Direct detection of early-stage cancers using circulating tumor DNA.

Phallen J1, Sausen M2, Adleff V1, Leal A1, Hruban C1, White J1, Anagnostou V1, Fiksel J1, Cristiano S1, Papp E1, Speir S1, Reinert T3, Orntoft MW3, Woodward BD4, Murphy D2, Parpart-Li S2, Riley D2, Nesselbush M2, Sengamalay N2, Georgiadis A2, Li QK1, Madsen MR5, Mortensen FV6, Huiskens J7,8, Punt C8, van Grieken N9, Fijneman R10, Meijer G10, Husain H4, Scharpf RB1, Diaz LA Jr1, Jones S2, Angiuoli S2, Ørntoft T3, Nielsen HJ11, Andersen CL3, Velculescu VE12.

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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.