Genome-wide copy number alteration (CNA) of circulating cell-free DNA (cfDNA) as a prognostic biomarker in esophageal squamous cell carcinoma (ESCC).

Abstract

e15582 Background: Although neoadjuvant chemoradiation (nCRT) plus surgery or definitive CRT (dCRT) are the standard treatment for locally advanced ESCC, there are no reliable clinical tools for predicting prognosis or monitoring treatment response for CRT in ESCC. We aimed to identify a biomarker for predicting outcomes using cfDNA in ESCC patients (pts) receiving CRT. Methods: This prospective biomarker study analyzed pretreatment plasma cfDNA from pts with nCRT plus surgery (n = 23) and pts with dCRT for locally advanced ESCC (n = 17) at Asan Medical Center in South Korea from Jul. 2017 to Jun. 2018. Low depth whole-genome sequencing of cfDNA was used to identify CNA and I-score was developed to express genomic instability. I-score was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. Results: The pathologic complete response (pCR) was achieved in 7 pts (30.4%) in the nCRT group, and the clinical complete response (cCR) was achieved in 3 pts (17.6%) and clinical partial response (cPR) in 8 pts (47.1%) in the dCRT. The baseline cfDNA concentrations were no significant association with the clinical T stage (cT 1-2 vs. cT 3-4; 0.27 vs. 0.28 ng/μL; p = 0.752), pathologic response (pCR vs. non-pCR; 0.26 vs. 0.30 ng/μL; p = 0.270), ypT stage (ypT 0-2 vs. ypT 3-4; 0.28 vs. 0.36 ng/μL; p = 0.161) and ypTNM stage (ypTNM 1 vs. ypTNM 2-4; 0.26 vs. 0.36 ng/μL; p = 0.065). When analyzing cfDNA concentration before and after CRT, cfDNA concentration was significantly increased after CRT (0.31 vs. 0.55 ng/μL; p = 0.007). The baseline I-score was not associated with baseline clinical stage, but was significantly associated with ypT stage (ypT 1-2 vs. 3-4; 30.4 vs 839.1; p = 0.009), time to progression (median TTP; 11.8 mo in the I-score-low group vs. 6.1 mo in the I-score-high group; p = 0.036), and overall survival (median OS; not reached vs. 10.4 mo; p = 0.046) in the nCRT group. In the dCRT group, I-score was significantly associated with higher disease progression rate (33.3 vs. 58.8%; p = 0.024) with tendency of distant metastasis (33.5 vs. 57.1%; p = 0.490), and short response duration (median, 5.7 mo in the I-score-high group vs not reached in the I-score-low group). Conclusions: The cfDNA concentration is not a good biomarker for prognostication and monitoring the course of treatment in ESCC pts treated with CRT. But the I-score, an indicator of genomic instability in ctDNA, was a significant predictor of poor prognosis.