Consensus Statement From IASLC on Liquid Biopsy for Advanced NSCLC

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As reported in the Journal of Thoracic Oncology by Christian Rolfo, MD, PhD, and colleagues, the International Association for the Study of Lung Cancer (IASLC) has issued a consensus statement on the use of liquid biopsy in advanced non–small cell lung cancer (NSCLC). Select recommendations are reproduced/summarized herein.

As stated by the authors, “Liquid biopsy is a rapidly evolving field. Over the last few years, ctDNA [plasma circulating tumor DNA] analysis in NSCLC has moved from single-gene analysis (EGFR mutations) to guideline-recommended, broad-based plasma ctDNA analysis by next-generation sequencing (NGS), based on major technical advances and the dramatic change in application of targeted therapies in therapeutic algorithm for patients with NSCLC. The adoption of newer NGS approaches [has] dramatically improved the sensitivity and specificity of ctDNA analysis in clinical practice.”

Christian Rolfo, MD, PhD

Christian Rolfo, MD, PhD

Selected Recommendations

Liquid biopsy: Preanalytical phase

In clinical practice, plasma ctDNA collection, sample handling, and automated processing should be performed using standardized and clinically validated procedures to reduce operator variability and false-negative results.

Methodology of ctDNA analysis

Due to the growing number of guideline-recommended oncogene targets to be assessed in advanced NSCLC, testing of plasma ctDNA should be performed by a clinically validated NGS platform rather than single-gene polymerase chain reaction (PCR)-based approaches, both in treatment-naive patients and those associated with multiple mechanisms of acquired resistance to targeted agents. Where plasma NGS is not available due to technical and/or economic constraints, single-gene or low multiplex-based approaches may represent appropriate alternatives. Use of limited PCR analysis for EGFR mutations as the initial step in molecular assessment, for example, remains highly relevant in areas of the world where the EGFR mutation rate is high. However, single-gene testing should not be considered complete, and if negative, serial testing for additional actionable biomarkers must be pursued.

Reporting of liquid biopsy results

The benefit of tissue and plasma NGS is now established in several clinical practice settings. It is anticipated—due to broad-based coverage of requisite oncogenes, decreased turnaround times, and emerging data on cost-effectiveness—that in the near future, NGS will become increasingly available worldwide. Implementation of a multidisciplinary molecular tumor board to assist clinicians in treatment decision-making is advisable.

Tumor tissue genotyping vs liquid biopsy

Plasma ctDNA can now be considered a valid tool for genotyping of newly diagnosed patients with advanced NSCLC, and results are often complementary to tissue analysis. At the time of acquired resistance after tyrosine kinase inhibitor therapy in oncogene-driven NSCLC, initial use of ctDNA is preferred for determination of mechanisms of resistance (“plasma-first”), with repeat tissue biopsy if plasma ctDNA is uninformative. Due to ease of serial sampling and high patient acceptance, ctDNA is also emerging as the preferred method for real-time monitoring.

Role of ctDNA in patients with oncogene-addicted cancers

In patients with oncogene-addicted NSCLC, liquid biopsy is emerging as not only complementary to tissue-based analysis but also acceptable as the initial approach (“plasma-first”) for biomarker evaluation at the time of diagnosis, as well as for monitoring the efficacy of targeted therapies. Finally, a plasma-first approach is appropriate for identification of mechanisms of acquired resistance to targeted therapies in many clinical settings.

Role of ctDNA in patients with non–oncogene-addicted NSCLC

Indications for liquid biopsy in patients with non–oncogene-addicted NSCLC are less well-defined at this time, although there are several promising areas of investigation. Blood tumor mutational burden is an emerging biomarker, pending completion of ongoing prospective randomized trials and refinement of methodology.

The authors concluded, “Many advances have occurred in the field of liquid biopsy for NSCLC since the previous IASLC statement paper in 2018. Liquid biopsy is now the preferred method of molecular testing in some clinical settings and has proven complementary to tumor tissue testing in others. Additional opportunities exist where liquid biopsy is unique in its application, such as serial monitoring and detection of minimal residual disease. We fully anticipate that the role of liquid biopsy will continue to increase in the near and long-term future, to the betterment of practicing oncologists and the patients [with lung cancer] we treat.”

David R. Gandara, MD, of UC Davis Comprehensive Cancer Center, is the corresponding author for the Journal of Thoracic Oncology article.

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