Medical Policy

 

Subject: Circulating Tumor DNA Testing for Cancer (Liquid Biopsy)
Document #: GENE.00049 Publish Date:    08/29/2018
Status: New Last Review Date:    07/26/2018

Description/Scope

This document addresses cell-free circulating tumor DNA (ctDNA) testing, from a blood sample, as an alternative to tissue biopsy in the diagnosis of cancer and for clinical response to targeted agents of cancer treatment. These tests are also known as liquid biopsies. Examples of these tests include, but are not limited to:

Note: This document does not address circulating tumor cell (CTC) testing. For more information on CTC tests, please see the following:

Note: This document does not address single-gene EGFR testing, such as the cobas EGFR Mutation v2 test. For more information on EGFR tests, please see the following:

Note: For more information on related topics, please see the following:

Position Statement

Investigational and Not Medically Necessary:

The use of a circulating tumor DNA (ctDNA) test for the diagnosis or treatment of cancer is considered investigational and not medically necessary for all indications.

Rationale

According to the American Society of Clinical Oncology (ASCO), the significance of ctDNA tests are determined by assessing analytical validity (the test can accurately and reliably detect a biomarker), clinical validity (the test can detect the presence or absence of cancer), and clinical utility (the test can improve the outcomes of individuals with cancer). Even though several biomarkers have been shown to be useful for targeting and treating cancer, it cannot be assumed ctDNA tests that look for these biomarkers are automatically valid. Each ctDNA test must demonstrate accuracy, as compared to a tissue biopsy, before it can be used to make clinical decisions.

In a single-center observational study, Thompson and colleagues (2016) examined the concordance between tissue biopsy samples and Guardant360 blood samples for individuals with non-small cell lung cancer (NSCLC). A total of 102 subjects with a diagnosis of NSCLC or suspected NSCLC were included in the study. Tissue samples (n=50) were processed using the Illumina TruSeq Amplicon 47 gene cancer panel (n=38) or the 20 gene Penn Precision Panel (n=12). For the 50 subjects who had both blood and tissue tests, the overall concordance was 60%. For EGFR mutations, the overall concordance was 79%. The authors concluded that ctDNA testing has potential for real-time molecular monitoring for individuals with advanced cancer. Several studies have also compared Guardant360 to tissue-based broad molecular profile tests with similar or mixed conclusions (Chae, 2016; Hahn, 2017; Pishvaian, 2016; Sandulache, 2017; Schwaederle, 2016; Schwaederle, 2017; Villaflor, 2016; Yang, 2017). These studies were limited by small sample sizes, qualitative methods, or imperfect comparators; researchers stated the need for well-designed, prospective studies.

McCoach and colleagues (2018) performed an industry-supported retrospective cohort study to determine the clinical utility of Guardant360 for detecting anaplastic lymphoma kinase (ALK) fusions in NSCLC during diagnosis or during treatment with ALK inhibitors. The researchers included 88 subjects with 96 plasma-detected ALK fusions from the Guardant360 de-identified database. Subjects were separated into 4 cohorts: cohort 1 (n=42) contained subjects with a newly discovered ALK fusion, cohort 2 (n=31) contained subjects with a known or presumed ALK fusion and whose cell-free DNA (cfDNA) was obtained at progression, cohort 3 (n=13) contained subjects without additional clinical information, and cohort 4 (n=6) contained subjects who had been treated with anti-EGFR targeted therapy and found to have an ALK fusion by cfDNA. In cohort 1, the Guardant360 test found an ALK fusion in 16 subjects who had been reported as tissue-negative or tissue insufficient. Of the 42 subjects in the cohort, 10 had tissue samples available (5 ALK-positive, 5 ALK-negative), 11 had insufficient samples, and 21 did not have ALK information available. For the 5 subjects who were identified by Guardant360 as ALK-positive despite negative tissue biopsies, 3 eventually responded to ALK inhibitor therapy while clinical data was not available for the other 2 subjects. For cohort 2, 16 samples contained 1-3 ALK resistant mutations. For 5 samples, an ALK kinase domain mutation was identified in cfDNA despite the ALK fusion not detected in cfDNA and the prior tissue sample showing an ALK fusion. For cohort 3, the clinical status was unknown and no resistance mutations or bypass pathways were identified. For cohort 4, 6 subjects were found to have ALK fusions. The authors concluded that cfDNA NGS testing is an “additional tool” for detecting alterations, resistance mutations, and bypass pathways. Limitations of the study included the retrospective design and lack of clinical data for some subjects. The authors noted that tissue evaluation was at the providers’ discretion and the testing method was not available for all subjects. Furthermore, no sensitivity or specificity information was provided.

In an industry-supported study, Murray and colleagues (2017) investigated the analytical and clinical validity of the Colvera plasma test for the detection of methylated BCAT1 and IKZF1 in individuals with colorectal cancer. The researchers randomized 264 plasma samples and 120 buffer samples, divided the samples into 8 batches of 48, and processed the samples over 8 days using 2 equipment lines. Clinical validity was analyzed by using Colvera on 222 archived plasma samples (n=26 with known colorectal cancer) from individuals who were scheduled for colonoscopy as part of a previous trial (Pedersen, 2015). The researchers found that the limit of detection (LOD) was 12.6 pg/ml (95% confidence interval [CI], 8.6 to 23.9), the equivalent of 2 diploid genomes/ml of plasma. Colvera tested positive for 19/26 known cancer cases for an agreement of 73% (95% CI, 52% to 88%). For the 196 nonneoplastic subjects, Colvera had an agreement of 89% (95% CI, 84% to 93%). Total agreement was 87% (194/222; 95% CI, 82% to 91%). The researchers concluded that Colvera is suitable for its intended use. Limitations of the study included a small sample size.

CancerSEEK (Johns Hopkins Kimmel Cancer Center, Baltimore, MD) is a liquid biopsy test that is in research and development and not commercially available at this time. Cohen and colleagues (2018) developed CancerSEEK, a genetic alteration and protein biomarker assay, to detect early cancers and reveal the origin of the cancer. The researchers used CancerSEEK to evaluate 1005 subjects already diagnosed with stage I-III cancers of the ovary, liver, stomach, pancreas, esophagus, colorectum, lung, or breast. A control cohort consisted of 812 subjects with no known history of cancer. The researchers found that CancerSEEK had a median sensitivity of 70% and a specificity greater than 99%. In the healthy cohort, 7 subjects tested false-positive with CancerSEEK. The researchers compared CancerSEEK to tissue samples for 153 subjects and found that the mutation in the plasma sample was identical to the mutation in the tumor for 138 subjects (90%). The researchers used supervised machine learning to examine CancerSEEK’s ability to find the origin of cancer. The test was able to localize the origin of the cancer to two anatomic sites in a median of 83% of subjects and to a single organ in a median of 63% of subjects. While the results for CancerSEEK are promising, the researchers state that “to actually establish the clinical utility of CancerSEEK and to demonstrate that it can save lives, prospective studies of all incident cancer types in a large population will be required.”

There is a paucity of published peer-reviewed literature, especially large-scale, high-quality prospective randomized trials, which determine the validity and utility of these tests compared to traditional pathologic examination or established U.S. Food and Drug Administration (FDA)-approved tissue-based biomarker tests. In addition, there is insufficient evidence that these tests improve health outcomes.

Other Considerations

In a joint-review analysis on circulating tumor DNA (Merker, 2018), ASCO and the College of American Pathologists (CAP) state:

The 2018 National Comprehensive Cancer Network (NCCN) guidelines on non-small cell lung cancer state:

Data suggest that plasma genotyping (also known as liquid biopsy or plasma biopsy) may be considered instead of tissue biopsy to detect whether patients have T790M; however, if the plasma biopsy is negative, then tissue biopsy is recommended if feasible.

A joint guideline (Lindeman, 2018), Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment with Targeted Tyrosine Kinase Inhibitors, from the CAP, International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) states the following:

Background/Overview

The American Cancer Society estimates there will be 1,735,350 new cancer diagnoses and 609,640 cancer-related deaths in 2018. Cancer develops from genetic alterations in DNA that affect the way cells grow and divide. A tissue biopsy is the gold standard for detecting DNA alterations that can be used to identify cancer, determine treatment options, or evaluate responsiveness to treatment. Tissue biopsies have several disadvantages: the biopsy procedure may be painful, such as the insertion of a long needle or a surgical procedure; the retrieved tissue may be too small for analysis; or an individual may not be able to physically tolerate the procedure. In addition, because tissue biopsies only represent cellular samples from parts of a tumor, important diagnostic data could be missed (Weber, 2014).

Liquid biopsy is proposed as a less-invasive method for cancer identification, surveillance, and treatment guidance. The National Cancer Institute (NIH) defines liquid biopsy as “a test done on a sample of blood to look for cancer cells from a tumor that are circulating in the blood or for pieces of DNA from tumor cells that are in the blood.” ctDNA tests detect small fragments of mutated DNA that are released from tumors into blood, presumably by apoptosis and/or necrosis. Some ctDNA liquid biopsy tests are targeted for specific gene mutations. For example, in the instance of non-small cell lung cancer, a targeted liquid biopsy may be used to identify the presence of the EGFR mutation and determine if individuals may benefit from kinase inhibitor medication. Other liquid biopsy tests analyze multiple biomarkers and are purported to detect various cancers or treatments (Perakis, 2017).

There are several limitations of liquid biopsies. Many cancers do not have specific DNA mutations that can be identified and, when present, can be different in individuals with the same cancer. The DNA found in the fluid sample may not fully represent the tumor and mislead treatment decisions. The mutations found may not be “driver” mutations and may not provide useful information about the cancer. Furthermore, liquid biopsies can test positive for cancer when no cancer is present (false-positive) or test negative when cancer is present (false-negative). Because cancer cells release more mutated DNA fragments in later cancer stages, the test may not identify early cancer. Likewise, a liquid biopsy can detect cancerous cells that may never actually cause harm, leading to overtreatment (NIH, 2018). While liquid biopsies are promising, a great deal of research is still needed to determine if these tests improve outcomes for individuals with cancer.

Liquid biopsies are regulated by the Clinical Laboratory Improvement Amendments (CLIA) program, which oversees and certifies the laboratories conducting FDA-approved and non-FDA approved tests. In vitro diagnostic liquid biopsies, tests that are manufactured and then commercially sold to multiple labs, are also regulated by the FDA and must meet premarket review requirements. Liquid biopsies that are considered laboratory determined tests (LDTs), tests manufactured and performed in the same CLIA laboratory, have not thought to be subject to FDA regulations. However, in 1976, the FDA was given authority to regulate all in vitro diagnostics as devices. Because LDTs were not complex during that time, the FDA did not enforce premarket review and other requirements. As LDTs have grown more complex, the FDA has taken a renewed interest in overseeing LDTs to ensure public health and safety. On January 13, 2017, the FDA issued a discussion paper on LDTs but has not released an enforceable position at this time (FDA, 2018).

In 2012, the Institute of Medicine released recommendations on genomic-based test development and evaluation. They stated that genomic tests should be designed and properly validated in a CLIA-certified lab, and intended use of the tests, including LDTs, should be discussed with the FDA before validation studies begin. In addition, the authors stated the following:

Of note, FDA review of a biomarker test has been focused principally on analytical and clinical/biological validity, but not on demonstration of clinical utility…Therefore, FDA approval or clearance does not necessarily imply that the test improves clinical outcomes or should be used for patient management. LDTs performed in CLIA-certified laboratories also do not require evidence of clinical utility; only analytical and clinical validity of the test must be demonstrated prior to clinical use.

On March 16, 2018, the Centers for Medicare and Medicaid Services (CMS) approved NGS-based in vitro companion diagnostic laboratory tests for national coverage after an FDA-CMS parallel review. In the decision memo they state that “at this time, liquid-based multi-gene sequencing panel tests are left to contractor discretion if certain patient criteria are met.”

Definitions

Circulating tumor DNA (ctDNA): Fragments of DNA that are released from a tumor and migrate into bodily fluids, such as blood plasma.

Cell-free DNA (cfDNA): DNA that is circulating freely in body fluids, such as blood plasma, and is released from all types of cells.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
For the following procedure codes; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

CPT

 

81479

Unlisted molecular pathology procedure [when specified as a liquid biopsy using plasma specimen]

 

 

ICD-10 Diagnosis

 

 

All diagnoses

References

Peer Reviewed Publications:

  1. Chae YK, Davis AA, Benedito A, et al. Concordance between genomic alterations assessed by next-generation sequencing in tumor tissue or circulating cell-free DNA. Oncotarget. 2016; 7(40):65364–65373.
  2. Cohen JD, Li L, Wang Y, et al. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science. 2018; 359(6378):926-930.
  3. Hahn AW, Gill DM, Maughan B, et al. Correlation of genomic alterations assessed by next-generation sequencing (NGS) of tumor tissue DNA and circulating tumor DNA (ctDNA) in metastatic renal cell carcinoma (mRCC): potential clinical implications. Oncotarget. 2017; 8(20):33614–33620.
  4. McCoach CE, Blakely CM, Banks KC, et al. Clinical utility of cell-free DNA for the detection of ALK fusions and genomic mechanisms of ALK inhibitor resistance in non-small cell lung cancer. Clin Cancer Res. 2018; 24(12):2758-2770.
  5. Murray DH, Rohan TB, Gaur S, et al. Validation of a circulating tumor-derived DNA blood test for detection of methylated BCAT1 and IKZF1 DNA. J Appl Lab Med. 2017; 2(2)165-175.
  6. Pedersen SK, Symonds EL, Baker RT, et al. Evaluation of an assay for methylated BCAT1 and IKZF1 in plasma for detection of colorectal neoplasia. BMC Cancer. 2015; 15:654.
  7. Perakis S and Speicher MR. Emerging concepts in liquid biopsies. BMC Med. 2017; 15(1):75.
  8. Pishvaian MJ, Bender RJ, Matrisian LM, et al. A pilot study evaluating concordance between blood-based and patient-matched tumor molecular testing within pancreatic cancer patients participating in the Know Your Tumor (KYT) initiative. Oncotarget. 2017; 8(48):83446–83456.
  9. Sandulache VC, Williams MD, Lai SY, et al. Real-time genomic characterization utilizing circulating cell-free DNA in patients with anaplastic thyroid carcinoma. Thyroid. 2017; 27(1):81-87.
  10. Schwaederle M, Husain H, Fanta PT, et al. Use of liquid biopsies in clinical oncology: pilot experience in 168 patients. Clin Cancer Res. 2016; 22(22):5497-5505.
  11. Schwaederle M, Patel SP, Husain H, et al. Utility of genomic assessment of blood-derived circulating tumor DNA (ctDNA) in patients with advanced lung adenocarcinoma. Clin Cancer Res. 2017; 23(17):5101-5111.
  12. Tan G, Chu C, Gui X, et al. The prognostic value of circulating cell-free DNA in breast cancer: A meta-analysis. Medicine. 2018; 97(13):e0197.
  13. Villaflor V, Won B, Nagy R, et al. Biopsy-free circulating tumor DNA assay identifies actionable mutations in lung cancer. Oncotarget. 2016; 7(41):66880–66891.
  14. Yang M, Topaloglu U, Petty WJ, et al. Circulating mutational portrait of cancer: manifestation of aggressive clonal events in both early and late stages. J Hematol Oncol. 2017; 10(1):100.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Centers for Medicare and Medicaid Services (CMS). Decision memo for next-generation sequencing (NGS) for Medicare beneficiaries with advanced cancer. CAG-00450N. March 16, 2018. Available at: https://www.cms.gov/medicare-coverage-database/‌‌details/nca-decision-memo.aspx?NCAId=290&SearchType‌=Advanced&CoverageSelection. Accessed on June 22, 2018.
  2. Institute of Medicine. Evolution of translational omics: lessons learned and the path forward. Washington (DC): National Academies Press (US). 2012. Available at: https://www.ncbi.nlm.nih.gov/books/NBK202168/. Accessed on July 7, 2018.
  3. Lindeman NI, Cagle PT, Aisner DL, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: Guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018; 142(3):321-346.
  4. NCCN Clinical Practice Guidelines in Oncology®. ©2018 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http//www.nccn.org/index.asp. Accessed on June 22, 2018.
    • Non-Small-Cell Lung Cancer (V.4.2018). Revised April 26, 2018.
  5. Merker JD, Oxnard GR, Compton C, et al. Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists joint review. J Clin Oncol. 2018 Mar 5. Available at: http://ascopubs.org/doi/pdfdirect/10.1200/JCO.2017.76.8671. Accessed on June 22, 2018.
  6. U.S. Food and Drug Administration. Laboratory Developed Tests. Rockville, MD: FDA. March 26, 2018. Available at: https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/‌InVitroDiagnostics/‌LaboratoryDevelopedTests/default.htm. Accessed on June 22, 2018.
Websites for Additional Information
  1. American Cancer Society. Available at: http://www.cancer.org/. Accessed on June 22, 2018.
  2. National Cancer Institute. Liquid biopsy: using DNA in blood to detect, track, and treat cancer. November 8, 2017. Available at: https://www.cancer.gov/news-events/cancer-currents-blog/2017/liquid-biopsy-detects-treats-cancer. Accessed on June 22, 2018.
Index

CancerIntercept
CancerSEEK
Cell-Free DNA (cfDNA)
CellMax-LBx
Circulating Tumor DNA (ctDNA)
Circulogene Theranostics
ClearID
Colvera
FoundationACT
GeneStrat
Guardant360
Liquid Biopsy
LiquidGx
OncoBEAM
Oncotype SEQ
PlasmaSelect-R 64
Target Selector

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

New

07/26/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

New

07/18/2018

Hematology/Oncology Subcommittee review. Initial document development.