Post-surgery Sequelae Unrelated to Disease Progression and Chemotherapy Revealed in Follow-up of Patients with Stage III Colon Cancer

Background: We studied the poorly-known dynamics of circulating DNA (cir-nDNA), as monitored prospectively over an extended post-surgery period, in patients with cancer.

Methods: On patients with stage III colon cancer (N = 120), using personalised molecular tags we carried out the prospective, multicenter, blinded cohort study of the post-surgery serial analysis of cir-nDNA concentration. 74 patients were included and 357 plasma samples tested.

Findings: During post-operative follow-up, the patients' median cir-nDNA concentration was greater (P < 0.0001 in the [43-364 days range]) than both the median value in healthy individuals and the pre-surgery value. These cir-nDNA levels were highly associated with NETs markers (P-value associating MPO and cir-nDNA, and NE and cir-nDNA are 6.6 x 10, and 1.9 x 10), in accordance with previous reports which indicate that cir-nDNA are NETs by-products. Unexpectedly, in 34 out of 50 patients we found that NETs continued to be formed for an extended duration post-surgery, even in patients without disease progression. Given that this phenomenon was observed in patients without adjuvant CT, and in patients >18 months post-surgery, the data suggest that the persistence of NETs formation is not due to the adjuvant CT.

Interpretation: (1), Given the inter-patient heterogeneity, the post-surgery cir-nDNA level cannot be considered a reliable value, and caution must be exercised when determining mutation allele frequency or the mutation status; and (2), specific studies must be undertaken to investigate the possible clinical impact of the persistent, low-grade inflammation resulting from elevated NETs levels, such as observed in these post-surgery patients, given that such levels are known to potentially induce adverse cardiovascular or thrombotic events.

Funding: This work was supported by the H2020 European ERA-NET grant on Translational Cancer Research (TRANSCAN-2).