Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies

TLDR

Noninvasive tumor detection and monitoring remain major challenges in oncology. We employed digital PCR to assess ctDNA detection across 640 patients, evaluated KRAS mutation sensitivity and specificity in 206 metastatic colorectal cases, and examined ctDNA’s role in EGFR‑blockade resistance in 24 responders. ctDNA was detectable in over 75% of advanced cancers and in 48–73% of localized tumors, was often present when circulating tumor cells were absent, showed 87.2% sensitivity and 99.2% specificity for KRAS mutations, and was associated with MAPK pathway mutations in 96% of patients who relapsed after EGFR blockade, supporting its broad clinical utility.

Abstract

The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, 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. ctDNA 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% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.