Abstract: Purpose: Chemotherapy plus anti-EGFR is standard first-line therapy in RAS wt metastatic colorectal cancer (mCRC) but biomarkers of early response are clinically needed. We aimed to define the utility of ctDNA to assess early response in mCRC patients receiving first-line anti-EGFR therapy. Experimental design: Prospective multicentric study of tissue RAS wt mCRC patients treated with first-line chemotherapy plus cetuximab undergoing sequential liquid biopsies. Baseline and early (C3) ctDNA were analyzed by NGS. Trunk mutations were assessed as surrogate marker of total tumor burden. RAS/BRAF/MEK/EGFR-ECD were considered mutations of resistance. ctDNA results were correlated with clinical outcome. Results: 100 patients were included. ctDNA was detected in 72% of patients baseline and 32% at C3. Decrease in ctDNA trunk mutations correlated with progression-free survival (PFS) (HR= 0.23 P=0.001). RAS/BRAF were the only resistant mutations detected at C3. An increase in the relative fraction of RAS/BRAF at C3 was followed by an expansion of the RAS clone until PD, and was associated with shorter PFS (HR= 10.5, P<0.001). The best predictor of response was combined analysis of trunk and resistant mutations at C3. Accordingly, patients with "early molecular response" (decrease in trunk and decrease in resistant mutations) had better response (77.5% vs. 25%, P=0.008) and longer PFS (HR=0.18, P<0.001) compared to patients with "early molecular progression" (increase in trunk and/or increase in resistant mutations). Conclusions: ctDNA detects early molecular response and predicts benefit to chemotherapy plus cetuximab. A comprehensive NGS-based approach is recommended to integrate information on total disease burden and resistant mutations.

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