Abstract 5212: Braf-altered microsatellite-stable metastatic colorectal cancer: A niche for immunotherapy

Abstract

Abstract Background: The successful inhibition of the PD-1/PD-L1 axis and CTLA-4 has opened the era of immuno-oncology, however only a few patients with metastatic colorectal cancer (mCRC) and microsatellite instability (MSI, ~5%) derive survival benefits from these treatments. BRAF genomic alterations, mainly V600 point mutations, comprise 10-15% of cases and have a poorer prognostic phenotype. Method: The public domain genomic database (via cBioPortal and AACR Project GENIE) was used as an external control to explore the genomic make-up of BRAF-mutated and BRAF-wild mCRC tumors. The Wilcoxon sum rank test was used for the genome-wide association analysis, and the Kaplan-Meier method was used to estimate survival. Besides, clinical observations on extraordinary responses to regorafenib plus nivolumab therapy in two patients with microsatellite stable (MSS) mCRC with BRAF genomic alterations were reported. Result: The CRC cohort comprised 2,936 patients and the immune checkpoint inhibitor (ICI) treated cohort comprised 1,661 patients, of which 110 (6.6%) were CRC patients. BRAF genomic alterations (CRC versus ICI cohort: 12.4% versus 11.8%, respectively) were significantly associated with POLE and PRKDC gene mutations (p<0.001). The genomic signatures, such as higher mutation count (MC) (log2 [6.54 versus 3], Wilcoxon p<10-10) and lower fraction genome altered (FGA) (log2 [-3.62 versus -2.22], Wilcoxon p=2.08e-9) were similar to that of POLE and PRKDC in the CRC cohort. Also, BRAF genomic alterations are associated with higher mutation counts in not only MSI but MSS cohorts (p=0.033 and p<0.001, respectively). In the ICI cohort, BRAF-altered colorectal tumors were associated with a higher TMB (43.3 versus 7.81, Wilcoxon p=0.016). In the CRC cohort, BRAF-altered tumors were associated with poorer overall survival (median 38.04 versus >80 month, log rank p<0.0001); and in the ICI cohort, BRAF-altered colorectal tumors were associated with a trend of better overall survival after ICI treatment (median >80 versus 15 months, log rank p=0.121) Conclusion: BRAF-mutated malignancies represent a sub-population of MSS CRC with higher TMB, which could benefit from a combination of regorafenib and nivolumab therapy. Citation Format: Feng-Che Kuan, Chung-Sheng Shi, Yu-Ying Wu, Meng-Hung Lin. Braf-altered microsatellite-stable metastatic colorectal cancer: A niche for immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5212.