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Guidelines highlight ‘best practices’ for liquid biopsy during treatment of non-small cell lung cancer
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Knowing how and when to use a liquid biopsy for molecular analysis of advanced non-small cell lung cancer is crucial to obtaining actionable information, according to a statement paper from International Association for the Study of Lung Cancer.
“Liquid biopsy and its subsequent molecular analysis is a powerful tool that can determine the patient’s molecular tumor profile in order to determine the best therapeutic option and can be applied as an alternative to tissue testing in cases where tumor testing is not possible or tissue is not adequate,” Fred R. Hirsch, MD, PhD, professor of medicine and pathology at University of Colorado Denver School of Medicine and CEO of the International Association for the Study of Lung Cancer (IASLC), said in a press release. “Gathering experts to collect and interpret a vast amount of information and to distribute best practices ensures that general oncologists and clinicians have access to the latest and best information in the emerging field of liquid biopsies.”
Tissue biopsy specimens had been the only source of tumor molecular information, but it is difficult to obtain adequate tissue from all patients with advanced NSCLC. Further, it is often challenging to rebiopsy patients to monitor responses to treatment and identify emergent molecular mechanisms of resistance.
Thus, liquid biopsy — or isolation of tumorderived DNA, RNA and cells from the peripheral circulation — has been developed as a tool to overcome the challenges of traditional tumor biopsy and provide information for the clinical management of NSCLC via identification of predictive biomarkers at treatment or progression.
Due to the growing number of targets and treatment advances that have been made over the last decade, IASLC formed a task force to create recommendations on liquid biopsy to guide the clinical management of advanced NSCLC patients and identify unmet needs.
Recommendations covered a number of topics, ranging from methods of extraction and analysis for circulating tumor DNA to proper reporting of results.
Regarding sample extraction, the guidelines state:
- Plasma, rather than serum, is preferred for extraction of circulating tumor DNA;
- The researchers highly recommended a “double spin” plasma isolation procedure;
- Blood should never be frozen prior to extracting plasma; and
- A draw of two tubes is recommended to ensure an adequate amount of blood for analysis. Total volume depends on institutional standard operating procedures.
Regarding methods of circulating tumor DNA analysis, researchers stated:
- Validated quantitative polymerase chain reaction panels are acceptable for targeting specific mutations, such as EGFR, but the technology has limited capabilities and can miss rare but clinically relevant mutations;
- Despite their high cost and limited availability, next-generation sequencing multiplex panels that focus on clinically relevant genes are preferred, especially panels that employ error-proofing technologies and that evaluate single-base variants, indels, copy number variations and chromosomal rearrangements; and
- If the expected turnaround time for a tissue biopsy analysis is longer than 2 weeks, liquid biopsy should be considered over the tissue biopsy analysis.
The guidelines state all treatment-naive patients should be considered for liquid biopsy using the same criteria specified for testing DNA from tissue samples — namely, all patients with advanced or metastatic nonsquamous NSCLC, patients with squamous NSCLC with clinical features suggesting a molecular driver and in cases where there is a nonsquamous component in diagnostic histology. Liquid biopsy also can be considered at the time of diagnosis for all patients who require tumor profiling, but especially those for whom tumor tissue is scarce, unavailable or would require a substantial delay to obtain.
Regarding tests for first-line treatment, the guidelines state:
- The cobas EGFR Mutation Test v2 (Roche) is acceptable for detecting EGFR sensitizing mutations, and a positive result is sufficient to guide first-line treatment with an EGFR tyrosine kinase inhibitor. However, negative results should be further interrogated using either tissue biopsy or more sensitive tests;
- The ddPCR Mutation Detection Assay (Bio-Rad) also is acceptable for detecting EGFR mutations, although a negative result also should prompt further investigation using either a next-generation sequencing test with circulating tumor DNA or tumor biopsy DNA;
- Polymerase chain reaction-based methods should not be used for detecting ALK or ROS1 rearrangements in circulating tumor DNA; and
- Multiplex panels using next-generation sequencing platforms are the preferred method. A negative result should not exclude therapy, however, and should be confirmed with tumor biopsy.
For progressing patients:
- Test EGFR alterations with an assay of sufficient sensitivity for those undergoing treatment with first- or second-generation EGFR TKIs. Negative results should be considered inconclusive;
- A next-generation sequencing panel is preferred over polymerase chain reaction-based methods because it can detect the common resistance mechanism T790M and others; and
- Information from a next-generation sequencing panel may be valuable for patients progressing on an ALK TKI, even though information on acquired resistant mutations is not required to switch to a different ALK TKI, because the panel may reveal a mechanism of resistance that makes the patient eligible for treatment on a clinical trial.
When reporting results, researchers should name the platform used and include all of the findings from the molecular analysis, specify whether the detected alterations are relevant in current clinical practice, and report the variant allele frequency of a given mutation, according to the recommendations.
Areas for future exploration include whether liquid biopsy can provide information in the setting of resistance to checkpoint inhibitors, the tool’s ability to monitor residual disease, the value of RNA in the biopsy, and collection of other fluids for liquid biopsy.
“Liquid biopsy has shown considerable promise toward improvements in the management of NSCLC patients, offering an alternative to standard procedures when tissue biopsies are insufficient or unfeasible, and providing a rapid and dynamic assessment of emergent resistance mechanisms that can be used to guide treatment decision-making,” the researchers wrote. “It is the commitment of IASLC to update this consensus yearly, in order to include all the new developments in the exciting topic of liquid biopsy.” – by Andy Polhamus
Disclosures: Unrestricted grants from AstraZeneca, Biocept, Guardant Health and Roche supported this work. Hirsch reports being a co-inventor of a University of Colorado owned patent, “EGFR IHC and- FISH as predictive biomarkers for EGFR Therapy” and reports participating in advisory boards for submitted work. Please see the statement for all other authors’ relevant financial disclosures.
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