Direct detection of early-stage cancers using circulating tumor DNA

TLDR

Early detection and intervention are likely the most effective means for reducing cancer morbidity and mortality, yet noninvasive methods for detecting early‑stage tumors remain challenging. The authors developed targeted error correction sequencing (TEC‑Seq) to ultrasensitively evaluate sequence changes in circulating cell‑free DNA. TEC‑Seq was applied to 81 kb of 58 cancer‑related genes in plasma samples. In 44 healthy controls, clonal hematopoiesis was seen in 16 % but no solid‑tumor driver mutations; in 200 patients with stage I/II colorectal, breast, lung, or ovarian cancer, somatic mutations were detected in 71 %, 59 %, 59 %, and 68 % respectively, with high concordance to tumor tissue and preoperative ctDNA levels predicting recurrence and survival, demonstrating a broadly applicable noninvasive early‑stage tumor detection approach.

Abstract

Early detection and intervention are likely to be the most effective means for reducing morbidity and mortality of human cancer. However, development of methods for noninvasive detection of early-stage tumors has remained a challenge. We have developed an approach called targeted error correction sequencing (TEC-Seq) that allows ultrasensitive direct evaluation of sequence changes in circulating cell-free DNA using massively parallel sequencing. We have 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. These analyses provide a broadly applicable approach for noninvasive detection of early-stage tumors that may be useful for screening and management of patients with cancer.