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Clinical Relevance of Circulating Cell-Free DNA Level in Patients With Squamous Cell Carcinoma of the Esophagus
Chih-Cheng Hsieh*1,2, Han-Shui Hsu1,4, Shih-Ching Chang3,4
1Division of Thoracic Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; 2Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan; 3Division of Colon & Rectal Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; 4School of Medicine, National Yang-Ming University, Taipei, Taiwan
Background:
Esophageal cancer is an aggressive malignant disease and esophagectomy is still the main treatment method. There were only several valuable and convenient markers for the detection or prediction of the disease progression, but low sensitivity of the markers limited the practice use, such as squamous cell carcinoma related antigen (SCC) and cytokeratin 19 fragment (CYFRA). The concentration of circulating cell-free DNA (cfDNA) was used as a prognostic factor in different solid tumor. However, these reports in patients with esophageal cancer were fewer, especially in squamous cell carcinoma. The aim of this study is to investigate the relationship between different level of cfDNA and the treatment results after esophagectomy for the patients with esophageal cancer.
Material and methods:
From 2006 to 2013, 85 patients with squamous cell carcinoma of esophagus received esophagectomy in a single institution were enrolled in this study. Patients received pre-operative chemoradiotherapy or non-squamous cell carcinoma were excluded. The clinicopathological information were prospectively collected and stored in database. Tumor staging was classified according to the 7th edition of AJCC cancer staging system. Concentrations of cfDNA were measured by Taqman qPCR. According the median value of DNA copies/ml, the patients were divided into low cfDNA and high cfDNA subgroups. Categorical variables were analyzed by Spearman’s correlation test. Disease free survival and overall survival were estimated using Kaplan-Meier plots and compared with the log-rank test.
Results:
There were 72 males and 13 females with a mean age of 60.5 years (range 39-84 years). The median cfDNA was 13749 copies/ml (range 1126-161170). The mean cfDNA concentration in low cfDNA and high cfDNA subgroups were 5821 and 53090 copies/ml. There were no correlations between the factors and the cfDNA subgroups. The median follow-up time was 27.2 months (IQR: 15.4-43.7 months). There were 45 patients with tumor recurrence or metastasis. The 3-year and 5-year disease-free survival (DFS) rate were 39.3% and 37.1%, respectively. Patients with nodal free status, early stage and no lymphovascular invasion had a better DFS (Table 1). DFS was also significantly different between lower cfDNA and higher cfDNA subgroups (p=0.042, Figure 1). The 3-year and 5-year overall survival rate were 42.2% and 33.7%, respectively. However, there was no significant difference between low cfDNA and high cfDNA subgroups in overall survival.
Conclusions:
In this study, we demonstrated that in patient with low cfDNA, the DFS after esophagectomy for squamous cell carcinoma of esophagus was better than those with high cfDNA, but not shown in overall survival. The detail pathway influencing the results will need to further study.
Table 1 The survival analysis of prognostic factors influencing disease free survival and overall survival after esophagectomy
| Variables | Number | Disease free survival | Overall survival | | | | | 5-year survival rate (%) | p value | 5-year survival rate (%) | p value | | cfDNA | | | | 0.042 | | 0.480 | | | low | 43 | 50.2 | | 41.3 | | | | high | 42 | 24.5 | | 26.0 | | | Locaction | | | | 0.136 | | 0.259 | | | u-m | 48 | 49.9 | | 40.7 | | | | lower | 37 | 22.7 | | 26.7 | | | Size | | | | 0.614 | | 0.667 | | | <4cm | 37 | 38.9 | | 37.0 | | | | >4cm | 48 | 36.0 | | 31.7 | | | T status | | | | 0.512 | | 0.967 | | | T1-2 | 24 | 40.9 | | 36.1 | | | | T3-4 | 61 | 35.9 | | 33.0 | | | N status | | | | 0.039 | | 0.010 | | | N0 | 31 | 50.7 | | 54.1 | | | | N1-3 | 54 | 28.3 | | 20.9 | | | Stage | | | | 0.008 | | 0.009 | | | I-II | 37 | 52.1 | | 52.2 | | | | III | 48 | 24.4 | | 19.5 | | | Lymphovascular invasion | | | | 0.001 | | 0.256 | | | no | 47 | 51.2 | | 40.3 | | | | yes | 38 | 20.6 | | 25.0 | | | Perineural invasion | | | | 0.720 | | 0.310 | | | no | 61 | 38.2 | | 29.9 | | | | yes | 24 | 33.0 | | 45.2 | | | Post-op treatment | | | | 0.311 | | 0.144 | | | no | 37 | 27.7 | | 26.4 | | | | yes | 48 | 42.4 | | 39.1 | |
 Figure 1 The disease free survival curve stratified by cf DNA level. The 5-year DFS of patients with low cfDNA was 50.2% and significantly better than those with high cfDNA (24.5%, p=0.042)
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