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Study Identifies Patient and Tumor Characteristics Associated With BRAF and KRAS Mutations in Colon Cancer

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Key Points

  • Age ≥ 70 years, smoking, high-grade histology, and defective mismatch repair status were associated with a lower incidence of mutant KRAS tumors but a higher incidence of BRAF V600E-mutant tumors.
  • Among KRAS mutant tumors, those with KRAS Gly13Asp mutation tended to be associated with defective mismatch repair status and high-grade histology.

In a study in the population of the North Central Cancer Treatment Group (NCCTG)/Alliance N0147 adjuvant trial reported in the Journal of the National Cancer Institute, Gonsalves et al identified patient and tumor characteristics that are associated with KRAS and BRAF V600E mutations in colon cancer. Further study is needed to define the involved causal mechanisms.

Study Details

The study involved data from 2,326 of the 3,397 patients in the NCCTG/Alliance N0147 trial of adjuvant therapy in patients with stage III colon cancer. Primary tumors were assessed for KRAS and BRAF V600E mutations and defective mismatch repair status.

The majority of patients were aged < 70 years (83%) and were white (87%); 75% had T3 primary tumors and 46% of tumors were located distally. KRAS mutations were found in 35% of tumors, including KRAS Gly13Asp in 24%, and BRAF V600E mutations were found in 14%, with the KRAS and BRAF mutations being nearly mutually exclusive. Overall, 13% of tumors were characterized as defective mismatch repair.

Factors Associated With Mutant KRAS

Compared with patients with mutant KRAS tumors, those with wild-type KRAS tumors were more likely to be aged ≥ 70 years (86% vs 14%, P = .03), be former/current smokers (56% vs 50%, P = .01), have a first-degree relative with a history of colorectal cancer (15% vs 10%, P < .001), have defective mismatch repair status (17% vs 5%, P < .001), have high-grade histology (27% vs 21%, P < .001), and have a distal tumor (51% vs 40%, P < .001). Compared with patients with other KRAS mutations, those with KRAS Gly13Asp mutation were more likely to have high-grade histology (28% vs 18%, P = .006) and defective mismatch repair status (9% vs 4%, P = .003).

Factors Associated With BRAF V600E Mutation

Compared with patients without BRAF V600E–mutant tumors, patients with BRAF V600E–mutant tumors were more likely to be aged ≥ 70 years (34% vs 14%, P < .001), be female (63% vs 45%, P < .001), be white (94% vs 85%, P < .001), be a current/former smoker (62% vs 52%, P < .001), have defective mismatch repair tumors (47% vs 7%, P < .001), have four or more positive nodes (49% vs 39%, P < .001), have high-grade histology (47% vs 22%, P < .001), have proximal location of tumor (86% vs 48%, P < .001), and have T4 depth of invasion (14% vs 10%, P = .04).

Multivariate Analyses

Multivariate analyses including all factors found to be significant in univariate analysis were performed separately for patient and tumor characteristics. On multivariate analysis, patients with mutated KRAS tumors were less likely to have a first-degree relative with colorectal cancer (odds ratio [OR] = 0.59, P < .001), be a current/former smoker (OR = 0.80, P = .01), have high histologic grade (OR = 0.73, P = .007), and have defective mismatch repair status (OR = 0.21, P < .001) and more likely to have right-sided tumors (OR = 2.05, P < .001).

On multivariate analysis, patients with BRAF V600E mutation were more likely (all P < .001) to be aged ≥ 70 years (OR = 3.33), be a current/former smoker (OR = 1.64), have four or more positive nodes (OR = 1.73), have high-grade histology (OR = 1.71), and have right-sided tumors (OR = 4.01) and less likely to be nonwhite (OR = 0.33) and male (OR = 0.41).

The investigators concluded, “Specific patient and tumor characteristics are associated with KRAS and BRAF V600E mutations…. Further studies are warranted to define the mechanism and temporal order of events brought about by [these] epidemiologic and clinicopathologic characteristics that may explain their association with these specific mutations.”

Robert R. McWilliams, MD, of the Mayo Clinic is the corresponding author for the Journal of the National Cancer Institute article.

The NCCTG/Alliance N0147trial was supported by National Cancer Institute grants and by Bristol-Myers Squibb, ImClone, sanofi-aventis, and Pfizer. The study authors reported no potential conflicts of interest.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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