Circulating tumor DNA for early relapse detection and monitoring disease status in patients with early-stage pancreatic adenocarcinoma

Background Pancreatic adenocarcinoma (PDAC) is one of the most aggressive cancer histologies, as evidenced by high recurrence rate (85%) and poor 5-year overall survival of 9%. Numerous circulating biomarkers have been evaluated for the detection of molecular monitoring and residual disease (MRD) detection in PDAC, however, the application of these techniques has been limited in early-stage PDAC due to poor sensitivity and specificity. Recently, an ultrasensitive, personalized, and tumor-informed ctDNA assay (Signatera TM) has been shown to overcome many of the challenges that have limited the clinical utility of the aforementioned biomarkers, for the first time allowing for reliable MRD detection in PDAC and other histologies. Methods In this cohort, 7 patients with pancreatic cancer and 1 patient with ampullary adenocarcinoma were prospectively enrolled for ctDNA analysis and followed up for a median of 316 days (range: 152-684). Personalized mutational profiles derived from tumor tissue via whole-exome sequencing were used to design patient-specific ctDNA assays for variant detection in plasma samples. Apart from ctDNA analysis, patients were also monitored using carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA-19-9), and radiological imaging. Results In these 8 cases of resectable pancreatic/ampullary adenocarcinoma, 7 patients received mFOLFIRINOX adjuvant chemotherapy and 2 received additional rounds of gemcitabine/oxaliplatin and gemcitabine/paclitaxel. Three patients had plasma collected after surgery, of which 2 patients (MRD rate of 66%) were found to be ctDNA-positive with both experiencing relapse. During the course of the follow-up, 50% (4/8) of patients relapsed, of which 100% had ctDNA detected prior or at the time of recurrence (100% sensitivity). The presence of ctDNA was associated with reduced recurrence-free survival (HR: 10.14; 95%: CI: 1.07 - 1347.9; p =0.03). ctDNA findings were found to correlate and precede imaging results. However, CA 19-9 and CEA, in certain cases showed discordance with imaging and were found to be elevated due to other conditions, such as gastritis. Conclusions Our findings suggest, presence of ctDNA after surgery in early-stage PDAC is associated with reduced recurrence-free survival. During monitoring, ctDNA was found to be a better prognostic marker compared to CA-19-9 and CEA and can be used to inform on disease status prior to imaging. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure M. Abdelrahim: Speaker Bureau / Expert testimony: Houston Methodist- Cancer Center. A. Esmail: Full / Part-time employment: Houston Methodist- Cancer Center. T. Katz: Full / Part-time employment: Natera. E. Kalashnikova: Shareholder / Stockholder / Stock options: Natera, Natera. M. Malhotra: Shareholder / Stockholder / Stock options: Natera, Inc.; Full / Part-time employment: Natera, Inc. P. Olshan: Shareholder / Stockholder / Stock options: Natera, Inc.; Full / Part-time employment: Natera, Inc. P. Billings: Leadership role: Natera Shareholder / Stockholder / Stock options: Natera; Full / Part-time employment: Natera. A. Aleshin: Leadership role: Natera, Inc.; Shareholder / Stockholder / Stock options: Natera, Inc.; Full / Part-time employment: Natera, Inc. All other authors have declared no conflicts of interest.