. 46.8%) than patients with wild-type BRAF and wild-type KRAS.
Median follow-up was 28.3 months.
BRAF V600E mutations — but not non-V600E BRAF mutations — appeared associated with worse OS (HR = 2.76; 95% CI, 1.74-4.37) and DFS (HR = 2.04; 95% CI, 1.3-3.2).
Researchers observed stronger associations between BRAF V600E mutations and OS and DFS than with KRAS mutations and those endpoints ( for OS, 10.15 vs. 2.94; for DFS, 7.14 vs. 2.27).
“A novel (in surgical colorectal liver metastasis cohorts) finding is that the V600E mutation alone (rather than V600E and non-V600E mutations together) may confer a distinctly aggressive clinical phenotype, thus driving the adverse outcomes associated with BRAF mutation,” the researchers wrote. “However, this finding needs to be interpreted with great caution because of the small number of patients with non-V600E mutations in the cohort.” – by Cassie Homer
Disclosures: The authors report no relevant financial disclosures.
Perspective
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Colorectal cancer clinical subgroups include those with mutated KRAS/NRAS genes, mutated BRAF, those with neither mutation — wild-type for KRAS/NRAS/BRAF — and those with microsatellite instability. We already knew that BRAF-mutated colon cancers are rarer at only approximately 8% to 10% of colorectal tumors, tend to be right-sided and are more aggressive and carry the worst prognosis compared with the other subgroups. Some progress has been made with targeted (triplet) therapies for patients with BRAF-mutated metastatic colorectal cancer, including vemurafenib (Zelboraf, Genentech), irinotecan and cetuximab (Erbitux, Eli Lilly), or dabrafenib (Tafinlar, Novartis), trametinib (Mekinist, Novartis) and panitumumab (Vectibix, Amgen).
We’ve also known for years that even if colon cancer metastasizes in a limited manner to the liver or lungs, a more aggressive approach involving surgery, if possible, and chemotherapy can improve upon long-term outcomes in terms of patient survival and ultimate cure. What wasn’t known was whether a BRAF mutation might negatively impact patient outcomes, including survival, if treated with surgery.
Between 2000 and 2016, researchers analyzed 849 patients with colorectal tumors and liver metastases, 43 of whom had BRAF mutations and wild-type KRAS, 326 of whom had KRAS mutations, and 480 of whom had neither KRAS nor BRAF mutation. Researchers observed some difference in the prehepatectomy chemotherapy use between the patients whose tumors were part of the wild-type-BRAF/KRAS (69.5%) and mutated-BRAF/wild-type-KRAS (48.8%) subgroups. Researchers found no difference in use of chemotherapy posthepatectomy (63.8% vs. 57.1% for these same two subgroups).
On the one hand, the study confirms that patients with BRAF-mutated colon cancers and liver metastases have a worse outcome when surgically resected compared with the nonmutated or even the KRAS-mutated tumors. However, those patients with BRAF-mutated tumors tended to get less prehepatectomy chemotherapy and perhaps that may improve the outcomes in the future. The lack of prehepatectomy chemotherapy is unlikely to explain the outcomes data, though, and is a minor component.
The choice of chemotherapy for the period during which the study was performed very likely excluded the newer triple therapies, which have not yet been studied in the neoadjuvant setting, and also likely would not have been used posthepatectomy. In the future, use of such agents for the BRAF-mutated colon cancers might impact patient survival in the setting where surgery is performed.
The observed median survival for the 43 patients with BRAF-mutated colorectal cancer with liver metastasis was 26 months. This compares somewhat favorably to the historical median survival for BRAF-mutant metastatic colorectal cancer of 12 months when treated with chemotherapy. Of the 43 BRAF-mutated tumors, 33 were V600E, six were non-V600E and four were unspecified. The main conclusion of the paper showed worse outcomes apply to the BRAF V600E -mutant tumors — vs. wild-type-BRAF/wild-type-KRAS tumors or mutant-KRAS tumors — whereas there may be less of a poor outcome with non-V600E vs. the BRAF -nonmutated tumors, but the numbers are small for the non-V600E tumors. From the data provided, it is not possible to know whether there is a tail on the BRAF-mutated metastatic colorectal cancer curve in terms of long-term survivors.
The authors state that no recommendations can be made for surgery or medical therapy for patients with BRAF-mutated colorectal cancer based on their reported findings. Taken together, it appears as though there may be some improvement in median OS with surgery for the BRAF-mutated group vs. historical numbers, but that was not directly compared in this study in terms of surgery vs. no surgery. It is unclear whether the patients with the BRAF-mutated metastatic colorectal tumors might do as well or better with the currently available targeted triple therapies on top of the older conventional chemotherapies without surgery. However, from the available data, it is not possible to state that surgery would not offer any benefit, at least in the short-term, for the median OS effect. Regardless, BRAF-mutated metastatic colorectal cancer has a poor prognosis and needs better therapy development, including more clear integration of surgery when it may be helpful.