Outcome prediction in resectable esophageal adenocarcinoma based on clinical variables, radiomics, and ctDNA.
Authors: van den Ende Tom , Kuijper Steven C. , Widaatalla Yousif , Noortman Wyanne A. , van Velden Floris H.P. , Woodruff Henry C. , van der Pol Ymke , Moldovan Norbert , Pegtel D. Michiel , Derks Sarah , Bijlsma Maarten F. , Moulière Florent , de Geus-Oei Lioe-Fee , Lambin Philippe , Van Laarhoven Hanneke W.M. 
Published: January 2023

423

Background: Despite the advent of precision medicine, prediction of survival outcome of esophageal cancer patients remains a challenge. Here we aim to investigate the value of prediction models integrating multi-signal data including radiomics and circulating tumor DNA (ctDNA) data in addition to clinical data for the prediction of resectable esophageal adenocarcinoma (rEAC) related outcomes. Methods: In total n=111 rEAC patients treated with neoadjuvant chemoradiotherapy (nCRT; n=71) +/- anti-PD-L1 (n=40) were included. Baseline clinical variables (n=9) were based on the SOURCE survival prediction model (van den Boorn et al. JNCCN. 2021). The baseline ctDNA data from plasma was derived from fragmentomic and copy number aberrations (ichorCNA) from shallow whole genome sequencing (<5-fold coverage) and a custom next-generation sequencing panel (n=23 genes). Baseline radiomic original features were extracted by the pyradiomics package from CT-image delineated tumor volumes. An initial redundancy filtering was performed to remove correlating variables (r>0.6). We evaluated the predictive performance of baseline ctDNA and radiomics features on overall survival (OS), progression free survival (PFS), and time to progression (TTP), through fitting Cox-regression models. Four ctDNA features were included in the models: P20-150, ichorCNA, fragment end score and mutation detection. For the radiomics features we performed an additional back- and forward variable selection based on Akaike’s Information Criterion. Using the likelihood ratio test we tested if the model fit changed after adding ctDNA and radiomics features to a model with clinical variables. Results: The addition of radiomics to clinical variables improved model fit for OS (p=0.017). Baseline prediction of OS resulted in a C-index of 0.65 using clinical variables only, 0.65 with ctDNA, 0.68 with radiomics and 0.68 with ctDNA and radiomics combined. For PFS model fit improved after adding radiomics (p=0.020) and ctDNA and radiomics combined (p=0.017). Baseline prediction of PFS resulted in a C-index of 0.64 using clinical variables, 0.65 with ctDNA, 0.67 with radiomics, and 0.68 with ctDNA and radiomics combined. For TTP model fit improved after adding radiomics (p=0.008) and radiomics and ctDNA combined (p=0.002). Baseline prediction of TTP resulted in a C-index of 0.64 with clinical variables, 0.65 with ctDNA, 0.71 with radiomics, and 0.72 with ctDNA and radiomics combined. Based on the cox-regression models using clinical variables and radiomics, risk stratification by splitting the cohort in a high and low risk group was possible for OS, PFS and TTP (p<0.001). Conclusions: Combining clinical variables from SOURCE with radiomics data improved predictions of OS, PFS, and TTP among patients with rEAC. Multi-signal integration of clinical and radiomics variables could potentially be used to identify risk groups.