Abstract 928: Correlation among actionable gene mutations, microsatellite instability and tumor mutational burden in advanced colorectal cancer and association with survival
Authors: Miyashita Hirotaka , Brooks Gabriel , Kurzrock Razelle , Kato Shumei 
Published: April 2023

Introduction: Targeted therapies and immunotherapies have changed the treatment strategy for advanced colorectal cancer. Characterizing associations of actionable gene mutations with microsatellite instability (MSI) and tumor mutational burden (TMB) could suggest mechanistically intriguing combinations of targeted and immunotherapies.

Methods: Publicly available genetic and overall survival (OS) data of patients with colorectal cancer were analyzed. (N=3,548, MSK-MET through cBioPortal for cancer genomics) We investigated the correlations among actionable gene mutations (BRAF V600E, KRAS G12C, HER2 amplification, NTRK fusion, and RET fusion), MSI and TMB (&gt;20/Mb). The association of actionable mutations, MSI and TMB patterns with OS was analyzed.

Results: BRAF V600E, KRAS G12C, HER2 amplification, NTRK fusion, RET fusion, MSI and TMB &gt;20 was observed in 6.9, 3.1, 2.8, 0.3, 0.2, 9.2 and 9.9%, respectively. BRAF V600E showed mutual exclusivity toward KRAS G12C and HER2 amplification. MSI and TMB &gt; 20 were associated with the presence of BRAF V600E, NTRK fusion, and RET fusion and the absence of KRAS G12C and HER2 amplification. MSI and TMB &gt; 20 were highly correlated. (Table) Among patients with MSI (N=316), BRAF V600E was associated with shorter OS. (Hazard ratio (HR) 2.22, 95% confidence interval (CI); 1.12 - 4.41) In the patients without MSI, TMB &gt;20 showed significantly longer OS, compared with TMB ≤20. (HR 0.26, 95% CI; 0.085 - 0.82) Association of NTRK or RET fusion with survival could not be reliably assessed due to small sample size (n &lt; 10 for both).

Conclusion: There is significant correlation among targetable genetic mutations, MSI and TMB in colorectal cancer, and biomarker profiles are associated with differences in OS. Future studies should evaluate whether combinations of targeted therapies and immunotherapy have better efficacy than monotherapy approaches in selected patients.

Correlation among actionable gene mutations and immunomic signatures (OR and 95 % CI) KRAS G12C HER2 amp NTRK fusion RET fusion MSI TMB &gt;20 BRAF V600E 0 (0 - 0.44) * 0 (0 - 0.49) * 0 (0 - 6.79) 0 (0 - 9.31) 10.0 (7.39 - 13.5) * 8.76 (6.52 - 11.7) * KRAS G12C 0.31 (0.01 - 1.78) 0 (0 - 16.0) 0 (0 - 21.9) 0.18 (0.02 - 0.67) * 0.16 (0.02 - 0.61) * HER2 amp 0 (0 - 17.5) 0 (0 - 23.9) 0.10 (0.00 - 0.57) * 0.09 (0.00 - 0.51) * NTRK fusion 0 (0 - 315) 20.0 (4.25 - 124) * 18.4 (3.91 - 115) * RET fusion 24.9 (4.06 - 261) * 23.0 (3.74 - 241) * MSI 1.52 x 104 (4.20 x 103 - 4.50 x 1015) *

Citation Format: Hirotaka Miyashita, Gabriel Brooks, Razelle Kurzrock, Shumei Kato. Correlation among actionable gene mutations, microsatellite instability and tumor mutational burden in advanced colorectal cancer and association with survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 928.