Abstract 5606: Detection of circulating tumor DNA in early and late stage human malignancies

Abstract

Abstract The development of minimally-invasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital PCR-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We initially use targeted, exomic, or whole genome sequencing to identify sequence or structural alterations in tumor tissues of 410 patients using targeted, exomic, or whole genome sequencing. We found that at least one tumor-specific mutant molecule could be identified in <5 mL of plasma in >75% of patients with advanced ovarian, colorectal, bladder, gastroesophoageal, pancreatic, breast, melanoma, hepatocellular and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73%, 57%, 48% and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. Circulating tumor DNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% while and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor (EGFR) blockade in 24 patients who objectively responded to therapy but who subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase (MAPK) pathway. Remarkably, nearly half (45%) of the observed mutations observed were in codon 61 of either the KRAS or NRAS gene. Taken together, these data suggest that ctDNA is a broadly applicable, sensitive, specific and robust biomarker that can be used for a variety of clinical and research purposes in patients with several multiple different types of cancer. Note: This abstract was not presented at the meeting. Citation Format: Chetan Bettegowda, Mark Sausen, Rebecca Leary, Isaac Kinde, Nishant Agrawal, Bjarne Bartlett, Hao Wang, Brandon Luber, Kenneth Kinzler, Bert Vogelstein, Nickolas Papadopoulos, Luis Diaz. Detection of circulating tumor DNA in early and late stage human malignancies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5606. doi:10.1158/1538-7445.AM2014-5606