Liquid biopsies can be performed when a tissue biopsy is inaccessible or unavailable. While the current focus is dominated by DNA, additional components of a liquid biopsy include ribonucleic acids (RNA), circulating tumor cells (CTCs), extracellular vesicles (EVs), and tumor educated platelets (TEPs). The latter components are mainly of research interest. As more translational research is performed, these additional components of a liquid biopsy may have increasing clinical use in the future. Methods that are currently used to detect or measure ctDNA can broadly be divided into two categories: polymerase chain reaction (PCR) based and next-generation sequencing (NGS) based. NGS is broader and has greater promise. Although liquid biopsy may be an attractive tool for cancer screening in asymptomatic patients, such applications will need to be carefully and thoughtfully considered to avoid excessive patient suffering and cost due to false-positive results. In the short term, liquid biopsies may be more helpful to confirm malignancy in patients with already clinically or radiographically apparent lesions.

Guardant is one of several panels of tumor markers designed to give the oncologist an option of treating in a personalized manner directed to the specific markers that the cancer expresses. It is a clinical diagnostic test based on sequencing 72 genes and Guardant claims to be highly accurate in identifying genomic alterations. The National Comprehensive Cancer Network (NCCN) does recommend “broader molecular profiling” for non-small lung cancer, albeit without specifically naming the Guardant test. Therefore, tissue Guardiatn360 test as meant or included by NCCN, since it is one of the more established tests of this kind. However, this patient underwent cDNA test and this is different and it is specifically mentioned in NCCN as not being included in the NCCN recommendations. Therefore, based on the documentation provided, the Guardant 360 Guardant Health test considered was not medically necessary.

“A central goal of precision medicine in oncology is to target genomic alterations with novel therapeutic agents in a timely manner as the tumor genomic profile evolves. Currently, genomic analysis of tissue biopsy is accepted as the gold standard strategy for identifying DNA genomic alterations in tumors using next-generation sequencing (NGS) among other techniques. For advanced tumors, cfDNA is variable with some tumor types such as pancreatic, ovarian, colorectal, breast, bladder, esophageal, melanoma, and hepatocellular carcinoma expressing higher percentages of cfDNA while others, such as brain, renal, prostate, and thyroid cancers having detectable circulating DNA in less than 50% of patients [9].” (Chae et al 2016).

“ctDNA monitoring may have clinical utility throughout the course of disease, from prediagnosis to advanced disease, and in the setting of surveillance as well as that of initial diagnosis. These evolving areas require further prospective study before becoming part of routine clinical practice;” (Komatsubara, K. M., & Sacher, A. G., 2017).

“Nonsmall cell lung cancer (NSCLC) is the most common type of lung cancer and a tumor with a broad spectrum of targeted therapies already available or in clinical trials. Thus, molecular characterization of the tumor using next generation sequencing (NGS) technology, has become a key tool for facilitating treatment decisions and the clinical management of NSCLC patients. The performance of a custom 23 gene multiplex amplification hot spot panel, based on Ion AmpliSeq technology, was evaluated for the analysis of tumor DNA extracted from formalin-fixed and paraffin-embedded (FFPE) tissues. Furthermore, the Ion AmpliSeq RNA Fusion Lung Cancer Research Panel was used for fusion RNA transcript analysis. The mutation spectrum of the tumors was determined in a cohort of 502 patients with NSCLC using the aforementioned targeted gene panels. The panel used for tumor DNA analysis in this study exhibited high rates (100%) of sensitivity, specificity and reproducibility at a mutation allelic frequency of 3%. At least one DNA mutation was detected in 374 patients (74.5%) and an RNA fusion was identified in 16 patients, (3.2%). In total, alterations in a cancer-driver gene were identified (including point mutations, gene rearrangements and MET amplifications) in 77.6% of the tumors tested. Among the NSCLC patients, 23% presented a mutation in a gene associated with approved or emerging targeted therapy. More specifically, 13.5% (68/502) presented a mutation in a gene with approved targeted therapy (EGFR, ALK, ROS1) and 9.4% (47/502) had an alteration in a gene related to emerging targeted therapies (ERBB2, BRAF, MET and RET). Furthermore, 51.6% of the patients had a mutation in a gene that could be related to an off label therapy or indicative for access to a clinical trial. Thus, the targeted NGS panel used in this study is a reliable approach for tumor molecular profiling and can be applied in personalized treatment decision making for NSCLC patients.” (Tsoulos, N., Papadopoulou, E., Metaxa-Mariatou, V., Tsaousis, G., Efstathiadou, C., Tounta, G., Scapeti, A., Bourkoula, E., Zarogoulidis, P., Pentheroudakis, G., Kakolyris, S., Boukovinas, I., Papakotoulas, P., Athanasiadis, E., Floros, T., Koumarianou, A., Barbounis, V., Dinischiotu, A., & Nasioulas, G., 2017).Guardant is one of several panels of tumor markers designed to give the oncologist an option of treating in a personalized manner directed to the specific markers that the cancer expresses. It is a clinical diagnostic test based on sequencing 72 genes and Guardant claims to be highly accurate in identifying genomic alterations. The National Comprehensive Cancer Network (NCCN) does recommend “broader molecular profiling” for non-small lung cancer, albeit without specifically naming the Guardant test. Therefore, tissue Guardiatn360 test as meant or included by NCCN, since it is one of the more established tests of this kind. However, this patient underwent cDNA test and this is different and it is specifically mentioned in NCCN as not being included in the NCCN recommendations. Therefore, based on the documentation provided, the Guardant 360 Guardant Health test considered was not medically necessary.

“A central goal of precision medicine in oncology is to target genomic alterations with novel therapeutic agents in a timely manner as the tumor genomic profile evolves. Currently, genomic analysis of tissue biopsy is accepted as the gold standard strategy for identifying DNA genomic alterations in tumors using next-generation sequencing (NGS) among other techniques. For advanced tumors, cfDNA is variable with some tumor types such as pancreatic, ovarian, colorectal, breast, bladder, esophageal, melanoma, and hepatocellular carcinoma expressing higher percentages of cfDNA while others, such as brain, renal, prostate, and thyroid cancers having detectable circulating DNA in less than 50% of patients [9].” (Chae et al 2016).

“ctDNA monitoring may have clinical utility throughout the course of disease, from prediagnosis to advanced disease, and in the setting of surveillance as well as that of initial diagnosis. These evolving areas require further prospective study before becoming part of routine clinical practice;” (Komatsubara, K. M., & Sacher, A. G., 2017).

American College of pathologist says: “The clinical use of the liquid biopsy has significantly increased since 2014, when the first commercially available multigene liquid biopsy platform became available. Several assays are commercially available and FDA-approved, and some are considered as sufficient for treatment eligibility by insurance companies. For example, in 2016 the FDA approved the cobas® EGFR Mutation Test v2 to determine the eligibility of non-small cell lung cancer patients to receive certain EGFR tyrosine kinase inhibitors [7]. Adoption of the liquid biopsy to exclude patients from targeted therapy has seen much slower clinical adoption, mostly due to concerns for false negatives and generally accessible tumor tissue 3. Increasing clinical utilization has also been driven by patients and physicians wanting to identify targetable mutations for off-label use or clinical trial enrollment.

Emerging uses for liquid biopsies include their use as a complement to tissue biopsy mutational profiling, assessing treatment response, residual disease monitoring, detection of disease recurrence, and monitoring for emergence of resistance mutations”.

Tumor molecular profiling of NSCLC patients using next generation sequencing,  Oncology Reports December 2017 Volume 38 Issue 6

Diaz LA Jr, Bardelli A. Liquid Biopsies: Genotyping Circulating Tumor DNA. J Clin Oncol 2014 Feb 20; 32(6):579-86.

Liquid biopsy as per NCCN that indicates cfDNA can be used in specific circumstances if 1) pt is not medically fit for invasive tissue sampling or 2) there is insufficient tissue for molecular analysis.. Recent data suggest that plasma cell free /circulating tumor DNA testing can be used to identify EGFR, ALK and other oncogenic biomarkers that would not otherwise be identified in pts with metastatic NSCLC.

NCCNV3.2021 MS-13

https://www.cap.org/member-resources/articles/the-liquid-biopsy, Accessed 10/7/2021