Medical Policy

This document addresses the use of selected protein biomarker algorithmic assays, which involve the qualitative or quantitative analysis of protein constituents in a biological sample that are reported as a predictive, diagnostic or prognostic algorithmic result. Protein biomarker algorithmic assays are under investigation in certain tumors and for other applications such as predicting the likelihood of preterm delivery in pregnancy.

Note: Please see the following related documents for additional information on protein biomarker tests for specific indications:

• LAB.00033 Protein Biomarkers for the Screening, Detection and Management of Prostate Cancer
• LAB.00035 Multi-biomarker Disease Activity Blood Tests for Rheumatoid Arthritis
• LAB.00037 Serologic Testing for Biomarkers of Irritable Bowel Syndrome (IBS)
• LAB.00040 Serum Biomarker Tests for Risk of Preeclampsia
• LAB.00048 Pain Management Biomarker Analysis

Note: For a high-level overview of this document, please see “Summary for Members and Families” below. 

Investigational and Not Medically Necessary:

The following protein biomarker algorithmic assays are considered investigational and not medically necessary for all indications:

1. BDX-XL2 (Nodify XL2^®)
2. EarlyCDT^®-Lung test (Nodify CDT^®)
3. IMMray^® PanCan-d
4. LC-MS/MS Targeted Proteomic Assay
5. PreTRM^®
6. REVEAL Lung Nodule Characterization
7. Theralink^® Reverse Phase Protein Array
8. VeriStrat^®.

This document describes clinical studies and expert recommendations and explains whether certain blood tests that look at proteins in the blood to check for cancer, lung problems, or risk of early birth during pregnancy are clinically appropriate. The following summary does not replace the medical necessity criteria or other information in this document. The summary may not contain all of the relevant criteria or information. This summary is not medical advice. Please check with your healthcare provider for any advice about your health.

Key Information

Many blood tests look at proteins in the blood to try to answer a health question. EarlyCDT-Lung (Oncimmune Holdings plc, Nottingham, United Kingdom [UK]United Kingdom (UK)) checks for signs in the blood that may point to lung cancer. VeriStrat (Biodesix, Inc., Boulder, CO) is a blood test for people with lung cancer that tries to predict whether certain cancer treatments will work. Nodify XL2 (Biodesix, Inc., Boulder, CO) is a blood test for people who have a spot (called a nodule) found on a lung scan. PreTRM (Sera Prognostics, Inc., Salt Lake City, UT) is a blood test for pregnant people that tries to predict whether a baby might be born too early. IMMray PanCan-d (Immunovia, Inc., Marlborough, MA) is a blood test that tries to find pancreatic cancer early in people who are at high risk. Theralink Reverse Phase Protein Array (Theralink Technologies, Inc., Golden, CO) is a lab test that looks at protein activity in tumor samples. REVEAL Lung Nodule Characterization (formerly Integrated Diagnostics, Inc., Seattle, WA) was a blood test for lung nodules that is no longer offered. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) Targeted Proteomic Assay is a general type of lab method that measures specific proteins in the blood.

What the Studies Show

The largest study of EarlyCDT-Lung followed more than 12,000 people in Scotland for 5 years. People who got the blood test and then had follow-up lung scans had fewer deaths from lung cancer than people who did not get the test. However, the test missed most cancers, and only found about 1 in 5 cancers. A separate review by health experts in the UK found that the test’s ability to spot cancer was too low to know whether it helps save lives.

Studies of VeriStrat have shown that it can sort people with lung cancer into groups that may respond differently to treatment. However, a recent review of the research found that no protein-based blood test for lung cancer, including VeriStrat, is ready for routine use in treating people due to various concerns, including uncertainty about whether the test improves survival.

For PreTRM, the original study showed the test could predict early birth with moderate accuracy. However, when other researchers tested it in different groups of people around the world, the test worked less well. In some groups, it barely performed better than chance. A major medical group for pregnancy care, the American College of Obstetricians and Gynecologists (ACOG), does not recommend this test or any similar blood test for predicting early birth.

For Nodify XL2, a large study is underway but not yet finished. It is not clear at this time what benefit the use of this test may provide people with possible lung cancer.

For IMMray PanCan-d, one study has been completed, but the company is moving to a newer version of the test. There is currently not enough information available to understand what benefits the use of this new version of the test may provide.

For Theralink and REVEAL, there are currently no completed studies available. Thus, there is no information available to understand what benefits the use of these tests may provide.

No major medical group recommends any of these tests.

Is This Clinically Appropriate?

None of these blood tests are considered clinically appropriate at this time. The studies done so far do not show clearly enough that using them leads to better health. For some of the tests, the research is still in early stages. For others, the tests have been studied but did not show strong enough results to be recommended.

Why Are These Tests Not Clinically Appropriate?

Better studies are needed to know if these tests improve health. For EarlyCDT-Lung, the test misses most cancers and cannot be used on its own for screening. For VeriStrat, the proteins it measures are tied to general inflammation, not just to cancer, and more proof is needed to show it helps in care. For PreTRM, independent testing showed the test did not work as well as expected. For the other tests, there are either not enough studies, the studies are too small, or the tests are still being developed. It is also important to know that getting a test that has not been proven to work can sometimes cause harm. None of these tests have been approved or cleared by the U.S. Food and Drug Administration (FDA). They are all offered as lab-developed tests.

(Return to Description/Scope)

Summary

The protein biomarker algorithmic assays addressed in this document have been evaluated for multiple indications, including lung cancer screening and treatment selection, ovarian cancer risk assessment, pancreatic cancer early detection, and spontaneous preterm birth prediction. While several assays have demonstrated some degree of analytical validity, the clinical utility of these tests has not been established through prospective evidence demonstrating improved health outcomes in the intended populations. The largest randomized trial to date, examining an autoantibody-based lung cancer biomarker, showed a mortality signal favoring the biomarker-guided screening pathway, but the test’s low sensitivity limits its standalone application. No professional society guidelines have incorporated any of these tests into their recommendations. The evidence remains insufficient to establish that the use of these protein biomarker algorithmic assays leads to clinically meaningful changes in management that result in improved outcomes for the individuals tested.

Discussion

Ovarian Cancer

Proteomic approaches to ovarian cancer risk assessment have been under investigation since Petricoin and colleagues reported on the technical feasibility of protein biomarker screening using mass spectrometry-generated serum protein profiles from 50 individuals with and 50 individuals without ovarian cancer (Petricoin, 2002).

Lung Cancer

VeriStrat Test

The VeriStrat test (Biodesix, Inc., Boulder, CO) is a matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry-based serum proteomic assay that classifies individuals with non-small cell lung cancer (NSCLC) as “VeriStrat Good” (VS-G) or “VeriStrat Poor” (VS-P) based on eight spectral features. The test was initially developed to predict differential benefit from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor therapy in individuals with advanced NSCLC.

Carbone and colleagues reported the prognostic value of VeriStrat in a subpopulation of participants enrolled in the National Cancer Institute of Canada (NCIC) Clinical Trials Group BR.21 Phase III trial (Carbone, 2012). Among 441 participants tested, individuals classified as VS-G survived significantly longer than those classified as VS-P. For individuals classified as VS-G, the median survival was 10.5 months on erlotinib versus 6.6 months for placebo (p=0.002). For individuals classified as VS-P, there was no significant difference in the median survival between erlotinib and placebo (4 months vs. 3.1 months, p=0.11).

More recently, translational work by Koc and colleagues characterized the molecular basis of the VeriStrat test, identifying beta-2 microglobulin (B2M), C-reactive protein (CRP), and multiple proteoforms of serum amyloid A1, A2, and A4 (SAA1, SAA2, and SAA4) as the primary proteins measured by the assay (Koc, 2023). These are established acute phase reactants involved in systemic inflammation and cancer immunobiology, which provides a potential mechanistic explanation for VeriStrat’s observed correlations with treatment outcomes. However, the finding that VeriStrat’s signal is driven by general inflammatory markers rather than tumor-specific analytes raises questions about diagnostic specificity.

A systematic review of multi-omics approaches for predicting immune checkpoint inhibitor (ICI) response in NSCLC evaluated 9 proteomic studies using a standardized evidence rubric (Elayeh, 2025). A deep MALDI mass-spectral classifier (the VeriStrat platform) scored 13 of 14 points and demonstrated the ability to classify individuals as sensitive, intermediate, or resistant to ICI therapy in 2 independent validation cohorts, including 1 blinded validation cohort. However, the review concluded that “only a subset of biomarkers have reached consistent validation across independent cohorts, and none yet meet the threshold for routine clinical use.”

The INSIGHT observational study (NCT03289780), enrolling 5006 individuals with NSCLC across 42 sites, is evaluating the clinical effectiveness of VeriStrat for ICI treatment guidance. Results are pending, with primary completion anticipated in December 2025.

EarlyCDT-Lung test

The EarlyCDT-Lung test (Oncimmune Holdings plc, Nottingham, United Kingdom (UK)) is a blood-based assay that detects elevated levels of seven tumor-associated autoantibodies (p53, SOX-2, CAGE, NY-ESO-1, GBU 4-5, MAGE-A4, and HuD) generated in response to immune recognition of cancerous cells. These autoantibodies have been investigated as a potential early detection tool for lung cancer, either as a standalone risk classifier or as a complement to low-dose computed tomography (LDCT) screening.

The Early Detection of Cancer of the Lung Scotland (ECLS) trial (NCT01925625) is the only completed randomized controlled trial (RCT) of EarlyCDT-Lung. Sullivan and colleagues randomized 12,208 individuals aged 50 to 75 at high risk for lung cancer to either the EarlyCDT-Lung test or standard clinical care (Sullivan, 2025). In the intervention arm, test-positive individuals underwent LDCT screening. At 2 years, the primary end point showed a significant reduction in late-stage (III/IV) lung cancer presentation (adjusted hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.41 to 0.99). At 5 years, 326 lung cancers were detected (2.7% of enrollees), with 73 lung cancer deaths in the intervention arm and 90 in the control arm (adjusted HR for lung cancer mortality, 0.789; 95% CI, 0.636 to 0.978). Among individuals diagnosed with lung cancer within 2 years of randomization, the HR for all-cause mortality was 0.610 (95% CI, 0.398 to 0.934) and for lung cancer mortality was 0.598 (95% CI, 0.378 to 0.946). The investigators concluded that EarlyCDT-Lung “may have an important role in future lung cancer screening programmes” but acknowledged that the test’s low sensitivity “precludes its use as a sole screening method.”

Despite the mortality signal in the ECLS trial, the diagnostic accuracy of EarlyCDT-Lung remains a concern. An independent health technology assessment (HTA) commissioned by the UK National Institute for Health and Care Research (NIHR) conducted a systematic review and bivariate meta-analysis of 5 cohorts encompassing 695 individuals with pulmonary nodules (Duarte, 2022). The summary sensitivity was 20.2% (95% CI, 10.5% to 35.5%) at a specificity of 92.2% (95% CI, 86.2% to 95.8%). This sensitivity estimate was substantially lower than the manufacturer’s reported sensitivity of 41.3% at 90.6% specificity. The HTA concluded that “the evidence on EarlyCDT Lung among individuals with pulmonary nodules is insufficient to draw any firm conclusions as to its diagnostic accuracy or clinical or economic value” and noted that “poor diagnostic accuracy may mean that EarlyCDT Lung can add little when combined with existing approaches in the diagnostic pathway.” No economic evaluation was possible due to insufficient evidence.

Allen and colleagues examined longitudinal prediagnostic samples from 142 individuals who developed lung cancer during the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and 142 matched controls (Allen, 2025). Elevated autoantibodies were detectable a median of 4.2 years and up to 8.4 years before clinical presentation, demonstrating that the immune response to early malignancy can precede diagnosis by several years. However, panel sensitivity was only 26.1% (95% CI, 18.8% to 33.3%), lower than the 37.1% reported in clinical-use populations, and the cohort was entirely female and included approximately 20% never-smokers; neither characteristic represents the intended screening population.

A secondary analysis of the ECLS trial examined comorbidity burden and screening safety (Romeikat, 2025). Among 8494 individuals analyzed, 59.8% had at least 1 comorbidity at baseline. At 5-year follow-up, the incidence of newly discovered comorbidities did not differ significantly between the intervention and control arms (20.40% vs. 20.15%), suggesting that the biomarker-guided screening approach did not increase detection of incidental findings beyond what would occur through standard care.

The UK National Institute for Health and Care Excellence (NICE) independently reviewed EarlyCDT-Lung (HTG611, 2022) and concluded: “There is not enough evidence to recommend routine use of EarlyCDT Lung for assessing the risk of lung cancer in solid lung nodules.”

Nodify XL2 Test

The Nodify XL2 test (Biodesix, Inc., Boulder, CO), also known as BDX-XL2, is a plasma proteomic classifier designed to assist in distinguishing benign from malignant lung nodules in individuals undergoing evaluation for incidentally detected pulmonary nodules. The test combines protein expression data with clinical risk factors to generate a probability score.

The ORACLE trial (NCT04171492), a multicenter randomized controlled study of 2000 individuals, is evaluating the clinical utility of Nodify XL2 in incidentally discovered low- to moderate-risk lung nodules. This trial is active but not recruiting, with primary completion listed as December 2025 and study completion estimated for December 2026. A completed registry study (NCT03766958, n=842) evaluated the test’s performance in clinical settings.

No Food and Drug Administration (FDA)-labeled indications have been identified for Nodify XL2; it is offered as a laboratory-developed test (LDT) through the manufacturer’s Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Nationally recognized clinical practice guidelines, including the National Comprehensive Cancer Network (NCCN) Guidelines for Non-Small Cell Lung Cancer (Version 5.2026) and the NCCN Guidelines for Lung Cancer Screening (Version 1.2026), do not include Nodify XL2 or any blood-based proteomic classifier in their recommended evaluation algorithms for pulmonary nodules.

Pancreatic Cancer

IMMray PanCan-d test

IMMray PanCan-d (Immunovia, Inc., Marlborough, MA) is a blood-based laboratory-developed test intended for early detection of pancreatic ductal adenocarcinoma (PDAC) in high-risk individuals. Although a completed prospective multicenter study is listed for high-risk individuals with familial or hereditary risk factors, including familial pancreatic cancer and familial atypical mole malignant melanoma (FAMMM) syndrome (NCT03693378; planned n=1349), the available materials do not include published final results from that full prospective trial. Published evidence consists instead of a blinded validation study reporting that the assay distinguished stage I-II PDAC from high-risk individuals with 85% sensitivity and 98% specificity, and all-stage PDAC with 87% sensitivity and 98% specificity; however, the authors stated that clinical utility was not assessed and has not been established (Brand, 2022). No FDA clearance has been obtained.

Preterm Delivery

The PreTRM test uses a serum proteomic assay measuring the ratio of insulin-like growth factor-binding protein 4 (IBP4) to sex hormone-binding globulin (SHBG) to predict the risk of spontaneous preterm birth (sPTB) in pregnant individuals.

Saade and colleagues reported findings from the Proteomic Assessment of Preterm Risk (PAPR) study, in which 5501 pregnant individuals were enrolled and 217 experienced sPTB (Saade, 2016). The IBP4/SHBG predictor demonstrated an area under the receiver operating characteristic curve (AUC) of 0.75 in the total population. A secondary analysis by Burchard and colleagues found the AUC improved to 0.80 when pregnancies dated by last menstrual period alone were excluded (Burchard, 2022).

The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin No. 234 (2021) does not mention PreTRM and explicitly classifies serum biomarkers for preterm birth prediction as investigational, stating that “until the efficacy, predictive values, and cost-effectiveness of these modalities and applications are clearer, these emerging prediction methods should be considered investigational.” The only recommended prediction method with Level A evidence is serial endovaginal cervical length ultrasonography.

Independent validation by Luo and colleagues evaluated the IBP4/SHBG ratio (the PreTRM test) as a comparator in a multi-cohort study across 4 geographically and ethnically diverse populations (n=456) (Luo, 2026). PreTRM achieved AUCs of 0.68 (95% CI, 0.50 to 0.89) in an Alabama cohort, 0.77 (95% CI, 0.67 to 0.88) in a California cohort, 0.59 (95% CI, 0.52 to 0.65) in a Chinese cohort, and 0.61 (95% CI, 0.50 to 0.75) in a second Chinese cohort. Prevalence-adjusted positive predictive values ranged from 0% to 21%. Kaplan-Meier survival curves for time to delivery were not statistically significant for PreTRM in two of three validation sites. A novel three-protein panel, consisting of glutathione peroxidase 3 (GPX3), nidogen 1 (NID1), and pappalysin 2 (PAPPA2), consistently outperformed the IBP4/SHBG ratio across all cohorts.

Branch and colleagues published findings of an RCT evaluating the impact of PreTRM testing on birth outcomes in singleton pregnancies (Branch, 2023). The study included 1191 individuals with a mid-trimester ultrasound finding of a cervical length at least 2.5 cm who were at low risk for sPTB. Participants were randomized to PreTRM testing (n=595) or to no PreTRM testing (n=596). The PreTRM test was used to stratify participants as having an increased risk of sPTB (screen-positive, risk ≥ 14%) or lower risk of sPTB (screen-negative, risk < 14%). Screen-positive individuals were offered a risk reduction protocol including progesterone supplementation, cervical length surveillance, daily low-dose aspirin, and weekly review of symptoms. Data were not available for 10 participants; 1181 were included in the analysis. sPTB < 37 weeks occurred in 16 (2.7%) of screened and 21 (3.5%) of unscreened individuals; the difference in the rate of sPTB did not differ significantly between groups (p=0.413). There were also no differences between groups in neonatal secondary outcomes such as gestational age at delivery, rate of admission to the neonatal intensive care unit (NICU) or NICU length of stay. In this study, randomization to PreTRM testing and subsequent management based on PreTRM results did not improve birth outcomes.

The Prematurity Risk Assessment Combined with Clinical Interventions for Improving Neonatal Outcomes (PRIME) trial (NCT04301518) is a multicenter RCT conducted at 19 sites in the United States evaluating whether IBP4/SHBG screen-guided care improves neonatal outcomes (Iriye, 2026). A total of 5018 participants with singleton pregnancies at 18 to 20 weeks’ gestation underwent biomarker testing and were randomized to screen-guided care or routine care. In the screen-guided care arm, 23.5% (594/2526) were identified as higher risk and offered a bundled intervention consisting of daily vaginal progesterone, low-dose aspirin, and weekly telephonic nurse support. In the intent-to-treat population (n=4806), screen-guided care was associated with reduced composite neonatal morbidity (odds ratio [OR], 0.80; 95% CI, 0.66 to 0.96; p=0.015), shortened neonatal hospital stays (incidence rate ratio [IRR], 0.95; 95% CI, 0.92 to 0.98; p=0.004), and fewer NICU admissions (OR, 0.78; 95% CI, 0.65 to 0.93; p=0.006). The trial was halted for efficacy at an interim analysis. However, the open-label design, industry sponsorship (Sera Prognostics, Inc.), and bundled intervention preclude isolation of the test’s independent contribution to the observed outcomes. No professional society has incorporated the IBP4/SHBG test into clinical practice guidelines in response to the PRIME trial findings.

Other Tests

The Theralink Reverse Phase Protein Array (RPPA) (Theralink Technologies, Inc., Golden, CO) uses phosphoproteomics to characterize signaling pathway activation in solid tumors, particularly breast cancer. No registered clinical trials were identified for this test on ClinicalTrials.gov, and no published studies of clinical use are currently available.

The REVEAL Lung Nodule Characterization test (formerly offered by Integrated Diagnostics, Inc., Seattle, WA; subsequently acquired by Biodesix) was a protein-based LDT for assessing pulmonary nodule malignancy risk. No registered clinical trials were identified, and the test has been effectively replaced by the Nodify platform.
The liquid chromatography-tandem mass spectrometry (LC-MS/MS) Targeted Proteomic Assay is a mass spectrometry-based protein biomarker algorithmic assay for solid tumors. As with the other selected assays addressed in this document, clinical utility has not been established through prospective evidence demonstrating improved health outcomes.

Professional Society Guidelines and Health Technology Assessments

Nationally recognized clinical practice guidelines do not recommend any of the protein biomarker algorithmic assays addressed in this document. The NCCN Guidelines for Non-Small Cell Lung Cancer (Version 5.2026), Lung Cancer Screening (Version 1.2026), Ovarian Cancer (Version 2.2026), Breast Cancer (Version 2.2026), and additional NCCN disease-specific guidelines were reviewed, and none include or recommend any of the eight named assays. The American Cancer Society (ACS) lung cancer screening guideline (2024) recommends LDCT only, with no mention of blood-based biomarker tests (Wolf, 2024). The American College of Chest Physicians (CHEST) 2025 policy statement identifies molecular biomarkers only as future strategies “in various stages of development” that “require evaluation of clinical validity and usefulness” (Barta, 2025). NICE reviewed EarlyCDT-Lung (HTG611, 2022) and concluded there is insufficient evidence to recommend its routine use. NICE also reviewed the Risk of Ovarian Malignancy Algorithm (ROMA) and Overa for ovarian cancer (HTG453, 2017) and found insufficient evidence to recommend routine adoption. No relevant guidance on any of these assays was identified from the Agency for Healthcare Research and Quality (AHRQ), the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), the Substance Abuse and Mental Health Services Administration (SAMHSA), or the Department of Veterans Affairs/Department of Defense (VA/DoD) clinical practice guidelines.

Other Relevant Information

No FDA-labeled indications have been identified for the selected protein biomarker algorithmic assays addressed in this document. VeriStrat, EarlyCDT-Lung, Nodify XL2, PreTRM, IMMray PanCan-d, REVEAL, Theralink Reverse Phase Protein Array (RPPA), and the liquid chromatography-tandem mass spectrometry (LC-MS/MS) Targeted Proteomic Assay are all offered as LDTs through their respective manufacturers’ CLIA-certified laboratories. The Centers for Medicare and Medicaid Services (CMS) Local Coverage Determination (LCD) L35396 (Biomarkers for Oncology, Novitas Solutions) includes VeriStrat in its list of covered non-molecular assays for NSCLC; other tests in this document are not mentioned in the LCD.

Conclusion

At this time, there is insufficient evidence of an impact of the selected protein biomarker algorithmic tests addressed in this document on health outcomes in clinical practice. Further investigation into the possible impact of testing, such as decreased cancer-related deaths and other positive outcomes, is needed.

Proteins are the functional units of cells and represent the end product of the interactions among the underlying genes. A number of tests have been developed to provide a qualitative or quantitative analysis of protein constituents in a biological sample that are reported as a predictive, diagnostic or prognostic algorithmic result. Protein biomarkers represent objectively measured indicators of normal or disease processes or measures of response to therapy. Protein biomarker algorithmic assays may include demographic factors, including age, gender, or race, as biologically relevant, and can include a range of protein constituents.

While protein biomarker algorithmic assays have the potential to offer powerful predictive and diagnostic capabilities, many are not supported by high-quality evidence. In some cases, algorithms may effectively predict disease risk, but the result of testing does not ultimately alter care in a manner that improves net healthcare outcomes (sometimes because an effective treatment does not exist). Faulty algorithm-based laboratory tests may lead to individuals being over- or undertreated or incorrectly diagnosed, which can result in exposure to unnecessary or harmful treatments, inappropriate therapies, or delayed or missed effective therapies. Algorithm-based tests are laboratory-developed tests (LDTs), which are designed, manufactured and used within a single laboratory, and are generally not reviewed by the Food and Drug Administration (FDA). Development of an algorithm may be heavily dependent on the dataset used as part of test development/validation, and some clinical, racial, or sociodemographic characteristics found in the test dataset may influence the algorithm test results, leading to findings that are biased or not generalizable to all populations. In some cases, algorithms have the potential to systematically under- or over-represent risk associated with individuals who differ from those assessed in the original dataset, thereby leading to disparate treatment and healthcare outcomes. Finally, the formulas used to develop the algorithm are often proprietary, meaning that values assigned to each individual biomarker or calculations necessary to produce the final test result may not be publicly available or independently reproducible by other researchers.

Algorithm: A set of mathematical rules for solving complex problems with the aid of computer technology.

Biomarker: A biological characteristic that can be objectively measured and evaluated as an indicator of a normal or abnormal biological process or a response to a pharmacologic or therapeutic intervention.

Proteomics: The study of the structure and function of proteins.

Screening: Checking or testing for disease when there are no symptoms.

Serum: The clear portion of clotted blood.

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:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Allen J, Healey G, Macdonald I. Lung cancer associated autoantibody responses are detectable years before clinical presentation. PLoS One. 2025; 20(3):e0315220.
2. Barta JA, Arenberg D, Backhus L, et al. Components necessary for high-quality lung cancer screening: a 10-year update. Chest. 2025; 168(5):1257-1270.
3. Branch DW, VanBuren JM, Porter TF, et al. Prediction and prevention of preterm birth: a prospective, randomized intervention trial. Am J Perinatol. 2023; 40(10):1071-1080.
4. Brand RE, Persson J, Bratlie SO, et al. Detection of early-stage pancreatic ductal adenocarcinoma from blood samples: results of a multiplex biomarker signature validation study. Clin Transl Gastroenterol. 2022; 13(3):e00468.
5. Burchard J, Saade GR, Boggess KA, et al. Better estimation of spontaneous preterm birth prediction performance through improved gestational age dating. J Clin Med. 2022; 11(10):2885.
6. Carbone DP, Ding K, Roder H, et al. Prognostic and predictive role of the VeriStrat plasma test in patients with advanced non-small-cell lung cancer treated with erlotinib or placebo in the NCIC Clinical Trials Group BR.21 trial. J Thorac Oncol. 2012; 7(11):1653-1660.
7. Duarte A, Corbett M, Melton H, et al. EarlyCDT Lung blood test for risk classification of solid pulmonary nodules: systematic review and economic evaluation. Health Technol Assess. 2022; 26(49):1-184.
8. Elayeh E, Aleidi SM, Aboud O, et al. Integrated multi-omics approaches for predicting immune checkpoint inhibitor response in NSCLC: insights from genomics, proteomics, and metabolomics. Lung Cancer (Auckl). 2025; 16:167-198.
9. Iriye BK, O’Brien JM, Ennen CS, et al. Neonatal impact of maternal biomarker screening for risk of preterm birth with targeted interventions (PRIME): a multicenter, randomized, controlled trial. Pregnancy. 2026; 2(1):e70202.
10. Koc MA, Wiles TA, Weinhold DC, et al. Molecular and translational biology of the blood-based VeriStrat proteomic test used in cancer immunotherapy treatment guidance. J Mass Spectrom Adv Clin Lab. 2023; 30:51-60.
11. Luo Q, Wei J, Ding Y, et al. Early gestational prediction of spontaneous preterm birth using a validated three-protein serum biomarker panel. BMC Med. 2026; 24:138.
12. Petricoin EF, Ardekani AM, Hitt BA, et al. Use of proteomic patterns in serum to identify ovarian cancer. Lancet. 2002; 359(9306):572-577.
13. Romeikat NL, Sullivan F, Daly F, Kong W. The importance of comorbidities at baseline and 5-year follow-up in a lung cancer biomarker screening trial. J Clin Med. 2025; 14(6):2116.
14. Saade GR, Boggess KA, Sullivan SA, et al. Development and validation of a spontaneous preterm delivery predictor in asymptomatic women. Am J Obstet Gynecol. 2016; 214(5):633.e1-633.e24.
15. Sullivan FM, Mair FS, Anderson W, et al. Five year mortality in an RCT of a lung cancer biomarker to select people for low dose CT screening. PLoS One. 2025; 20(1):e0306163.
16. Wolf AMD, Oeffinger KC, Shih TY, et al. Screening for lung cancer: 2023 guideline update from the American Cancer Society. CA Cancer J Clin. 2024; 74(1):50-81.

Government Agency, Medical Society and Other Authoritative Publications:

1. American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Obstetrics. Prediction and prevention of spontaneous preterm birth: ACOG Practice Bulletin, Number 234. Obstet Gynecol. 2021; 138(2):e65-e90.
2. National Institute for Health and Care Excellence. EarlyCDT Lung blood test for risk classification of solid pulmonary nodules. NICE Health Technology Guidance HTG611. Published February 23, 2022. Available at: https://www.nice.org.uk/guidance/htg611. Accessed on March 24, 2026.
3. National Institute for Health and Care Excellence. Tests in secondary care to identify people at high risk of ovarian cancer. NICE Health Technology Guidance HTG453. Published November 15, 2017. Available at: https://www.nice.org.uk/guidance/htg453. Accessed on March 24, 2026.
4. NCCN Clinical Practice Guidelines in Oncology^®. 2026 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: https://www.nccn.org. Accessed on March 27, 2026.
   • Biliary Tract Cancers (Version 1.2026).
   • Bladder Cancer (Version 1.2026).
   • Breast Cancer (Version 2.2026).
   • Hepatocellular Carcinoma (Version 1.2026).
   • Lung Cancer Screening (Version 1.2026).
   • Multiple Myeloma (Version 5.2026).
   • Non-Small Cell Lung Cancer (Version 5.2026).
   • Occult Primary (Cancer of Unknown Primary [CUP]) (Version 1.2026).
   • Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer (Version 2.2026).
   • Prostate Cancer (Version 5.2026).
   • Prostate Cancer Early Detection (Version 2.2026).
   • Small Cell Lung Cancer (Version 5.2026).
   • Testicular Cancer (Version 1.2026).
5. The Centers for Medicare and Medicaid Services (CMS) Local Coverage Determination (LCD) L35396, Biomarkers for Oncology. Updated December 13, 2020. Available at: https://www.cms.gov/medicare-coverage-database/view/lcd.aspx?LCDId=35396. Accessed on March 24, 2026.
6. U.S. Food and Drug Administration. Erlotinib (Tarceva). October 18, 2016. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021743s025lbl.pdf. Accessed on March 24, 2026.

EarlyCDT
IMMray PanCan-d
Nodify XL2
Paraneoplastic Autoantibody Evaluation
PreTRM
Serum-Based Diagnostic Test for Ovarian Cancer
Theralink
VeriStrat

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.

Applicable to Commercial HMO members in California: When a medical policy states a procedure or treatment is investigational, PMGs should not approve or deny the request. Instead, please fax the request to Anthem Blue Cross Grievance and Appeals at fax # 818-234-2767 or 818-234-3824. For questions, call G&A at 1-800-365-0609 and ask to speak with the Investigational Review Nurse.

Federal and State law, as well as contract language, including definitions and specific contract provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The member’s contract benefits in effect on the date that services are rendered must be used. Medical Policy, which addresses medical efficacy, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving, and we reserve the right to review and update Medical Policy periodically.

No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, mechanical, photocopying, or otherwise, without permission from the health plan.

© CPT Only – American Medical Association