A universal cell-free DNA approach for response prediction to preoperative chemoradiation in rectal cancer

Albert Grinshpun*, Anatoli Kustanovich, Daniel Neiman, Roni Lehmann-Werman, Aviad Zick, Karen Meir, Elez Vainer, Roy Z. Granit, Amit Arad, Noa Daskal, Ruth Schwartz, Eli Sapir, Myriam Maoz, Esther Tahover, Joshua Moss, Iddo Z. Ben-Dov, Tamar Peretz, Ayala Hubert, Ruth Shemer, Yuval Dor

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


The standard treatment approach for stage II/III rectal cancer is neoadjuvant chemoradiation therapy (nCRT) followed by surgery. In recent years, new treatment approaches have led to higher rates of complete tumor eradication combined with organ-preservation strategies. However, better tools are still needed to personalize therapy for the individual patient. In this prospective observational study, we analyzed colon-derived cell-free (cf)DNA (c-cfDNA) using a tissue-specific DNA methylation signature, and its association with therapy outcomes. Analyzing plasma samples (n = 303) collected during nCRT from 37 patients with locally advanced rectal cancer (LARC), we identified colon-specific methylation markers that discriminated healthy individuals from patients with untreated LARC (area under the curve, 0.81; 95% confidence interval, 0.70-0.92; P <.0001). Baseline c-cfDNA predicted tumor response, with increased levels linked to larger residual cancer. c-cfDNA measured after the first week of therapy identified patients with maximal response and complete cancer eradication, who had significantly lower c-cfDNA compared with those who had residual disease (8.6 vs 57.7 average copies/ml, respectively; P =.013). Increased c-cfDNA after 1 week of therapy was also associated with disease recurrence. Methylation-based liquid biopsy can predict nCRT outcomes and facilitate patient selection for escalation and de-escalation strategies.

Original languageAmerican English
Pages (from-to)1444-1451
Number of pages8
JournalInternational Journal of Cancer
Issue number7
StatePublished - 1 Apr 2023

Bibliographical note

Publisher Copyright:
© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.


  • cell-free DNA
  • chemoradiation
  • methylation
  • neoadjuvant
  • rectal cancer


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