Detection of circulating tumor DNA (ctDNA) post-treatment is an emerging marker of residual disease. ctDNA constitutes only a minor fraction of the cell-free DNA (cfDNA) circulating in cancer patients, complicating ctDNA detection. This is exacerbated by trauma-induced cfDNA. To guide optimal blood sample timing, we investigated the duration and magnitude of surgical trauma-induced cfDNA in patients with colorectal or bladder cancer. DNA levels were quantified in paired plasma samples collected before and up to six weeks after surgery from 436 patients with colorectal cancer and 47 patients with muscle invasive bladder cancer. To assess if trauma-induced cfDNA fragments are longer than ordinary cfDNA fragments, the concentration of short (<1Kb) and long (>1Kb) fragments were determined for 91 patients. Previously reported ctDNA data from 91 patients with colorectal cancer and 47 patients with bladder cancer was used to assess how trauma-induced DNA affects ctDNA detection. The total cfDNA level increased postoperatively - both in patients with colorectal cancer (mean 3-fold) and bladder cancer (mean 8-fold). The DNA levels were significantly increased up to four weeks after surgery in both patient cohorts (P=0.0005 and P≤0.0001). The concentration of short, but not long, cfDNA fragments increased postoperatively. Of 25 patients with radiological relapse, eight were ctDNA positive and 17 ctDNA negative in the period with trauma induced DNA. Analysis of longitudinal samples revealed that five of the negative patients, became positive shortly after the release of trauma-induced cfDNA had ceased. In conclusion, surgery was associated with elevated cfDNA levels, persisting up to four weeks, which may have masked ctDNA in relapse patients. Trauma-induced cfDNA was of similar size to ordinary cfDNA. To mitigate the impact of trauma-induced cfDNA on ctDNA detection, it is recommended that a second blood sample collected after week 4 is analyzed for patients initially ctDNA negative.
Molecular oncology. 2020 May 29 [Epub ahead of print]
Tenna V Henriksen, Thomas Reinert, Emil Christensen, Himanshu Sethi, Karin Birkenkamp-Demtröder, Mikail Gögenur, Ismail Gögenur, Bernhard G Zimmermann, IMPROVE study group , Lars Dyrskjøt, Claus L Andersen
Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens, Boulevard 99, 8200, Aarhus N, Denmark., Natera Inc, Industrial Rd, San Carlos, CA, 94070, USA., Center for Surgical Sciences, Zealand University Hospital, Lykkebaekvej 1, 4600, Køge, Denmark.