Abstract 5916: Tumor-informed patient-specific panel outperforms tumor-naïve and tumor-informed fixed panel for circulating tumor DNA (ctDNA)-based postoperative monitoring of non-small cell lung cancer (NSCLC)

Abstract Background: Patient-specific flexible gene panels designed based on whole-exome sequencing (WES) of resected tumor tissues is a promising strategy for ctDNA-based detection of molecular residual disease (MRD) in early-stage NSCLC. Flexible gene panels could potentially overcome the limitations of fixed panels by incorporating more unique genomic regions that might be absent in fixed panels; however, no study has reported a head-to-head comparison of these two approaches in postoperative disease monitoring. In this study, we investigated the clinical utility of a novel Patient-specific pROgnostic and Potential tHErapeutic marker Tracking (PROPHET) tumor-informed ctDNA assay. Using the same set of longitudinal blood samples, we further compared the performance of PROPHET assay with tumor-informed (TI) and tumor-naïve (TN) fixed panels for predicting MRD and prognosis in surgical NSCLC patients. Methods: Fifty-three patients with stage I-III resected NSCLC from the MEDAL study (NCT03634826) with adequate samples and median follow-up of 647 days were analyzed. Matched surgical tumor tissue and blood samples collected at various time points, including before surgery (baseline), 3-days (B) and 1-month (C) postoperative time points before any adjuvant therapy and subsequent follow-up time points (F) were analyzed. PROPHET assay involved four major steps: identify somatic mutations using WES, customized design of a patient-specific panel consisting of 50 single nucleotide variants, ultra-deep unique molecular-identifier-based next-generation sequencing (UMI-NGS) of serial blood samples using the patient-specific panel, and MRD risk prediction. Fixed panel assay of serial blood samples was performed using UMI-NGS with 168 gene panel spanning 273 kb of human genome. Results: At 1-month post-surgery, PROPHET assay accurately predicted MRD-positive cases among relapsed patients (50%, 13/26), whereas all disease-free patients were MRD-negative (100%, 21/21). Three-year prognostication with PROPHET assay at B+C yielded higher sensitivity (59% vs 26% vs 22%), negative predictive value (66% vs 51% vs 50%), and hazard ratio (7.15, 95%CI [3.2-15.9] vs 4.48 [1.9-10.9] vs 5.58 [2.1-14.7]) as compared with TI and TN fixed panel assays. Disease monitoring using PROPHET assay at B/C/F accurately predicted the MRD risk in 70% (21/30) of relapsed patients at a median lead time of 318 days (range: 20-751), whereas TI assay predicted 43% (13/30) at 282 days (range 20-716) and TN assay predicted 37% (11/30) at 282 days (range: 20-634). Conclusion: Patient-specific tumor-informed ctDNA-based postoperative monitoring enables risk stratification at early postoperative settings better than fixed panel, which paves an alternative strategy in the individualized management of surgical NSCLC patients. Citation Format: Kezhong Chen, Haifeng Shen, Shuailai Wu, Pengfei Zhu, Chenyang Wang, Analyn Lizaso, Guannan Kang, Yang Wang, Juan Lv, Shuai Fang, Wenjun Wu, Fujun Qiu, Yuan Sun, Qiang Lu, Heng Zhao, Shannon Chuai, Fan Yang, Zhihong Zhang. Tumor-informed patient-specific panel outperforms tumor-naïve and tumor-informed fixed panel for circulating tumor DNA (ctDNA)-based postoperative monitoring of non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5916.