Background First-line therapeutic strategies for patients with BRAFV600E-mutated (BRAFmt) metastatic colorectal cancer (mCRC) mainly rely on subgroup analyses from randomized controlled trials (RCTs). We aimed at assessing the prognostic and predictive impact of BRAFmt for the efficacy of targeted therapies with first-line chemotherapy. Methods Individual patient data from first-line RCTs with BRAF and KRAS status data in the ARCAD database were pooled. Progression-free survival and overall survival (OS) were assessed using Kaplan-Meier and Cox models. Outcomes were compared between treatment groups that were concurrently randomized whenever possible. Results 6391 patients from 10 RCTs were included: 573 BRAFmt (9.0%), 2059 KRASmt (32.2%) and 3759 double wild-type (58.8%). BRAFmt mCRC patients experienced statistically significantly poorer OS than those with KRASmt (adjusted hazard ratio [HRadj] =1.46, 95% confidence interval [95%CI] = 1.30-1.64) and patients with double wild-type tumors (HRadj =2.14, 95%CI = 1.94-2.36). Anti-EGFR agents did not improve progression-free survival or OS of BRAFmt mCRC patients, based on 4 RCTs testing chemotherapy ± anti-EGFR (HRadj =0.96, 95%CI = 0.71-1.30 and HRadj =0.85, 95%CI = 0.66-1.14, respectively). Conclusion Our data suggest that the addition of anti-EGFR agents to chemotherapy is ineffective as first-line treatment for BRAFmt mCRC patients.

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Introduction: Correlation between TMB and objective response to checkpoint inhibitors has been shown. MSI-High tumors usually exhibit high TMB. Relationship between the level of TMB and alterations in the four-mismatch repair deficiency (MMR) genes in gastrointestinal tumors has not been comprehensively studied. Methods: MSI-High status was determined by examining altered microsatellite (MS) loci using NextGen sequencing (cutoff: > ¼46) on a 592-gene panel. TMB was calculated by enumerating somatic missense mutations. MMR protein expression was evaluated by IHC. ANOVA and chi-square tests were used for comparisons. Results: In total, 395 MSI-High gastrointestinal tumors were examined. High TMB (! 17 mutations/megabase [mt/MB]) was seen in 89% of the MSI-High tumors. Overall, MSI-High CRC exhibited the highest TMB compared to "all other MSI-High gastrointestinal cancers" (39 vs. 27 mt/MB, respectively, p < 0.0001). Left-sided MSI-High tumors had a higher TMB compared to right-sided tumors (51 vs. 35 mt/MB, p ¼ 0.01). No significant differences were observed in TMB between BRAF V600 mutant and wild type MSI-High CRC (38.7 vs. 39 mt/MB). Significant association between the microsatellite loci and TMB (Rho¼0.60, p < 0.0001) was observed. The mean TMB among MSI-High gastrointestinal tumors were as follow: 39 (mt/MB) CRC, 33 (mt/MB) gastric adenocarcinomas, 31 (mt/MB) small bowel adenocarcinomas, and 29 (mt/MB) in esophageal, GEJ, and pancreatic cancers, and cholangiocarcinoma. The most frequently altered (IHC loss or mutation) MMR genes in the MSI-High gastrointestinal tumors were MLH1 and PMS2. In CRC, MSH2 was more frequently altered in left-sided than right-sided tumors (45% vs. 12%), as was MSH6 (67% vs. 40%), p ¼ 0.01.

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