Perioperative Circulating Tumor DNA in Colorectal Liver Metastases: Concordance with Metastatic Tissue and Predictive Value for Tumor Burden and Prognosis

Yiping He,1,2,* Xiaoji Ma,1,2,* Ke Chen,2,3,* Fangqi Liu,1,2 Sanjun Cai,1,2 Han Han-Zhang,4 Ting Hou,4 Jianxing Xiang,4 Junjie Peng1,2 1Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China; 3Department of Endoscopy, Fudan University Shanghai Cancer Center, Shanghai 200032, People’s Republic of China; 4Burning Rock Biotech, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Junjie PengDepartment of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong’An Road, Shanghai 200032, People’s Republic of ChinaTel +86 21 64175590Email pengjj67@hotmail.comBackground: The surgical resection of colorectal cancer with liver metastases (CLM) has proven to be the most important modality for long-term survival, while effective biomarkers for outcome prediction or postoperative surveillance are still lacking. Currently, circulating biomarkers obtained from a liquid biopsy are widely used to assess the treatment response, disease recurrence and progression. In this study, we analyzed the value of the liquid biopsy, which includes circulating tumor DNA (ctDNA) and cell-free DNA (cfDNA), in patients with CLM.Methods: Capture-based targeted deep sequencing was performed on matched pre-surgery, post-surgery and liver metastatic tissues of 20 CRC patients who underwent the resection of liver metastases between May and September 2017 using a panel consisting of 41 genes. Mutation landscapes obtained from pre-surgery plasma samples and metastatic tissue samples were compared.Results: Collectively, we identified 47 mutations from 17 pre-surgery plasma samples (85%), and the remaining 3 patients had no mutation detected from the panel. We revealed a high by-variant concordance rate of 82.14% between pre-surgery plasma samples and liver metastatic tissue samples. We further analyzed the correlation between ctDNA, cfDNA, CEA and tumor burden and revealed a positive correlation between ctDNA and tumor burden (R=0.69, p=0.002). As of the date for data cutoff, 8/20 patients experienced relapse. Our study also demonstrated that pre-surgery ctDNA (p< 0.001), cfDNA (p=0.001) and CEA (p=0.012) levels had predictive value for relapse. Patients with low pre-surgery ctDNA (p< 0.001), cfDNA (p=0.001) or CEA (p=0.012) levels were more likely to experience prolonged progression-free survival.Conclusion: Our data demonstrate that the genomic profile obtained from ctDNA is comparable with the genomic profile obtained from metastatic liver tumors. Furthermore, our study also show that pre-surgery ctDNA levels are positively correlated with tumor burden. In addition, pre-surgery ctDNA, cfDNA and CEA levels have predictive value for relapse.Keywords: colorectal liver metastases, CLM, circulating tumor DNA, ctDNA, tumor burden, prognosis