Circulating tumour DNA at baseline for individualised prognostication in patients with chemotherapy-naïve metastatic colorectal cancer. An AGEO prospective study.

Purpose: Baseline circulating tumour DNA (ctDNA) is a potential prognostic marker in metastatic colorectal cancer (mCRC) patients. However, few studies have compared ctDNA with the usual prognostic factors, and no ctDNA cut-off has been proposed for daily use in clinical practice.
Patients and Methods: Chemotherapy-naive patients with mCRC were prospectively included. Plasma samples were collected at diagnosis and analysed centrally by both NGS and methylation digital PCR. Baseline patient and disease characteristics, treatment regimens, and secondary surgeries were collected. The restricted cubic spline method was used to define the optimal cut-off of ctDNA mutated allelic frequency (MAF). Prognostic values were assessed on overall survival (OS) using Cox models.
Results: From July 2015 to December 2016, 412 patients were included. ctDNA was undetectable in 83 patients (20%). ctDNA was an independent prognostic marker for OS considering the whole study population. The optimal cut-off for ctDNA MAF was 20% with median OS of 16.0 and 35.8 months for patients with MAF ≥20% and<20%, respectively (hazard ratio = 0.40; 95% confidence intervals: 0.31-0.51; P < 0.0001). The independent prognostic value of ctDNA MAF at 20% was confirmed in subgroups defined by RAS/BRAF status or resectability of metastases. Combining ctDNA MAF and carcinoembryonic antigen levels allowed us to define three different prognostic groups with median OS of 14.2, 21.1, and 46.4 months (P < 0.0001).
Conclusion: ctDNA with a MAF cut-off of 20% improves prognostication of chemotherapy-naïve mCRC patients and may be useful in the future for individualised therapeutic decisions and as a stratification factor in clinical trials.
Trial Registration: Clinicaltrials.gov, NCT02502656.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J.B. Bachet has received personal fees from Amgen, Bayer, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme, Pierre Fabre, Sanofi, Servier, and non-financial support from Amgen, Merck Serono, and Roche, outside the submitted work. P. Laurent-Puig has received grants from AGEO during the conduct of the study; personal fees from Amgen, Biocartis, Merck Serono, Astrazeneca, Sanofi, Pierre Fabre, MSD, outside the submitted work. O. Bouché has received personal fees from Merck Serono, Amgen, Bayer, Apmomia Therapeutics, MSD, Servier and Pierre Fabre, outside the submitted work. V. Taly has received honoraria from Raindance Technologies during the conduct of the study, and honoraria from Boehringer Ingelheim, outside the submitted work. P. Artru has received personal fees from Merck Serono during the conduct of the study; personal fees from Roche, Sanofi, Celgene, Sanofi, outside the submitted work. D. Tougeron has received personal fees from Amgen, MSD, BMS, Merck Serono, Pierre Fabre, Servier, Sirtex, Ipsen, Roche, outside the submitted work. T. Lecomte has received personnel fees from Amgen, Merck Serono, Sanofi, Ipsen, Bayer, Pierre Fabre and Servier, outside the submitted work. F. Mary has received personal fees from Bayer, Amgen, Merck Serono and Ipsen, outside the submitted work. T. Aparicio has received personal fees from Bristol Myers Squibb, Pierre Fabre, Servier, Amgen, Merck Sharp & Dohme, Sirtex, outside the submitted work. L. Marthey has received personal fees from Roche, personal fees and non-financial support from Takeda, non-financial support from Amgen and Novartis, outside the submitted work. H. Blons has received personal fees from Astra-Zeneca, Merck Serono, Amgen, Boehringer Ingelheim and Pfizer, outside the submitted work. D. Vernerey has received personal fees from HalioDx, outside the submitted work. J. Taieb has received honoraria for speaker or advisory role from BMS, Roche, Merck Serono, Amgen, Servier, Pierre Fabre, Astra Zeneca and MSD, outside the submitted work. A. Meurisse, L. Mas, J.M. Gornet, R. Cohen, S. Louafi, A.Thirot-Bidault, I. Baumgaertner, R. Coriat declare no competing interests.
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