Early evaluation of circulating tumor DNA as marker of therapeutic efficacy in metastatic colorectal cancer patients (PLACOL study)

Purpose. Markers of chemotherapy efficacy in metastatic colorectal cancer (mCRC) are essential for optimization of treatment strategies. We evaluated the applicability of early changes in circulating tumor DNA (ctDNA) as a marker of therapeutic efficacy. <p>Experimental design. This prospective study enrolled consecutive mCRC patients receiving a first- or second-line chemotherapy. CtDNA was assessed in plasma collected before the first (C₀), second (C₁) and/or third (C₂) chemotherapy cycle, using picodroplet-digital PCR assays based either on detection of gene mutation (KRAS, BRAF, TP53) or hypermethylation (WIF1, NPY). Computed tomography scans were centrally assessed using RECIST v1.1 criteria. Multivariate analyses were adjusted on age, gender, ECOG performance status (PS), metastatic synchronicity and treatment line.</p> <p>Results. Eighty-two mCRC patients treated in first (82.9%) or second (17.1%) line chemotherapy were included. Patients with a high (>10ng/mL) versus low (≤0.1ng/mL) ctDNA concentration at C₀ had a shorter overall survival (OS) (6.8 versus 33.4 months: adjusted HR=5.64; CI_95%[2.5-12.6], P<0.0001). By analyzing the evolution of the ctDNA concentration between C₀ and C₂ or C₁ (C_2or1), we classified the patients in two groups (named "good" or "bad ctDNA responders"). In multivariate analysis, patients belonging to the group called "good ctDNA responder" (n=58) versus "bad ctDNA responder" (n=15) had a better objective response rate (P<0.001), and a longer median progression-free survival (8.5 vs 2.4 months: HR=0.19, CI_95%[0.09-0.40], P<0.0001) and OS (27.1 vs 11.2 months: HR=0.25, CI_95%[0.11-0.57], P<0.001).</p> <p>Conclusion. This study suggests that early change in ctDNA concentration is a marker of therapeutic efficacy in mCRC patients.</p> <p> 

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