Biomarkers of prognosis and efficacy in patients with metastatic colorectal cancer (mCRC) are crucial for optimizing therapeutic strategies. The aim of our study was to explore the applicability of circulating tumor DNA (ctDNA) as a prognostic and predictive marker in mCRC.
Sequential Patients with mCRC were included. Both plasma ctDNA and serum CEA were assessed in samples obtained before treatment and after 4 cycles of chemotherapy (C4). Target-capture deep sequencing with a panel covering 1021 genes was performed to detected somatic mutations in ctDNA. Clonal population structures were identified based on variations from ctDNA using Bayesian cluster with Pyclone. Molecular tumor burden index (mTBI) was calculated with the mean variant allele frequency of mutations in trunk clonal population. Cox regression analysis, Spearman's rank correlation, Receiver operating characteristic (ROC) curves and Kaplan-Meier plots were used for statistical analyses.
A total of 20 patients were prospectively included and treated with FOLFOX (15/20) or FOLFIRI (5/20) from Sep 2015 to Aug 2016. Median follow-up was 6.9 months (range 1.6-26.6). Somatic mutations for baseline ctDNA analysis were identified in 17/20 (85%) of the patients. In a multivariable analysis, a high baseline mTBI was associated with the risk of disease progression (HR, 1.091; 95% CI, 1.032–1.153; P = 0.002). The optimal baseline mTBI for predicting progression-free survival (PFS), as determined by the ROC curves (ROC area = 0.83, P = 0.0126), was 6.81%. Patients with baseline mTBI below 6.81% had longer PFS compared to those above (median 9.9 versus 4.35 months; HR, 2.966; 95% CI: 1.075-8.184; P = 0.0115). Fold reductions of mTBI from baseline to post-C4 were obtained in 16/20 (80%) of the patients. In a bivariate correlations analysis, fold reduction of mTBI was related to tumor response (r = -0.661, P = 0.005). In contrast, serum CEA level and its variation did not correlate with PFS and tumor response, respectively.
High baseline mTBI and inferior PFS were correlated in mCRC, so were fold reduction of mTBI and tumor response. Therefore, ctDNA could be potentially a biomarker for prognosis and efficacy.
Clinical trial identification
Legal entity responsible for the study
Department of Medical Oncology, Peking Union Medical College Hospital.
National Natural Science Foundation of China (81472785, 61435001), CAMS Innovation Fund for Medical Sciences (No. 2016-I2M-1-001).
All authors have declared no conflicts of interest.