Prognostic impact of circulating tumor RAS and BRAF mutation dynamics in patients with metastatic colorectal cancer

Abstract

Summary Post-treatment alterations in circulating tumor DNA (ctDNA) hold potential for refining treatment strategies in metastatic colorectal cancer (mCRC). In this multi-institutional study of 1,391 patients from the SCRUM-Japan GOZILA platform, we evaluated the prognostic significance of post-treatment rat sarcoma viral oncogene homolog (RAS) and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E mutation (MT) dynamics by comparing baseline tissue profiling with subsequent longitudinal ctDNA analysis. While patients with NeoRAS or NeoBRAF wild-type (WT) achieved an overall survival (OS) comparable to the persistent RAS WT cohort, those with persistent or acquired mutations demonstrated significantly impaired outcomes. Multivariable analysis identified baseline tissue RAS and BRAF MT status before treatment initiation, NeoBRAF WT, ctDNA fraction, number of treatment lines at the time of sampling, and prior anti-vascular endothelial growth factor therapy as independent correlates of OS. These results show that post-treatment circulating tumor RAS and BRAF MT dynamics may serve as useful prognostic indicators, particularly with regard to BRAF MT.