Yizhen Fu1,2, Zhenyun Yang1,2, Zili Hu1,2, Zhoutian Yang1,2, Yangxun Pan1,2, Jinbin Chen1,2, Juncheng Wang1,2, Dandan Hu1,2, Zhongguo Zhou1,2, Li Xu1,2, Minshan Chen3,4, Yaojun Zhang5,6. 1. State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China. 2. Department of Liver Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People's Republic of China. 3. State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China. chenmsh@sysucc.org.cn. 4. Department of Liver Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People's Republic of China. chenmsh@sysucc.org.cn. 5. State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People's Republic of China. zhangyuj@sysucc.org.cn. 6. Department of Liver Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong, 510060, People's Republic of China. zhangyuj@sysucc.org.cn.
Abstract
BACKGROUND: Circulating tumor DNA (ctDNA) can be useful in tumor diagnosis and surveillance. However, its value in hepatocellular carcinoma (HCC) patients receiving curative resection remains unknown. Here, we aim to determine the prognostic value of ctDNA in HCC patients. METHODS: A prospective cohort enrolled 258 HCC patients who underwent curative liver resection from April 1, 2019, to September 31, 2020. Blood samples were collected before surgery for the detection of ctDNA. RESULTS: The number of total mutant genes in ctDNA was associated with early tumor relapse (HR = 2.2, p < 0.001). We defined a gene set consisting of APC, ARID1A, CDKN2A, FAT1, LRP1B, MAP3K1, PREX2, TERT and TP53 as high-risk genes (HRGs) associated with early recurrence. Patients were classified into low-, median- and high-risk levels based on the number of mutant genes in the HRGs. High-risk patients had worse recurrence free survival, especially single-tumor patients (HR = 13.0, p < 0.001). The risk level and TNM stage were independently associated with tumor recurrence. A preoperative recurrence estimation nomogram based on those two factors was constructed and demonstrated good accuracy with a C index of 0.76 (95% CI 0.70-0.82). Patients preserved FAT1 or LRP1B variants but without TP53 variants had worse progression free survival for receiving lenvatinib combined with immune checkpoint inhibitors after recurrence (HR = 17.1, p < 0.001). Furthermore, RNA sequencing data revealed that ctDNA status was associated with tumor immune infiltration. CONCLUSION: Preoperative serum ctDNA can be a practical noninvasive approach to predict recurrence after surgery and response to systemic therapies. ctDNA-guided HCC management should be recommended.
BACKGROUND: Circulating tumor DNA (ctDNA) can be useful in tumor diagnosis and surveillance. However, its value in hepatocellular carcinoma (HCC) patients receiving curative resection remains unknown. Here, we aim to determine the prognostic value of ctDNA in HCC patients. METHODS: A prospective cohort enrolled 258 HCC patients who underwent curative liver resection from April 1, 2019, to September 31, 2020. Blood samples were collected before surgery for the detection of ctDNA. RESULTS: The number of total mutant genes in ctDNA was associated with early tumor relapse (HR = 2.2, p < 0.001). We defined a gene set consisting of APC, ARID1A, CDKN2A, FAT1, LRP1B, MAP3K1, PREX2, TERT and TP53 as high-risk genes (HRGs) associated with early recurrence. Patients were classified into low-, median- and high-risk levels based on the number of mutant genes in the HRGs. High-risk patients had worse recurrence free survival, especially single-tumor patients (HR = 13.0, p < 0.001). The risk level and TNM stage were independently associated with tumor recurrence. A preoperative recurrence estimation nomogram based on those two factors was constructed and demonstrated good accuracy with a C index of 0.76 (95% CI 0.70-0.82). Patients preserved FAT1 or LRP1B variants but without TP53 variants had worse progression free survival for receiving lenvatinib combined with immune checkpoint inhibitors after recurrence (HR = 17.1, p < 0.001). Furthermore, RNA sequencing data revealed that ctDNA status was associated with tumor immune infiltration. CONCLUSION: Preoperative serum ctDNA can be a practical noninvasive approach to predict recurrence after surgery and response to systemic therapies. ctDNA-guided HCC management should be recommended.
Authors: Hong Yan Zhu; Guan Yi Cao; Shi Ping Wang; Yu Chen; Guo Dong Liu; Yu Jie Gao; Jian Ping Hu Journal: Am J Cancer Res Date: 2017-08-01 Impact factor: 6.166