Combined circulating tumor DNA and protein biomarker-based liquid biopsy for the earlier detection of pancreatic cancers

Joshua D. Cohen, Ammar A. Javed, Christopher Thoburn, Fay Wong, Jeanne Tie, Peter Gibbs, C. Max Schmidt, Michele T. Yip-Schneider, Peter J. Allen, Mark Schattner, Randall E. Brand, Aatur D. Singhi (+28 others)
2017 Proceedings of the National Academy of Sciences of the United States of America  
The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182
more » ... patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient's primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types. early cancer detection | liquid biopsy | circulating tumor DNA | protein biomarkers | pancreatic cancer P ancreatic ductal adenocarcinoma (PDAC, hereafter "pancreatic cancer") is the third leading cause of cancer death and is predicted to become the second most common cause in the United States by 2030 (1). Pancreatic cancer is notoriously lethal, with fewer than 9% of patients surviving 5 y after diagnosis (2). The poor prognosis of patients with pancreatic cancer is in part due to the fact that 80-85% of patients are diagnosed at advanced stages, when either tumor invasion into the surrounding major vessels or distant metastases are evident upon radiologic studies (3). At this late point in the disease, pancreatic cancer is not amenable to surgical resection, and the 3-y survival rate is <5%. In contrast, a 5-y survival of almost 60% is reported for very small, localized tumors; among resectable cancers, the smaller the tumor, the better the prognosis (4-8). Pancreatic cancer is not different from other cancers with respect to its strong correlation between tumor stage and prognosis (4). Very few patients with cancers of the lung, colon, esophagus, or stomach who have distant metastasis at the time of diagnosis survive for more than 5 y (9). The size of cancers is also important in a general sense, in that smaller tumors have less often metastasized than larger tumors at the time of diagnosis and are therefore more likely to be curable by surgery alone. Even when cancers have metastasized to distant sites, a smaller burden of disease is much more easily managed than bulky lesions (10). Thus, adjuvant chemotherapeutic agents administered to patients
doi:10.1073/pnas.1704961114 pmid:28874546 pmcid:PMC5617273 fatcat:qdu2qb4mvjbudbl6qjr3kh4lfe