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Medical Policy Molecular Testing in the Management of Pulmonary Nodules Table of Contents • Policy: Commercial • Description • Information Pertaining to All Policies
• Authorization Information • Policy History • References
• Coding Information

Policy Number: 029 BCBSA Reference Number: 2.04.142 (For Plan internal use only) Related Policies
None Policy Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity

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 Percepta® Genomic Sequencing Classifier, in individuals with indeterminate bronchoscopy results from undiagnosed pulmonary nodules is considered INVESTIGATIONAL.

Prior Authorization Information
Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.
Outpatient • For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient.

Outpatient Commercial Managed Care (HMO and POS) This is not a covered service. Commercial PPO and Indemnity This is not a covered service. CPT Codes / HCPCS Codes / ICD Codes Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

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Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.

CPT Codes
The following CPT code is considered investigational for Commercial Members: Managed Care (HMO and POS), PPO, Indemnity, Medicare HMO Blue and Medicare PPO Blue:

CPT Codes CPT codes:

Code Description 0092U Oncology (lung), three protein biomarkers, immunoassay using magnetic nanosensor technology, plasma, algorithm reported as risk score for likelihood of malignancy

The following CPT code is considered investigational for Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity:

CPT Codes CPT codes:

Code Description 0080U Oncology (lung), mass spectrometric analysis of galectin-3-binding protein and scavenger receptor cysteine-rich type 1 protein M130, with five clinical risk factors (age, smoking status, nodule diameter, nodule-spiculation status and nodule location), utilizing plasma, algorithm reported as a categorical probability of malignancy

Description 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

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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 (GEP) 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 GEP. An important role of GEP 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, GEP 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.

Summary 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 carry 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.

Summary of Evidence

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For individuals with undiagnosed pulmonary nodules detected by computed tomography who receive plasma-based proteomic screening, the evidence includes prospective cohorts, retrospective studies, and prospective-retrospective studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, morbid events, hospitalizations, and resource utilization. Clinical validation studies were identified for 2 versions (Xpresys Lung, and Xpresys Lung version 2 [now Nodify XL2]) of a proteomic classifier and another lung nodule characterization test (REVEAL). Nodify XL2 classifier has undergone substantial evolution, from a 13-protein assay to a 2-protein assay integrated with clinical factors. Because of this evolution, the most relevant studies are with the most recent version 2 (Xpresys Lung version 2 [now Nodify XL2]). One validation study on version 2 has been identified. The classifier has been designed to have high specificity for malignant pulmonary nodules, and the validation study showed a specificity of 97% for patients with a low-to-moderate pretest probability (≤50%) of a malignant pulmonary nodule. The primary limitation of this study is that a high number of patients were excluded from the study due to incomplete clinical data or because they were subsequently determined to be outside of the intended use population. It is unclear if the intended use population was determined a priori. Validation in an independent sample in the intended use population is needed. No recent clinical validation studies were identified for the Nodify CDT test or the Nodify Lung testing strategy. The REVEAL validation study was a retrospective study that demonstrated use as a rule-out test in conjunction with the Veteran's Affairs (VA) Clinical Factors Model when the samples were considered inconclusive or intermediate risk by the VA model. The REVEAL model subsequently correctly identified 65% intermediate-risk samples as either low or high risk. The negative predictive value and sensitivity were both 94%. Limitations included a small sample size and use in conjunction with just 1 type of testing model. Validation in an independent sample in the intended use population with additional probability models is needed. Indirect evidence suggests that a proteomic classifier with a high negative predictive value has the potential to reduce the number of unnecessary invasive procedures to definitively diagnose benign disease versus malignancy. However, long-term follow-up data would be required to determine the survival outcomes in patients with a missed diagnosis of lung cancer at earlier, more treatable stages. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with undiagnosed pulmonary nodules following indeterminate bronchoscopy results for suspected lung cancer who receive gene expression profiling of bronchial brushings, the evidence includes multicenter prospective studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, morbid events, hospitalizations, and resource utilization. A 3-cohort, prospective, multicenter study validated the second generation Percepta Genomic Sequencing Classifier (GSC) test in an independent sample set, showing high sensitivity for the rule-out portion of the classifier and high specificity for the rule-in portion of the classifier. For intermediate pretest risk patients with an inconclusive bronchoscopy, Percepta GSC can down-classify the risk of primary lung cancer to low with a 91% negative predictive value, or up-classify the risk to high with a 65% positive predictive value. Further assessment of clinical utility is warranted. Also, where the test would fall in the clinical pathway (ie, other than indeterminate bronchoscopy) is uncertain. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Policy History Date Action 7/2025 Annual policy review. Policy updated with literature review through March 27, 2025; no references added. Minor editorial refinements to policy statements, intent unchanged. 10/2024 Annual policy review. Policy updated with literature review through March 27, 2024; references added. Policy statements updated to include the REVEAL Lung Nodule Characterization test. Effective 10/1/2024. 7/2023 Annual policy review. Minor editorial refinements to policy statements, intent unchanged. 7/2022 Annual policy review. References added. Policy statements unchanged. 6/2021 Annual policy review. Description, summary, and references updated. Policy statements unchanged.

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1/2021 Medicare information removed. See MP #132 Medicare Advantage Management for local coverage determination and national coverage determination reference.
10/2019 Clarified coding information. 7/2019 Annual review. Name of proteomic plasma assay changed from Xpresys® Lung to BDX-XL2. Clarified coding information. 1/2019 Clarified coding information. 11/2018 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 10/2017 New medical policy describing investigational indications. Effective 10/1/2017. Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines References

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