Joshua D. Cohen a , b , c , d , e , Ammar A. Javed f , Christopher Thoburn c , Fay Wong a , b , c , d , Jeanne Tie g , h , i , Peter Gibbs g , h , i , C. Max Schmidt j , k , Michele T. Yip-Schneider j , Peter J. Allen l , Mark Schattner m , Randall E. Brand n , Aatur D. Singhi o , Gloria M. Petersen p , Seung-Mo Hong q , Song Cheol Kim r , Massimo Falconi s , Claudio Doglioni t , Matthew J. Weiss f , Nita Ahuja f , Jin He f , Martin A. Makary f , Anirban Maitra u , Samir M. Hanash u , Marco Dal Molin d , Yuxuan Wang a , b , c , d , Lu Li v , Janine Ptak a , b , c , d , Lisa Dobbyn a , b , c , d , Joy Schaefer a , b , c , d , Natalie Silliman a , b , c , d , Maria Popoli a , b , c , d , Michael G. Goggins c , d , w , x , Ralph H. Hruban c , d , x , Christopher L. Wolfgang f , Alison P. Klein c , d , y , Cristian Tomasetti c , v , z , Nickolas Papadopoulos a , c , d , Kenneth W. Kinzler a , c , d , Bert Vogelstein a , b , c , d , 1 , Anne Marie Lennon d , w , 1
5 September 2017
Few patients with pancreatic cancer survive longer than 5 y, in part because most patients are identified only after their disease has progressed to an advanced stage. In this study, we show how combining mutations in circulating tumor DNA (ctDNA) with protein markers can result in a screening test with improved sensitivity while retaining specificity. The combination of the ctDNA and protein markers was superior to any single marker. Moreover, the combination detected nearly two-thirds of pancreatic cancers that had no evidence of distant metastasis at the time of surgical resection. The strategy may represent an approach to detect cancers of many types at an earlier stage.
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 control 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.