Circulating tumor DNA as a biomarker for cancer
MetadataShow full item record
Detection of circulating tumor DNA (ctDNA) has potential as a noninvasive, specific, broadly applicable biomarker for cancer. To evaluate the utility of ctDNA as a biomarker for pancreatic ductal adenocarcinoma (PDAC) we performed targeted analysis of tumors from 51 preoperative, stage II patients and examined tumor-specific mutations in the ctDNA. We detected ctDNA in 43% of preoperative patients, and found that detection post-resection predicted clinical relapse and poor outcome, with evidence of recurrence by ctDNA detected 6.5 months earlier than CT imaging. To further explore early detection of cancer using ctDNA we developed an approach called targeted error correction sequencing (TEC-Seq) that allows ultrasensitive direct evaluation of sequence changes in circulating cell-free DNA (cfDNA) using massively parallel sequencing. We used this approach to examine 58 cancer-related genes encompassing 81 kb. Analysis of plasma from 44 healthy individuals identified genomic changes related to clonal hematopoiesis in 16% of asymptomatic individuals but no alterations in driver genes related to solid cancers. Evaluation of 200 patients with colorectal, breast, lung, or ovarian cancer detected somatic mutations in the plasma of 71, 59, 59, and 68%, respectively, of patients with stage I or II disease. Analyses of mutations in the circulation revealed high concordance with alterations in the tumors of these patients. In patients with resectable colorectal cancers, higher amounts of preoperative circulating tumor DNA were associated with disease recurrence and decreased overall survival. We further applied the TEC-Seq approach to detect response to targeted tyrosine kinase inhibitors in lung cancer patients and found that patients with radiographic response to therapy had a drop in ctDNA from an average mutant allele fraction of 3.59% to 0.13% within 6-22 days, while non-responders had limited changes in ctDNA. Patients with ctDNA based molecular responses had improved progression-free survival (12.0 vs 1.5 months, P = 0.001), which was detected on average 38 days earlier and was more predictive than CT imaging. These observations provide a broadly applicable approach for noninvasive detection of cancer and highlight the utility of ctDNA as a biomarker for early detection, identification of windows of opportunity for therapeutic intervention, and prediction of outcome.