Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer: Overall survival and updated 5-year results from the randomized DYNAMIC trial.
Authors: Tie Jeanne , Wang Yuxuan , Lo Serigne N , Lahouel Kamel , Cohen Joshua D. , Wong Rachel , Shapiro Jeremy David , Harris Samuel John , Khattak Adnan , Burge Matthew E. , Lee Margaret , Harris Marion , McLachlan Sue-Anne , Ananda Sumitra , UNDERHILL CRAIG R , Papadopoulos Nickolas , Tomasetti Cristian , Kinzler Kenneth W. , Vogelstein Bert , Gibbs Peter 
Published: May 2024

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Background: Previous results of the DYNAMIC study demonstrated that a ctDNA-guided approach versus standard management in stage II colon cancer (CC) reduced adjuvant chemotherapy (ACT) use without compromising 2-year recurrence-free survival (RFS). MMR status defines two distinct subsets of stage II CC. Here, we report the impact of ctDNA burden, end of ACT (EOT) ctDNA, and updated survival data including overall survival (OS). Methods: DYNAMIC is a multi-center randomized phase II trial. Eligible patients (pts) had resected stage II CC and were suitable for ACT. Pts were randomly assigned 2:1 to ctDNA-guided management or standard management (clinician-guided based on conventional criteria). For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery with a tumor-informed assay prompted oxaliplatin-based or fluoropyrimidine ACT; ctDNA-negative pts were not treated. Between Aug 2015 and Aug 2019, 302 received ctDNA-guided and 153 standard management. The primary endpoint was RFS, with a non-inferiority margin of 8.5%. Pre-specified key secondary endpoints were ACT use and OS, with an additional secondary endpoint of ctDNA clearance rate. Results: With a median follow-up of 59.6 months (IQR 55.0–61.5), 5-year RFS were 88% and 87% with ctDNA-guided and standard management, respectively (difference 1.1%, 95% confidence interval, -5.8% to 8.0%). 5-year OS for ctDNA-guided treatment was 93.8% and standard management 93.3% (HR 1.05; 95% CI, 0.47 to 2.37; P = 0.887). 5-year OS was significantly worse in treated ctDNA-positive versus untreated ctDNA-negative pts (85.6% vs 95.3%, HR 3.30; 95% CI, 1.02 to 9.05; P = 0.014). The 5-year OS for ctDNA-negative T3 and T4 disease were 96.0% and 90.6%, respectively (HR 2.45; 95% CI, 0.65 to 9.25; P = 0.171). For treated ctDNA-positive pts, ctDNA clearance was observed at EOT in 35/40 (87.5%). The 5-year RFS for EOT ctDNA clearance vs ctDNA persistence were 85.2% and 20.0%, respectively (HR 15.4; 95% CI, 3.91 to 61.0; P < 0.001). Pts with ≥ 0.38 (the median) mutant tumor molecules (MTM/mL) had a lower ctDNA clearance rate and worse RFS than pts with < 0.38 MTM/mL (ctDNA clearance 75% vs 100%, P = 0.047; 5-year RFS 58.9% vs 95.2%, HR 10.62, P = 0.005). Post-op ctDNA was detected in 5/59 (8.5%) of dMMR and 40/235 (17%) of pMMR cases. In an exploratory analysis, ctDNA clearance was observed in 3/4 (75%) and 32/36 (89%) of dMMR and pMMR cases, respectively. Conclusions: Mature outcome data confirms the previous finding of non-inferiority of RFS with a ctDNA-guided approach to ACT for stage II CC. For ctDNA-positive pts, the post-surgery mutation burden provides additional prognostic information, as does the EOT ctDNA result. Additional data is needed to define any differential impact of ACT by MMR status. This data supports a role for ctDNA analysis, including serial sampling, in the management of stage II CC. Clinical trial information: ACTRN12615000381583 .