mp-711
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Plasma-Based Proteomic Screening of Pulmonary Nodules

Policy Number: MP-711

Latest Review Date: June 2020

Category: Laboratory

Policy Grade: B

POLICY:

Plasma-based proteomic screening including but not limited to Xpresys® Lung and Xpresys® Lung 2 (BDX-XL2) in patients with undiagnosed pulmonary nodules detected by computed tomography is considered not medically necessary and investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

Plasma-based proteomic screening is a test available in the diagnostic workup of pulmonary nodules. To rule out malignancy, invasive diagnostic procedures such as computed tomography (CT)-guided biopsies, bronchoscopies, or video-assisted thoracoscopic procedures are often required, but each carry procedure-related complications ranging from post procedure pain to pneumothorax. These type 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 (e.g., size, shape, density) and patient factors (e.g., 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 forgo 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.

Xpresys Lung and BDX-XL2 are 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 role of the test is to aid physicians in differentiating likely benign versus likely malignant nodules. If the test yields a likely benign result, patients may choose active surveillance via serial CT scans to monitor the pulmonary nodule. If the test yields a likely malignant result, invasive diagnostic procedures would be indicated. The test is therefore only used in the management of pulmonary nodules to rule in or out invasive diagnostic procedures and does not diagnose lung cancer.

KEY POINTS:

This evidence review has been updated regularly with searches of the PubMed database. The most recent literature update was performed through March 9, 2020.

Summary of Evidence

For individuals with undiagnosed pulmonary nodules detected by computed tomography (CT) who receive plasma-based proteomic screening, the evidence includes prospective cohort 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 two versions of a proteomic classifier. This classifier has undergone substantial evolution, from a 13 protein assay to a two protein assay integrated with clinical factors. Because of this evolution, the most relevant studies are with the most recent version two. One validation study on the version two 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 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. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

American College of Chest Physicians

The American College of Chest Physicians (2013) has published evidence-based clinical practice guidelines on the diagnosis and management of lung cancer, including pulmonary nodules, which is discussed in the patient population parameters in the Plasma-Based Proteomic Screening of Pulmonary Nodules section.

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

Xpresys Lung, Xpresys Lung 2, BDX-XL2, Biodesix, Integrated Diagnostics, Proteomics, Pulmonary Nodules

APPROVED BY GOVERNING BODIES:

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 (BDX-XL2 (Integrated Diagnostics [Indi], purchased by Biodesix) is available under the auspices of CLIA. Laboratories that offer laboratory-developed tests must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING:

CPT Codes:

83520

Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified

84999

Unlisted chemistry procedure.

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

REFERENCES:

  1. Detterbeck FC, Lewis SZ, Diekemper R, et al. Executive Summary: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. May 2013; 143(5 Suppl): 7S-37S.
  2. Kuang, MM, Tao, XX, Peng, YY, Zhang, WW, Pan, YY, Cheng, LL, Yuan, CC, Zhao, YY, Mao, HH, Zhuge, LL, Zhou, ZZ, Chen, HH, Sun, YY. Proteomic analysis of plasma exosomes to differentiate malignant from benign pulmonary nodules. Clin Proteomics, 2019 Feb 9; 16:5.
  3. Li XJ, Hayward C, Fong PY, et al. A blood-based proteomic classifier for the molecular characterization of pulmonary nodules. Sci Transl Med. Oct 16 2013; 5(207):207ra142.
  4. Li XJ, Lee LW, Hayward C, et al. An integrated quantification method to increase the precision, robustness, and resolution of protein measurement in human plasma samples. Clin Proteomics. 2015; 12(1):3.
  5. Martínez-Terroba, EE, Behrens, CC, de Miguel, FF, Agorreta, JJ, Monsó, EE, Millares, LL, Sainz, CC, Mesa-Guzman, MM, Pérez-Gracia, JJ, Lozano, MM, Zulueta, JJ, Pio, RR, Wistuba, II, Montuenga, LL, Pajares, MM. A novel protein-based prognostic signature improves risk stratification to guide clinical management in early-stage lung adenocarcinoma patients. J. Pathol., 2018 May 15; 245(4).
  6. Mazzone PJ, Sears CR, Arenberg DA, et al. Evaluating Molecular Biomarkers for the Early Detection of Lung Cancer: When Is a Biomarker Ready for Clinical Use? An Official American Thoracic Society Policy Statement. Am J Respir Crit Care Med. Oct 01 2017; 196(7): e15-e29.
  7. Pecot CV, Li M, Zhang XJ, et al. Added value of a serum proteomic signature in the diagnostic evaluation of lung nodules. Cancer Epidemiol Biomarkers Prev. May 2012; 21(5):786-792.
  8. Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. May 2013; 143(5 Suppl): e142Se165S.
  9. Silvestri, GG, Tanner, NN, et al. Assessment of Plasma Proteomics Biomarker's Ability to Distinguish Benign From Malignant Lung Nodules: Results of the PANOPTIC (Pulmonary Nodule Plasma Proteomic Classifier) Trial. Chest, 2018 Mar 3; 154(3).
  10. Vachani A, Hammoud Z, Springmeyer S, et al. Clinical utility of a plasma protein classifier for indeterminate lung nodules. Lung. Dec 2015; 193(6):1023-1027.
  11. Vachani A, Pass HI, Rom WN, et al. Validation of a multiprotein plasma classifier to identify benign lung nodules. J Thorac Oncol. Apr 2015; 10(4):629-637.

POLICY HISTORY:

Medical Policy Group, February 2020 (9): Individual policy created with full literature review for plasma proteomic screening of pulmonary nodules. Pulling previous applicable information from medical policy #644. No change to policy statement – still considered investigational.

Medical Policy Panel, May 2020

Medical Policy Group, June 2020 (9): 2020 Updates to Key Points, Description, References. No change to policy statement.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.