What’s Driving, and Blocking the Liquid Biopsy Evolution in Non–Small Cell Lung Cancer?

The application of liquid biopsies is becoming more common in the field of non–small cell lung cancer as the utility of liquid biopsies in the detection of key biomarkers continues to be confirmed through clinical trials.

Christian Rolfo, MD, PhD, MBA

The application of liquid biopsies is becoming more common in the field of non–small cell lung cancer (NSCLC) as the utility of liquid biopsies in the detection of key biomarkers continues to be confirmed through clinical trials. Popularity of blood-based assays is also growing as comparisons between liquid and tissue biopsies continue to demonstrate the noninferiority of liquid biopsies with quicker testing turnaround times.

In the Noninvasive versus Invasive Lung Evaluation (NILE) study of 282 patients with previously untreated NSCLC who submitted pretreatment blood samples for circulating tumor DNA (ctDNA) testing, liquid biopsy utilization increased the rate of biomarker detection by 48% over tissue alone. In total, the blood-based test identified 77 patients with a guideline-recommended biomarker compared with only 60 patients who had tissue biopsies (<.0001). It was also the NILE study that revealed swifter testing turnaround times were possible with liquid biopsies versus tissue biopsies.1

Expanding on the noninferiority of liquid biopsies as compared with tissue biopsies, a matched retrospective study of 80 cases demonstrated similar progression-free survival in patients with NSCLC who had actionable mutations whether the testing used to guide treatment was tissue-based or blood-based using circulating tumor DNA (ctDNA). The overall diagnostic accuracy of each test type was similar at 99.6% with liquid biopsy and 100% with tissue.2

“Since the first approval of EGFR TheraScreen in patients with lung cancer for the identification of EGFR mutations, the use of liquid biopsy is reshaping the diagnostic algorithm of different solid tumors, allowing a better characterization of the tumor biology. Nowadays, the use of plasma next-generation sequencing (NGS) is supported by robust data not only in lung cancer patients but also in other solid tumors with high positive predictive value,” Christian Rolfo, MD, PhD, MBA, professor of medicine and director of the Thoracic Medical Oncology and the Early Clinical Trials Departments at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, told Targeted Oncology in an interview.

“Plasma NGS can identify the presence of actionable oncogene drivers in patients with insufficient tissue for tumor genotyping and could rescue a significant proportion of oncogene-addicted tumors with inadequate tumor tissue, allowing for a more complete tumor genotyping,” Rolfo continued.

Because liquid biopsy is an area of active research, there are multiple opinions about its use. However, many papers published around NSCLC have stated that its best use is for patients that have no tissue available to biopsy. It is because of this advantage that some oncologists believe that liquid biopsy could potentially replace secondary tissue biopsies in NSCLC.

“The use of liquid biopsy could replace a tissue rebiopsy when it is clinically unfeasible due to comorbidities and/or other contraindications and can avoid unnecessary invasive procedures in the presence of a positive result. This could be particularly useful in patients with acquired resistance to targeted therapies or other antitumor agents for the identification of actionable mechanisms of resistance,” Rolfo explained.

“cfDNA analysis could better recapitulate the complex dynamics of tumor evolution under the selective pressure of anticancer treatments, and several studies have demonstrated its utility for treatment monitoring and disease prognostication. However, the indications of liquid biopsy are rapidly growing, and accumulating evidence suggests a potential role, in the next future, for minimal residual disease (MRD) monitoring in patients treated with curative-intent therapies and for early tumor detection.”

Hatim Hussain, MD

Although these pros are important for validating the use of liquid biopsies, the need for the wider utility of this testing format may be based on something deeper.

“The need for genomic data to base therapeutic decisions is driving the liquid biopsy evolution,” Hatim Hussain, MD, associate clinical professor of medicine, University of California San Diego, told Targeted Oncology in an interview.

Liquid biopsy assays are marketed as having the ability to detect EGFR, ALK, ROS1, BRAF, MET, RET, ERBB2, and NTRK genomic tumor alterations. But, the field of EGFR is farthest along with the FDA-approved Guardant360 companion diagnostic for identifying patients with EGFR-positive NSCLC who may benefit from treatment with osimertinib (Tagrisso). The approval was supported by clinical and analytical validation data from over 5000 patient samples. The use of other tests to detect other alterations may not be as widely approved or available, which can be a challenge, but it is one of many.

Challenges With Liquid Biopsy Adoption

With liquid biopsy showing so much promise for key biomarker detection, why is it not more widely adopted? The truth is, there are multiple factors at play.

“A wide adoption of liquid biopsy is hampered by several socio-economic issues. The costs of some commercially available tests, especially NGS, could represent a serious obstacle for clinical implementation and reimbursement in healthcare systems based on taxpayers or limited resources. Furthermore, the technical requirements and expertise in the use of these technologies might further limit the use of liquid biopsy in clinical practice, especially in non-academic institutions with limited economic and personnel resources,” stated Rolfo.

In terms of nonacademic settings, community clinics tend to be more impacted by the limitations of liquid biopsies than academic centers are. When asked about liquid biopsy adoption in the community setting compared with what has been observed in academic centers, Rolfo said: “A wider adoption of liquid biopsy, namely cfDNA analysis, is eagerly awaited. However, we should be aware that the use of this novel powerful tool is associated with some clinically relevant limitations. For instance, the use of liquid biopsy can be associated with false-negative results in a small proportion of ‘non-shedding’ patients. Indeed, some tumors do not shed tumor DNA in the circulation. This phenomenon is usually associated with small tumors or with metastatic disease with low tumor burden and/or metastases exclusively in sanctuary sites (central nervous system, bone). Furthermore, the use of NGS can provide a multitude of information that should be adequately interpreted. The creation of molecular tumor boards at the institutional level is advisable to avoid misinterpretation of the NGS reports.”

A review of recent developments in the liquid biopsy arena have identified key limitations such as the detection of fragile biomarkers, specific isolation requirement for plasma, and the lack of standardized protocols for isolation and interpretation.3 Another issue, as Rolfo explained during his interview, is validating the different assays that are available in the space.

“The term ‘liquid biopsy’ encompasses a wide variety of minimally invasive tumor-derived components that include ctDNA, extracellular vesicles (including exosomes), microRNAs, etc. Furthermore, several different bodily fluids can be used as a source of these biomarkers, ranging from plasma to urine and cerebrospinal fluid. Therefore, the major issue is the validation of the different tests and assays evaluating these biomarkers before clinical implementation and health authorities’ approval and reimbursement.”

Hussain stated that false-negative observed with liquid biopsies as compared with tissue biopsies is another limitation preventing wider adoption of liquid biopsies. Both Rolfo and Hussain explained during their interviews how they recommend community oncologists handle the limitations.

“Different scientific societies have created position papers and statements to increase the awareness of this novel useful tool. For instance, the International Society for the Study of Lung Cancer (IASLC) in 2018 published a statement on liquid biopsy in lung cancer and the 2nd edition is underway. Similarly, the ASCO-CAP published a joint review on liquid biopsy. Educational events on liquid biopsy have been done during the last year or have been planned, including the IASLC 2020 Lung Cancer Hot Topic: Liquid Biopsy, which was focused on thoracic malignancies and the Annual Congress of the International Society of Liquid Biopsy that will be held on October 30, 2020,” Rolfo stated.

He continued, “In addition, the implementation of levels of evidence tools for genomic alterations interpretation, such as the ESMO ESCAT scale and the MSKCC OncoKB, could help practicing oncologists to better interpret liquid biopsy results. Finally, a close collaboration with other healthcare providers, including biologists, geneticists, and pathologists in the context of a multidisciplinary molecular tumor board would be advisable and could contribute to a better and rational use of these novel diagnostic tools.”

In regard to the false-negative issue, Hussain stated that “one needs to think through the data obtained to understand the therapeutic implications of a result. If a liquid biopsy is negative, one may still need to have tissue tested because there is a false-negative rate with liquid biopsy technologies.”

Future application of liquid biopsy tests in NSCLC is widely dependent on active research. One important study topic is tumor mutation burden that is found through ctDNA NGS, as TMB has been found to correlate with patients’ responses to treatment with PD-1 inhibitors like atezolizumab ([Tecentriq] POPLAR, NCT01903993; OAK, NCT02008227). Another possible avenue for liquid biopsy assay utilization may be monitoring patients’ responses to immune checkpoint inhibition.


1. Leighl N, Page RD, Raymond VM, et al. Clinical utility of comprehensive cell-free DNA (cfDNA) analysis to identify genomic biomarkers in newly diagnosed metastatic non–small cell lung cancer (mNSCLC). Presented at: 2019 AACR Annual Meeting; March 29-April 3, 2019; Atlanta, GA. Abstract 4460.

2. Tran H, Lam V, Vasquez M, et al. Outcomes in advanced NSCLC patients treated with 1st line EGFR-TKI based on mutation detection from tissue or cfDNA-based genomic sequencing. Presented at: IASLC 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract P1.01-98.

3. Revelo AE, Martin A, Velasquez R, et al. Liquid biopsy for lung cancers: an update on recent developments. Ann Transl Med. 2019;7(15):349. doi: 10.21037/atm.2019.03.28

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