EPD400 - A National Cancer Database Study of NRAS and BRAF Mutations in Stage IV Colorectal Cancer

Monday, May 11, 2026

1:25 PM - 1:30 PM ET

ePoster of Distinction Presenter(s)

Sarah E. Rudasill, MD (she/her/hers)

General Surgery Resident
Massachusetts General Hospital
Massachusetts General Hospital
Anacortes, WA, United States

All of the relevant financial relationships listed below have been mitigated.
This individual has no financial relationships with ineligible companies.

Author(s)

Rebecca Tang, MD

General Surgery Resident
Massachusetts General Hospital
Boston, MA, United States

Disclosure information not submitted.
AP

Aparna R. Parikh, MD

Associate Professor
MGBCI
Boston, Massachusetts, United States

Disclosure information not submitted.
Christy Cauley, MD, MPH (she/her/hers)

Associate Professor
Mass General Brigham
Massachusetts General Brigham; Harvard Medical School
Winchester, Massachusetts, United States

All of the relevant financial relationships listed below have been mitigated.
This individual has no relevant relationships with ineligible companies.
Robert N. Goldstone, MD

Assistant Professor of Surgery
Massachusetts General Hospital
Harvard Medical School
Boston, MA, United States

All of the relevant financial relationships listed below have been mitigated.
This individual has no relevant relationships with ineligible companies.
HK

Hiroko Kunitake, MD MPH

Associate Professor
Harvard Medical School, Massachusetts General Hospital
Harvard Medical School, Massachusetts General Hospital
Boston, MA, United States

All of the relevant financial relationships listed below have been mitigated.
This individual has no financial relationships with ineligible companies.
Grace C. Lee, MD

Assistant Professor of Surgery
Massachusetts General Hospital
Harvard Medical School
Boston, MA, United States

Disclosure information not submitted.

Senior Author(s)

Rocco R. Ricciardi, MD

Chief, Division of Colon & Rectal Surgery
Massachusetts General Hospital
Harvard University
Boston, MA, United States

Disclosure information not submitted.

All of the relevant financial relationships listed below have been mitigated.

Sarah E. Rudasill, MD: This individual has no financial relationships with ineligible companies.

Christy Cauley, MD, MPH: This individual has no relevant relationships with ineligible companies.

Robert N. Goldstone, MD: This individual has no relevant relationships with ineligible companies.

Hiroko Kunitake, MD MPH: This individual has no financial relationships with ineligible companies.

Purpose/Background: NRAS and BRAF mutations occur in approximately 5% and 12% of metastatic colorectal cancers, respectively, and are associated with a poor prognosis. The role of tumor location and microsatellite instability (MSI) in this context remains uncertain. Therefore, we aimed to examine the impact of NRAS and BRAF mutations on overall survival and assess how immunotherapy influences MSI-associated outcomes. We hypothesized that these mutations confer worse survival, modified by tumor location and MSI status.

Methods/Interventions: We conducted a retrospective cohort study using the National Cancer Database (2021-2022). Adults with clinical Stage IV colon, rectosigmoid, or rectal cancer were stratified by the presence of an NRAS or BRAF mutation; patients missing mutation data were excluded. Patients were further stratified by MSI status and primary tumor location, with a subset analysis among patients who underwent surgical resection. The primary outcomes were one- and two-year survival. Kruskal-Wallis and chi-squared tests were used to assess univariate associations with continuous and categorical variables, respectively. Cox proportional hazards regression was used for survival outcomes.

Results/Outcomes: Among 13,071 patients with stage IV colorectal cancer, 2,074 (15.9%) had NRAS or BRAF mutations. NRAS/BRAF+ patients were older (68.0 vs. 62.3 years, p< 0.001) and more often had right-sided (40.3% vs. 26.2%, p< 0.001) and MSI (15.6% vs. 4.6%, p< 0.001) tumors, but they underwent resection at similar rates to those without mutations (47.0% vs. 45.4%, p=0.16). In the surgical cohort, NRAS/BRAF+ tumors more frequently exhibited poor differentiation (33.6% vs. 15.5%, p< 0.001) and pathologic T4 (51.4% vs. 39.4%, p< 0.001) and N2 (48.4 vs. 31.8%, p< 0.001) disease. Higher rates of positive margins (21.2% vs. 17.7%, p=0.02), as well as 30-day (2.3% vs. 1.0%, p=0.01) and 90-day (6.2% vs. 2.5%, p< 0.001) mortality, were observed in NRAS/BRAF+ patients.

NRAS/BRAF+ patients had worse one- and two-year overall survival (61.4% vs. 72.9% and 39.6% vs. 53.4%, respectively, both p< 0.001), a finding consistent in the surgical cohort (68.4% vs. 84.1% and 48.1% vs. 68.7%, both p< 0.001). The two-year survival difference was greatest in right-sided tumors (33.7% vs. 44.7%, p< 0.001), including among the subset resected (39.6% vs. 57.7%, p< 0.001), but was also evident for left colon and rectal tumors. Lower two-year survival was also observed for NRAS/BRAF+ patients across both MSI (45.7% vs. 54.6%, p=0.02) and MSS (38.0% vs. 54.4%, p< 0.001) tumors. However, NRAS/BRAF+ MSI patients who received immunotherapy had improved two-year survival compared to those who did not (56.3% vs. 32.7%, p< 0.001). On multivariable analysis, NRAS/BRAF+ tumors remained independent predictors of one-year (HR=1.40, p=0.007) and two-year (HR=1.37, p=0.002) mortality, with the strongest effect in right-sided (HR=1.63; p< 0.001) relative to left-sided tumors. These associations persisted in the surgical cohort (1-year HR=1.49; p< 0.001; 2-year HR=1.63; p< 0.001).

Conclusion/Discussion: In this National Cancer Database study of Stage IV colorectal cancer, NRAS/BRAF mutations were associated with worse one- and two-year overall survival, particularly for right-sided tumors, independent of MSI status. Immunotherapy was associated with improved survival in MSI tumors, including those with NRAS/BRAF mutations. These findings underscore the importance of risk stratification by tumor location and MSI status.

Figure 1. Kaplan-Meier Estimates for Two-Year Overall Survival by NRAS/BRAF Mutations Among Patients with Stage IV Colorectal Cancer, Stratified by MSI Status and Tumor Location

This multi-paneled figured displays the Kaplan-Meier estimates for two-year overall survival in a population with Stage IV colorectal cancer. Each panel displays the results of a subset analysis, stratified by presence of NRAS or BRAF mutations. Shaded regions represent 95% confidence intervals.