Molecular Testing in the Management of Pulmonary Nodules

POLICY NUMBER

A.2.04.142

DESCRIPTION

Plasma-based proteomic screening and gene expression profiling of bronchial brushing are molecular tests available in the diagnostic workup of pulmonary nodules. To rule out malignancy, invasive diagnostic procedures such as computed tomography-guided biopsies, bronchoscopies, or video-assisted thoracoscopic procedures are often required, but each carries procedure-related complications ranging from postprocedure pain to pneumothorax. Molecular diagnostic tests have been proposed to aid in risk-stratifying patients to eliminate or necessitate the need for subsequent invasive diagnostic procedures.

Pulmonary Nodules

Pulmonary nodules are a common clinical problem that may be found incidentally on a chest x-ray or computed tomography (CT) scan or during lung cancer screening studies of smokers. The primary question after the detection of a pulmonary nodule is the probability of malignancy, with subsequent management of the nodule based on various factors such as the radiographic characteristics of the nodules (eg, size, shape, density) and patient factors (eg, age, smoking history, previous cancer history, family history, environmental/occupational exposures). The key challenge in the diagnostic workup for pulmonary nodules is appropriately ruling in patients for invasive diagnostic procedures and ruling out patients who should forego invasive diagnostic procedures. However, due to the low positive predictive value of pulmonary nodules detected radiographically, many unnecessary invasive diagnostic procedures and/or surgeries are performed to confirm or eliminate the diagnosis of lung cancer.

Proteomics

Proteomics is the study of the structure and function of proteins. The study of the concentration, structure, and other characteristics of proteins in various bodily tissues, fluids, and other materials has been proposed as a method to identify and manage various diseases, including cancer. In proteomics, multiple test methods are used to study proteins. Immunoassays use antibodies to detect the concentration and/or structure of proteins. Mass spectrometry is an analytic technique that ionizes proteins into smaller fragments and determines mass and composition to identify and characterize them.

Plasma-Based Proteomic Screening for Pulmonary Nodules

Plasma-based proteomic screening has been investigated to risk-stratify pulmonary nodules as likely benign to increase the number of patients who undergo serial CT scans of their nodules (active surveillance), instead of invasive procedures such as CT-guided biopsy or surgery. Additionally, proteomic testing may also determine a likely malignancy in clinically low-risk or intermediate-risk pulmonary nodules, thereby permitting earlier detection in a subset of patients.

Nodify XL2 (BDX-XL2) is a plasma-based proteomic screening test that measures the relative abundance of proteins from multiple disease pathways associated with lung cancer using an analytic technique called multiple reaction monitoring mass spectroscopy. The test helps physicians identify lung nodules that are likely benign or at lower risk of cancer. If the test yields a "likely benign" or "reduced risk" result, patients may choose active surveillance via serial CT scans to monitor the pulmonary nodule. Earlier generations of the Nodify XL2 test include Xpresys Lung® and Xpresys Lung 2®.

Nodify CDT® is a proteomic test that uses multi-analyte immunoassay technology to measure autoantibodies associated with tumor antigens. The test helps physicians identify lung nodules that are likely malignant or at higher risk of cancer. Patients with a "high level" Nodify CDT test result have a higher risk of malignancy than predicted by clinical factors alone; invasive diagnostic procedures would be indicated in these cases.

The Nodify XL2 and Nodify CDT tests are therefore only used in the management of pulmonary nodules to rule out or rule in invasive diagnostic procedures; they do not diagnose lung cancer. These tests are offered together as Biodesix’s Nodify Lung® testing strategy, but physicians may also choose to order each test independently.

REVEAL Lung Nodule Characterization (MagArray) is a plasma-protein biomarker test that may aid clinicians in characterizing indeterminate pulmonary nodules (4 to 30 mm) in current smokers 25 years of age and older. The test is based on a multianalyte assay with a proprietary algorithmic analysis using immunoassay, microarray, and magnetic nanoparticle detection techniques to obtain laboratory data for calculation of the risk score for lung cancer. The REVEAL Lung Nodule Characterization is presented on a scale from 0 to 100 with a single cut point at 50. The score is based on the measurement of 3 clinical factors (age, sex, and nodule diameter) and 3 proteins (epidermal growth factor receptor, prosurfactant protein B, and tissue inhibitor of metalloproteinases 1) associated with the presence of lung cancer. It may aid a clinician in the decision to perform a biopsy or to consider routine monitoring. It is not intended as a screening or stand-alone diagnostic assay.

Gene Expression Profiling

Gene expression profiling is the measurement of the activity of genes within cells. Messenger RNA serves as the bridge between DNA and functional proteins. Multiple molecular techniques such as Northern blots, ribonuclease protection assay, in situ hybridization, spotted complementary DNA arrays, oligonucleotide arrays, reverse transcriptase polymerase chain reaction, and transcriptome sequencing are used in gene expression profiling. An important role of gene expression profiling in molecular diagnostics is to detect cancer-associated gene expression in clinical samples to assess the risk for malignancy.

Gene Expression Profiling for an Indeterminate Bronchoscopy Result

The first generation Percepta® Bronchial Genomic Classifier was a 23-gene, gene expression profiling test that analyzed genomic changes in the airways of current or former smokers to assess a patient’s risk of having lung cancer, without direct testing of a pulmonary nodule. This classifier was designed to be a “rule-out” test for intermediate-risk patients. The second generation Percepta Genomic Sequencing Classifier was developed to serve as both a “rule-in” test and a “rule-out” test, thereby increasing its potential utility in improving risk stratification. The test is indicated for current and former smokers following an indeterminate bronchoscopy result to determine the subsequent management of pulmonary nodules (eg, active surveillance or invasive diagnostic procedures), and does not diagnose lung cancer.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Xpresys Lung 2, now Nodify XL2 (BDX-XL2; Integrated Diagnostics [Indi], purchased by Biodesix); Nodify CDT (Biodesix); REVEAL Lung Nodule Characterization (MagArray); and Percepta Genomic Sequencing Classifier (Veracyte) are available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of these tests.

POLICY

Plasma-based proteomic screening, including but not limited to Nodify XL2® (BDX-XL2), Nodify CDT®, and REVEAL Lung Nodule Characterization (MagArray), in individuals with undiagnosed pulmonary nodules detected by computed tomography is considered investigational.

Gene expression profiling on bronchial brushings, including but not limited to the Percepta® Genomic Sequencing Classifier, in individuals with indeterminate bronchoscopy results from undiagnosed pulmonary nodules is considered investigational.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

07/20/2017: Approved by Medical Policy Advisory Committee.

06/14/2018: Policy reviewed; no changes.

11/15/2019: Policy updated to change the name of the proteomic plasma assay from "Xpresys® Lung" to "BDX-XL2."

06/19/2020: Policy description updated regarding tests. Policy statements unchanged.

07/30/2021: Policy reviewed; no changes.

06/17/2022: Policy description updated regarding screening tests. Policy statements updated to change "patients" to "individuals" and to include "Nodify XL2." Policy intent unchanged.

09/01/2023: Policy description updated regarding tests. Second policy statement revised to update the name of the test from "Percepta® Bronchial Genomic Classifier" to "Percepta® Genomic Sequencing Classifier."

07/15/2024: Policy description updated regarding a plasma-protein biomarker test for indeterminate pulmonary nodules. First investigational statement updated to include the following tests: Nodify CDT® and REVEAL Lung Nodule Characterization (MagArray).

08/11/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.142

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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