V600E BRAF mutation strong prognostic indicator in colorectal liver cancer metastases

Naveed Saleh, MD, MS, for MDLinx | June 25, 2018

The presence of the V600E BRAF mutation in patients undergoing hepatectomy for colorectal liver cancer metastases (CRLM) predicts worse prognosis and higher risk of recurrence, according to a new study published in JAMA Surgery. In fact, the V600E mutation was a stronger prognostic determinant than BRAF, and it was also the strongest overall prognostic determinant identified in the cohort study.

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“We assembled the largest cohort, to our knowledge, of surgically treated patients with CRLM and BRAF mutations to be reported in the literature to date,” wrote the researchers.

“Our results suggest that BRAF and KRAS mutations should not be used interchangeably as markers of aggressive tumor biology,” wrote the authors, led by Georgios Antonios Margonis, MD, PhD, Johns Hopkins University School of Medicine, Baltimore, MD. “Furthermore, our study suggests that the presence of the V600E BRAF mutation is associated with poor prognosis and may serve as a more useful tool for preoperative patient selection than KRAS mutation status.”

The number of studies examining the role of KRAS CRLM as a negative prognostic factor has increased since 2000. Although BRAF mutations involve the same signaling pathway as KRAS mutations—thus indicating a prognostic role for BRAF mutations—BRAF mutations in resected CRLM are uncommon and poorly described. Specifically, BRAF mutations are only present in between 2% and 4% of resected CRLM; KRAS mutations are present in 30% to 40% of resected CRLM.

“We aimed to investigate the clinical profile of patients with tumors with BRAF mutations and assess the prognostic association of BRAF mutations with survival and recurrence independently and compared with KRAS mutations,” the researchers wrote. They also looked at whether different types of BRAF mutations—V600E vs non-V600E—possess specific prognostic importance.

In this multi-institutional cohort study, Dr. Margonis and colleagues mined the International Genetic Consortium for Colorectal Liver Metastasis (IGCLM) for all BRAF and KRAS data on patients who received CRLM resection between January 1, 2000, and December 31, 2016. The primary outcomes in this study were the association of V600E and non-V600E BRAF mutation with disease-free survival (DFS) and overall survival (OS).

In total, the researchers included 849 patients with the following characteristics:

  • 43 patients (5.1%) with mutated (mut)BRAF/wild-type (wt)KRAS (V600E and non-V600E)
  • 480 patients (56.5%) with wtBRAF/wtKRAS
  • 326 patients (38.4%) with wtBRAF/mutKRAS

Patients with mutBRAF/wtKRAS were mostly women and were aged 65 years or older when compared with those with wtBRAF/wtKRAS. Furthermore, the majority of those with mutBRAF/wtKRAS exhibited right-sided primary tumors and a metachronous liver metastasis.

Using multivariate analysis, the researchers found that V600E—but not non-V600E BRAF—was positively correlated with worse OS (HR: 2.76; 95% CI: 1.74-4.37; P < 0.001) and worse DFS (HR: 2.04; 95% CI: 1.30-3.20; P=0.002). The V600E BRAF mutation was more strongly associated with OS and DFS than were KRAS mutations.

“In this international collaborative effort, we assembled the largest cohort, to our knowledge, of surgically treated patients with CRLM and BRAF mutations to be reported in the literature to date,” wrote the researchers. “In fact, the number of patients with BRAF mutations in the present study (n=47) exceeded the cumulative population of the most recent meta-analysis (n=22) by a factor greater than 2.”

Limitations of this study included that it was retrospective and involved only surgical patients. The authors note that because BRAF mutations are rare, assembling a prospective study of sufficient power is challenging.

“A novel (in surgical CRLM 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,” concluded the researchers.

To read more about this study, click here. 

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