Clinical Impact of Baseline ctDNA RAS/BRAF Mutations on Conversion Surgery and Outcomes in First-Line Anti-EGFR Therapy for Advanced Colorectal Cancer

Background: Baseline circulating tumor DNA (ctDNA) testing may detect minor resistant subclones in patients whose tumor tissue is classified as RAS/BRAF wild-type, but its clinical significance during first-line anti-EGFR therapy remains uncertain. Methods: We prospectively enrolled 98 patients with tissue-confirmed RAS/BRAF wild-type stage IV colorectal cancer treated with first-line anti-EGFR-based chemotherapy at multiple centers. Pretreatment plasma was analyzed by droplet digital PCR for KRAS, NRAS, and BRAF mutations; PIK3CA was assessed exploratorily. Results: Baseline ctDNA RAS/BRAF mutations were detected in 16 patients (16.3%; 95% CI, 10.3–24.9%), and any mutation including PIK3CA was detected in 20 (20.4%). Among 88 patients with measurable disease, objective response rates were similar in concordant and discordant groups (84.7% vs. 81.3%), as were conversion surgery rates (48.6% vs. 56.3%). Median progression-free survival was 14.0 months in both groups. Median overall survival was 44.5 and 33.8 months, respectively, without a statistically significant difference (log-rank p = 0.20). Conclusions: Restricted baseline ddPCR targeting RAS/BRAF did not reliably identify patients who would fail to achieve early tumor shrinkage or conversion surgery, and these results do not support withholding first-line anti-EGFR-based induction therapy solely on the basis of minor baseline ctDNA RAS/BRAF mutations detected by limited targeted testing. Given the limited number of discordant cases, however, a clinically meaningful prognostic role of baseline ctDNA discordance cannot be excluded, and findings from restricted hotspot testing should be contextualized within comprehensive NGS-based molecular profiling.