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Certain BRAF mutations improve prognosis in colorectal cancer
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Patients with metastatic colorectal cancer with non-V600 mutations to BRAF define a clinically distinct disease subtype with a good prognosis, according to results of a retrospective study.
“These findings not only have immediate clinical implications, but also provide valuable insights into a model of BRAF modulation that could potentially be exploited to better understand and treat BRAF–mutant cancers,” Jeremy C. Jones, MD, medical oncologist at Mayo Clinic in Rochester, Minnesota, and colleagues wrote.
Clinical, therapeutic and prognostic implications are unclear for a majority of mutations identified through next-generation sequencing. However, the relevance of mutations within the BRAF gene found outside of the 600th codon — or those that are non-BRAF V600 mutant — are particularly unknown. The researchers aimed to characterize the clinical, pathologic and survival implications of patients with non-V600 mutations to BRAF in metastatic colorectal cancer.
Jones and colleagues identified 208 patients with non-V600 mutations to BRAF from three next-generation sequencing databases — Mayo Clinic, The University of Texas MD Anderson Cancer Center and Foundation Medicine — between 2013 and 2016. For comparative analysis, researchers included patients from the Mayo Clinic database with BRAF V600E (n = 133) and BRAF wild-type metastatic colorectal cancer (n = 249).
Patients with non-V600 mutations to BRAF comprised 2.2% of all patients with metastatic colorectal cancer and accounted for 21.6% of all BRAF mutations, which indicated a “clinically distinct subtype” of this cancer, the researchers wrote.
Compared with patients with BRAF V600E mutations, patients who harbored non-V600 mutations to BRAF tended to be younger (58 years vs. 68 years), less likely to be a woman (46% vs. 65%) and less likely to have peritoneal metastases (15% vs. 59%); they also had fewer high-grade tumors (13% vs. 64%) or right-sided primary tumors (36% vs. 81%; P < .001 for all).
The survival analysis included 101 patients with non-V600 mutations to BRAF, 99 patients with BRAF V600E and 249 patients with BRAF wild-type tumors.
BRAF status appeared associated with OS (P < .001). Median OS was 11.4 months (95% CI, 9.4-13.5) for patients with BRAF V600E mutations compared with 43 months (95% CI, 30.7-62) among patients with BRAF wild-type tumors and 60.7 months (95% CI, 36.5-81.2) among patients with non-V600 mutations to BRAF (P < .001 for all).
After adjusting for covariates associated with OS, multivariable analysis showed a significant association between non-V600 mutations to BRAF and improved OS (HR = 0.18; 95% CI, 0.1-0.32).
Non-V600 mutations to BRAF can define a significant molecular subgroup of metastatic colorectal cancer, Eric Van Cutsem, head of clinical digestive oncology at University Hospitals Leuven and KULeuven, Belgium, and Jeroen Dekervel, also from University Hospitals Leuven and KULeuven, wrote in an accompanying editorial.
“Given the distinct disease course associated with non-V600 BRAF mutations, it seems reasonable to include them in next-generation sequencing panels of metastatic colorectal cancer used in clinical practice,” the researchers wrote.
However, Van Cutsem and Dekervel noted that retrospectively collecting the data created a major limitation.
“As a direct consequence, because of missing clinical data, only 5% of the initial cohort described is included in the survival analysis. This naturally exposes the study to potential bias,” they wrote, adding that these data may influence other groups to confirm the findings and further investigate the subgroup. – by Melinda Stevens
Disclosure: Jones reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures. Van Cutsem reports consultant/advisory roles with Bayer, Eli Lilly and Novartis, and research funding to his institution from Amgen, Bayer, Boehringer Ingelheim, Celgene, Ipsen, Eli Lilly, Merck, Merck Serono, Novartis, Roche and Sanofi. Dekervel reports no relevant financial disclosures.
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