Résumé
A gap currently exists in our understanding of causes of elevated total circulating DNA (cirDNA) levels in cancer patients following tumor resection, and the influence of anesthesia or surgery on cirDNA release. Indeed, the post-surgery dynamics of cirDNA have been largely overlooked to date, despite their importance in determining the optimal timing for assessment of minimal residual disease (MRD). Since cirDNA levels were recently found to be associated with neutrophil extracellular traps (NETs) formation in various cancers, we investigated NETs and cirDNA post-surgery.We conducted two clinical studies to explore the dynamics of cirDNA quantity and of neutrophil extracellular traps (NETs) markers: (1) a peri-surgery study over a duration of up to 72 hours, which involved stage I-III colon (n=10), prostate (n=10), and breast (n=9) cancer patients; and (2) a post-surgery study that extended up to two years post-surgery, and which involved 74 stage III colon cancer patients. We assessed plasma levels of cirDNA using qPCR, and assessed two protein markers of NETs using ELISA, in both cancer patients and control group of healthy individuals (HI) (N=114). This second study is the first prospective, multicenter, blinded study of the dynamics of the total cirDNA post-surgery, for a period of up to two years.We observed that (i), NETs formation contributes to post-surgery conditions; (ii), peri- and post-surgery cirDNA levels were highly associated with NETs formation in colon cancer; (iii), each tumor type showed a specific pattern of the peri-surgery dynamics of cirDNA and NETs markers; peri-operative levels of these markers are significantly lower in breast cancer patients as compared to prostate and colorectal cancer patients; (iv), a significant proportion of patients showed pre- (58.1%) and post-surgery (80.4%) median marker values higher than in HI, even after 2 years following tumor resection, (v) these markers were either equal to or greater (23.2%) than their pre-surgery counterparts; and (vi), elevated values of these markers did not derive from chemotherapy toxicity.We provide evidence that, for cancer patients in the post-surgery period, cirDNA originates mainly from NETs. This finding calls into question the current method of assessing MRD according to the fraction of mutant cirDNA, given that the level of NETs formation appears to be patient dependant. The peri-surgery dynamics of NETs formation and cirDNA release vary according to the surgical procedure and cancer type. In a significant part of patients with colon cancer, NETs continue to persist for more than a year after surgery, irrespective of disease progression or chemotherapy use. Nevertheless, cirDNA and NETs marker levels vary in cases with post-surgery inflammatory/thrombotic adverse events. Our work highlights the existence of long-lasting “sequelae” effects of cancer, previously unreported.
Citation Format: Andrei Kudriavtsev, Alexia Mirandola, Catalina I. Cofre Muñoz, Raquel Comas Navarro, Marco Macagno, Brice Pastor, Ekaterina Pisareva, Mireia Sanchis Marin, Javier Gonzalo Ruiz, Anna Sapino, Alice Bartolini, Massimo Di Maio, Cynthia Sanchez, Yann Gricourt, Xavier Capdevila, Gerald Lossaint, Evelyne Crapez, Marc Ychou, Ramon Salazar Soler, Elisabetta Fenocchio, Paula X. Fernandez Calotti, Philippe Cuvillon, Thibault Mazard, Cristina Santos Vivas, Elez M. Elez, Federica Di Nicolantonio, Alain R. Thierry. Post-surgery sequelae unrelated to disease progression and chemotherapy revealed in follow-up of stage III colon cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1026.