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. 2024 Nov:211:114314.
doi: 10.1016/j.ejca.2024.114314. Epub 2024 Sep 11.

Detection of circulating tumor DNA by tumor-informed whole-genome sequencing enables prediction of recurrence in stage III colorectal cancer patients

Amanda Frydendahl  1 , Jesper Nors  1 , Mads H Rasmussen  1 , Tenna V Henriksen  1 , Marijana Nesic  1 , Thomas Reinert  1 , Danielle Afterman  2 , Tomer Lauterman  2 , Maja Kuzman  3 , Santiago Gonzalez  3 , Dunja Glavas  3 , James Smadback  3 , Dillon Maloney  3 , Jurica Levativ  3 , Michael Yahalom  3 , Ryan Ptashkin  3 , Iman Tavassoly  3 , Zohar Donenhirsh  2 , Eric White  3 , Ravi Kandasamy  3 , Ury Alon  2 , Iver Nordentoft  1 , Sia V Lindskrog  1 , Lars Dyrskjøt  1 , Claudia Jaensch  4 , Uffe S Løve  5 , Per V Andersen  6 , Ole Thorlacius-Ussing  7 , Lene H Iversen  8 , Kåre A Gotschalck  9 , Asaf Zviran  3 , Boris Oklander  2 , Claus L Andersen  10
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Free article

Detection of circulating tumor DNA by tumor-informed whole-genome sequencing enables prediction of recurrence in stage III colorectal cancer patients

Amanda Frydendahl et al. Eur J Cancer. 2024 Nov.
Free article

Abstract

Introduction: Circulating tumor (ctDNA) can be used to detect residual disease after cancer treatment. Detecting low-level ctDNA is challenging, due to the limited number of recoverable ctDNA fragments at any target loci. In response, we applied tumor-informed whole-genome sequencing (WGS), leveraging thousands of mutations for ctDNA detection.

Methods: Performance was evaluated in serial plasma samples (n = 1283) from 144 stage III colorectal cancer patients. Tumor/normal WGS was used to establish a patient-specific mutational fingerprint, which was searched for in 20x WGS plasma profiles. For reproducibility, paired aliquots of 172 plasma samples were analyzed in two independent laboratories. De novo variant calling was performed for serial plasma samples with a ctDNA level > 10 % (n = 17) to explore genomic evolution.

Results: WGS-based ctDNA detection was prognostic of recurrence: post-operation (Hazard ratio [HR] 6.75, 95 %CI 3.18-14.3, p < 0.001), post-adjuvant chemotherapy (HR 28.9, 95 %CI 10.1-82.8; p < 0.001), and during surveillance (HR 22.8, 95 %CI 13.7-37.9, p < 0.0001). The 3-year cumulative incidence of ctDNA detection in recurrence patients was 95 %. ctDNA was detected a median of 8.7 months before radiological recurrence. The independently analyzed plasma aliquots showed excellent agreement (Cohens Kappa=0.9, r = 0.99). Genomic characterization of serial plasma revealed significant evolution in mutations and copy number alterations, and the timing of mutational processes, such as 5-fluorouracil-induced mutations.

Conclusion: Our study supports the use of WGS for sensitive ctDNA detection and demonstrates that post-treatment ctDNA detection is highly prognostic of recurrence. Furthermore, plasma WGS can identify genomic differences distinguishing the primary tumor and relapsing metastasis, and monitor treatment-induced genomic changes.

Keywords: Biomarker; Cell-free DNA; CfDNA; Circulating tumor DNA; Colorectal cancer; CtDNA; Liquid biopsy; Recurrence detection; Surveillance; Whole-genome sequencing.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. CLA reports collaborations with C2i Genomics and Natera. AZ, BO, RV, TL, and DM report stock options at C2i Genomics. AZ is the co-founder and a member of the board of directors of C2i Genomics. BO is the co-founder and CTO of C2i Genomics. SG, MK, JL, DG, RP, JS, DA, TL, YC, ZD, IT, and UA are employees of C2i Genomics. The opinions, results, and conclusions reported in this article are those of the authors and are independent of any competing interests. LD has sponsored research agreements with C2i Genomics, Natera, AstraZeneca, Photocure, and Ferring and has an advisory/consulting role at Ferring, MSD and UroGen. LD has received speaker honoraria from AstraZeneca, Pfizer and Roche and received travel support from MSD. LD is a board member at BioXpedia.

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