Analysis Supports Concurrent Plasma NGS, Tissue Testing for NSCLC

Integrating plasma next-generation sequencing (NGS) alongside tissue testing when determining lung cancer diagnosis may improve outcomes for patients.

Carrying out plasma next-generation sequencing (NGS) may increase the detection of actionable findings with a shorter time to results among patients with lung cancer, according to study findings published in Frontiers in Medicine.

In the first-line setting, the practice was highly concordant with tissue epidermal growth factor receptor (EGFR) testing, underscoring the clinical utility of complementary plasma mutation profiling in routine management, authors wrote.

Currently, the 5-year survival rate for patients with lung cancer is 18.6%, while for patients with late-stage non-small cell lung cancer (NSCLC), that number dips to 6%—approximately 40% of those diagnosed with any lung cancer will be at late-stage.

However, “molecular diagnostic testing combined with molecular targeted agents directed against driver mutations in EGFR, ALK, ROS1, BRAF, MET, RET, and most recently KRAS has significantly improved the outcomes for patients with advanced disease harboring these alterations,” authors explained.

Although tissue biopsy is the gold standard for NSCLC diagnosis, between 15% and 40% of patients cannot undergo this procedure due to insufficient tissue samples, while waiting for molecular test results can have detrimental impacts on the disease course.

Liquid biopsy using plasma cell-free DNA (cfDNA) as the substrate for molecular profiling serves as an alternative to tissue biopsy, but its use is limited.

To investigate whether adding “a concurrent plasma NGS test to tissue testing would improve the detection of actionable mutations in patients with NSCLC, improving prognostication, in addition to choice and timeliness of treatment initiation,” researchers prospectively enrolled 71 patients with suspected lung cancer from a hospital in Singapore into the current study.

The EGFR gene is mutated in 40% to 60% of Asian patients with NSCLC, and in 10% to 20% of White patients, authors explained.

Participants were enrolled between June 2015 and August 2018. Prior to histology diagnosis, blood samples for NGS-based plasma genotyping were collected, followed by baseline tissue sampling via bronchoscopy or effusion collection within 2 days.

For those diagnosed with NSCLC, “the standard of care targeted EGFR mutation tissue testing was performed on tumor biopsy samples.” In addition, EGFR, ERBB2, BRAF, KRAS, and MET, were defined as clinically actionable mutations, while the NGS assay did not examine fusions in ALK, RET, and ROS1.

The majority of study participants were male with a median age of 67; 54 patients had NSCLC, 7 had other cancers, and 10 did not have cancers. One patient with NSCLC did not have blood samples available; tissue EGFR test results were available for 70.3% (38/54) of patients due to sample inadequacies.

Analyses revealed:

  • Tissue EGFR testing identified sensitizing EGFR (L858R or exon 19 deletion) mutation in 31.6% (12/38) of cases
  • Plasma NGS identified clinically actionable mutations in 37.7% (20/53) of cases, including EGFR mutations in 2 cases with no tissue EGFR results, and mutations in KRAS, BRAF, and MET
  • Overall sensitivity of sensitizing EGFR mutation detection by plasma NGS was 75% (9/12), and specificity was 100% (25/25) in patients tested in both tissue EGFR and plasma NGS (n = 37)
  • Tissue EGFR testing alone informed clinical decisions in 22.2% (12/54) of cases
  • Adding plasma NGS to tissue EGFR testing increased the detection rate of actionable mutations to 42.6% (23/54), representing a 1.9-fold increase in clinically relevant findings
  • The average turnaround time of plasma NGS was shorter than standard tissue testing (10 vs. 29.9 days, P < .05)

Researchers described the inclusion of plasma NGS as “plasma-first" in cases involving "no tissue sample available for testing, or complementary where both tumor and plasma sample may be tested for comprehensive target coverage, or where there is uncertainty about the adequacy of a tissue sample for molecular testing."

Routine diagnostic EGFR profiling via tissue biopsy is invasive in nature and may not be suitable for those with advanced cancer or who have a later stage.

Findings of the current study are consistent with those of previous research that showed “addition of comprehensive liquid biopsy to targeted tissue testing increased the number of targetable mutations up to as much as 65%” in patients with NSCLC.

Disease stage information was only available for a subset of patients, marking a limitation to the analysis, while the study size was relatively small and reflective of only a single center.

Overall, “this study demonstrates that integrating plasma NGS with tissue testing increases actionable yield over conventional diagnostic approaches for NSCLC by allowing more patients to achieve comprehensive biomarker profiling,” authors said.

“Plasma NGS allows for quick and non-invasive molecular profiling that can rapidly guide treatment decisions and complement routine tissue testing or tissue NGS or could be a viable first-line alternative when tissue biopsy is not feasible,” they concluded.


Choudhury Y, Tan M, Shi J L, et al. Complementing tissue testing with plasma mutation profiling improves therapeutic decision-making for patients with lung cancer. Front Med. Published online February 11, 2022. doi:10.3389/fmed.2022.758464