365P Prognostic value of Lynch syndrome, BRAFV600E and RAS mutation status in dMMR/MSI-H metastatic colorectal cancer in a pooled analysis of the national Dutch and French cohorts

Abstract

Current knowledge on biomarkers (BRAFV600E/RAS mutations) is mainly based on metastatic colorectal cancer (mCRC) patients with proficient mismatch repair (pMMR) tumors. It is uncertain whether these biomarkers have the same implications in deficient mismatch repair (dMMR) mCRC patients. Our aim is to provide insight on the value of Lynch syndrome, BRAFV600E and RAS mutation status and treatment regimens on survival in dMMR mCRC patients treated outside clinical trials. This observational cohort study combined the national Dutch cohort, including almost all Dutch centers (2014-2019), and national French cohort, including 18 French centers (2007-2017). Clinical, molecular and survival data were collected in mCRC patients with dMMR tumors receiving chemotherapy ± targeted therapy. Multivariable Cox proportional hazard regression was used to analyze the prognostic value of BRAFV600E and RAS mutation status and Lynch syndrome on progression-free survival (PFS) and overall survival (OS). Inverse probability weighing was used to analyze impact of treatment regimens on survival. In our large real-world evidence cohort of 707 dMMR mCRC patients, 438 patients were treated with first-line systemic therapy. Mean age of first-line treated patients was 61.9 years and 40% had a proven/suspected Lynch syndrome. Most tumors were right-sided (74%) with synchronous metastases (62%). BRAFV600E and RAS mutations were observed in 42% and 33%, respectively. Median PFS and OS were 6.0 months and 19.3 months from start of first-line therapy. Multivariable regression analysis showed known clinical and pathological characteristics as predictors for OS and PFS, but not Lynch syndrome, mutation of BRAFV600E or RAS. In addition, there were no survival differences according to type of chemo- and targeted therapy used. BRAFV600E and RAS mutation status are not associated with poor prognosis in dMMR mCRC patients, in contrast to pMMR mCRC patients. Our findings may aid in estimating prognosis and clinical decision-making in dMMR mCRC treated with chemotherapy and targeted therapy.