A Prospective Study of Circulating Tumor DNA to Guide Matched Targeted Therapy in Lung Cancers

Joshua K. Sabari; Michael Offin; Dennis Stephens; Andy Ni; Adrian Lee; Nick Pavlakis; Stephen Clarke; Connie I. Diakos; Sutirtha Datta; Nidhi Tandon; Andres Martinez; Mackenzie L. Myers; Alex Makhnin; Ysleni Leger; Helena A. Yu; Paul K. Paik; Jamie E. Chaft; Mark G. Kris; Jeong O. Jeon; Laetitia A. Borsu; Marc Ladanyi; Maria E. Arcila; Jennifer Hernandez; Samantha Henderson; Tristan Shaffer; Kavita Garg; Dan DiPasquo; Christopher K. Raymond; Lee P. Lim; Mark Li; Matthew D. Hellmann; Alexander Drilon; Gregory J. Riely; Valerie W. Rusch; David R. Jones; Andreas Rimner; Charles M. Rudin; James M. Isbell; Bob T. Li


J Natl Cancer Inst. 2019;111(6):575-583. 

In This Article

Abstract and Introduction


Background: Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) is commercially available and increasingly adopted in clinical practice despite a paucity of prospective data to support its use.

Methods: Patients with advanced lung cancers who had no known oncogenic driver or developed resistance to current targeted therapy (n = 210) underwent plasma NGS, targeting 21 genes. A subset of patients had concurrent tissue NGS testing using a 468-gene panel (n = 106). Oncogenic driver detection, test turnaround time (TAT), concordance, and treatment response guided by plasma NGS were measured. All statistical tests were two-sided.

Results: Somatic mutations were detected in 64.3% (135/210) of patients. ctDNA detection was lower in patients who were on systemic therapy at the time of plasma collection compared with those who were not (30/70, 42.9% vs 105/140, 75.0%; OR = 0.26, 95% CI = 0.1 to 0.5, P < .001). The median TAT of plasma NGS was shorter than tissue NGS (9 vs 20 days; P < .001). Overall concordance, defined as the proportion of patients for whom at least one identical genomic alteration was identified in both tissue and plasma, was 56.6% (60/106, 95% CI = 46.6% to 66.2%). Among patients who tested plasma NGS positive, 89.6% (60/67; 95% CI = 79.7% to 95.7%) were also concordant on tissue NGS and 60.6% (60/99; 95% CI = 50.3% to 70.3%) vice versa. Patients who tested plasma NGS positive for oncogenic drivers had tissue NGS concordance of 96.1% (49/51, 95% CI = 86.5% to 99.5%), and directly led to matched targeted therapy in 21.9% (46/210) with clinical response.

Conclusions: Plasma ctDNA NGS detected a variety of oncogenic drivers with a shorter TAT compared with tissue NGS and matched patients to targeted therapy with clinical response. Positive findings on plasma NGS were highly concordant with tissue NGS and can guide immediate therapy; however, a negative finding in plasma requires further testing. Our findings support the potential incorporation of plasma NGS into practice guidelines.


Analysis of plasma circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) is an evolving technology that allows for rapid and noninvasive genotyping of tumors. ctDNA is a subset of cell-free DNA that can be found in plasma and represents genetic material from the primary tumor as well as metastases. ctDNA released by tumor cells undergoing apoptosis, necrosis, and in extracellular vesicles (exosomes) secreted from tumor cells is highly fragmented and ranges between 100 and 200 base pairs in size and is rapidly cleared from the peripheral circulation with a short half-life, ranging from 15 minutes to a few hours.[1–3] Plasma ctDNA harboring somatic mutations are highly specific for cancer and may serve as a useful surrogate of tumor burden, intratumor heterogeneity, and response to therapy.[4] Plasma-based NGS assays are now commercially available and are increasingly adopted in clinical practice. However, there is a paucity of prospective evidence-based guidance regarding in whom and when to order the test, and its utility in matching patients to targeted therapy. A recent joint review from the American Society of Clinical Oncology and the College of American Pathologists concluded that there was little evidence of clinical validity and clinical utility to support the widespread use of ctDNA in most patients with advanced cancers.[5]

Genetic sequencing is particularly important in patients with advanced-stage non-small cell lung cancers as their tumors may harbor somatic alterations that are sensitized to targeted therapies. Genetic sequencing can also detect mutations mediating resistance in patients with known driver alterations after exposure to targeted agents. Plasma-based genotyping may circumvent some of the limitations of standard tissue genotyping such as risks of repeat invasive procedures, insufficient tissue in biopsies, intratumor heterogeneity, and overall slow turnaround time of conventional tissue processing. However, it is unknown whether liquid biopsy could supplement or supplant tissue biopsy in clinical practice.

We hypothesized that plasma ctDNA NGS may be useful in matching patients with advanced non-small cell lung cancer to targeted therapy and in predicting their therapeutic benefit. We set out to prospectively study the utility of plasma-based ctDNA NGS in patients with advanced-stage non-small cell lung cancer in the real-world clinical practice setting.