Circulating DNA in the neoadjuvant setting of early stage colon cancer

Abstract

Background

While circulating tumour (ct)DNA is an indicator of minimal residual disease and negative prognostic factor in stage II-III colon cancer, no study has ever analysed the value of this biomarker in colon cancer patients treated with neoadjuvant chemotherapy. We sought to fill this gap by using prospectively collected plasma samples from 80 stage III colon cancer patients, receiving one cycle of neoadjuvant FOLFOX followed by surgery +/− adjuvant FOLFOX in the PePiTA trial.

Material and Methods

Samples were collected at baseline, 2 weeks and surgery. NPY and WIF1 were selected as universal methylation markers for ctDNA, and analysed with ddPCR technology. ROC curves were applied for cut-off points, and outcome measures included 5-year disease-free survival (DFS) and 6-year overall survival (OS).

Results

After a median follow-up of 52.5 months, baseline circulating-free (cf) DNA was an independent prognostic factor for DFS (HR 3.35, 95% CI: 1.15–9.77, p = .03), and a trend towards a similar association was observed for relative cfDNA changes between baseline and surgery (HR 2.57, 95% CI: 0.94–7.05, p = .07). Among 60 ctDNA assessable patients, 25 (42%) had detectable ctDNA at baseline. While detection of ctDNA at any pre-operative timepoint was not associated with outcome, patients with ctDNA increase (change of the worst trending methylation marker ≥11%, or mean ctDNA change of NPY and WIF1 ≥ 0%) between baseline and surgery showed a trend towards worse 5-year DFS (HR 3.66, 95% CI: 0.81–16.44, p = .09).

Conclusion

This is the first study of ctDNA in the neoadjuvant setting of early-stage colon cancer. Results are hypothesis-generating and should be confirmed in larger series.

Keywords:

• Colon cancer
• circulating tumour DNA
• cell-free DNA
• neoadjuvant treatment

Acknowledgements

This Research Project was supported by ESMO through a Research Fellowship granted to GB to attend the Institut Jules Bordet. Any views, opinions, findings, conclusions or recommendations expressed in this material are those solely of the Authors and do not necessarily reflect those of ESMO. FS is supported by the Fondation Contre le Cancer.

Disclosure statement

AD - Travel grants: Amgen, Ipsen. AH - Consultancy, advisory role, honoraria: Amgen, Bayer, Eli Lilly, Merck, Pierre Fabre, Servier, Sirtex. Research funding: Amgen, AstraZeneca, Ipsen, Leo Pharma, Merck, Roche, Sanofi, Teva Pharma. Travel grant: Merck, Roche, Sirtex. FS. Consultancy, advisory role, honoraria: Amal Therapeutics, Bayer, BMS, Dragonfly Therapeutics, Nordic Pharma, Roche. Research funding: Amgen (inst), AstraZeneca (Inst), Bayer (Inst), BMS (Inst), Roche (Inst), Sanofi (Inst). Travel grants: Amgen, Bayer, Lilly. Leadership role: Co-Chair EORTC Colon, Rectum, Anal Task Force. All other authors do not have any conflicts of interests.