Multianalyte Assays with Algorithmic Analyses for Cancer Indications Form

. Multianalyte assays with algorithmic analyses (MAAAs) are laboratory measurements that use a mathematic formula to analyze multiple markers that may be associated with a particular disease state and are designed to evaluate disease activity or an individual’s risk for disease. The laboratory performs an algorithmic analysis using the results of the assays and sometimes other individual information, such as gender and age and converts the information into a numeric score, which is conveyed on a laboratory report. Generally, MAAAs are exclusive (and/or proprietary) to a single laboratory which owns the algorithm. One proposed indication for the use of MAAA testing is to aid in the diagnosis and evaluation of malignancies. Examples include, but may not be limited to:

Multianalyte Assays with Algorithmic Analyses for Cancer Indications Effective Date: 12/14/2023 Revision Date: 12/14/2023 Review Date: 05/25/2023 Policy Number: HUM-0614-005 Page: 2 of 22 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. • Adrenal Cortical Carcinoma (ACC) o ACC Adrenal Mass Panel utilizes a 24-hour urine specimen, a biochemical assay of 25 steroid markers and clinical parameters (age at diagnosis, gender, mode of discovery and hormonal status along with tumor diameter and an unenhanced CT density measurement of the tumor) to report a clinical risk score for the probability of a malignant adrenal cortical carcinoma (ACC) or other malignancy (eg, sarcoma, lymphoma) as well as the probability of a benign mass (eg, adenoma, myelolipoma, cyst).
• Bladder Cancer o Oncuria Detect, Oncuria Monitor and Oncuria Predict are multiplex assays that analyze 10 protein biomarkers (A1AT, ANG, APOE, CA9, IL8, MMP9, MMP10, PAI1, SDC1 and VEGFA) in urine for different indications as described below:  Oncuria Detect is purported to detect urothelial cancer in an individual presenting with hematuria.  Oncuria Monitor is indicated for monitoring an individual diagnosed with nonmuscle-invasive or muscle-invasive bladder cancer to supposedly determine risk of recurrence.
 Oncuria Predict is proposed to predict if an individual with intermediate- to high-risk urothelial cancer will respond to bacillus Calmette-Guerin (BCG) therapy. • Breast Cancer o DCISionRT uses breast tissue from a biopsy or surgery to estimate the risk of recurrence of ductal carcinoma in situ (DCIS) or invasive carcinoma in an individual with DCIS as well as the benefit of adjuvant radiation therapy. The test analyzes individual tumor biology along with other clinical factor algorithms to identify a personalized recurrence risk score of low or elevated. See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

Multianalyte Assays with Algorithmic Analyses for Cancer Indications Effective Date: 12/14/2023 Revision Date: 12/14/2023 Review Date: 05/25/2023 Policy Number: HUM-0614-005 Page: 3 of 22 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. o PreciseDx Breast Biopsy Test provides algorithmic analysis of digitized whole slide imaging of histologic and immunohistochemical features to determine the risk of recurrence for an individual diagnosed with breast cancer.
o PreciseDx Breast Cancer Test uses an algorithm of 12 histologic and immunohistochemical features, AI analysis software and hematoxylin and eosin (H&E) digital images to provide a recurrence score for breast cancer.
• Colorectal Cancer o Immunoscore is a test that uses image analysis with AI assessment of four histologic and immunohistochemical features (CD3 and CD8 within tumor- stroma border and tumor core), tissue, reported as immune response and recurrence-risk score to purportedly predict the risk of relapse in an individual with localized colon cancer to assist with treatment (eg, chemotherapy). • Esophageal Cancer and Barrett’s Esophagus o Envisage and Esopredict are tests that analyze P16, RUNX3, HPP1 and FBN1 methylation to purportedly determine the risk of progression to high-grade dysplasia or esophageal cancer in an individual diagnosed with precancerous Barrett’s esophagus.
o EsoGuard is a biomarker-based, non-endoscopic method for detecting Barrett’s esophagus using methylated DNA retrieved via a swallowed balloon- based, esophageal sampling device. This test uses next-generation sequencing (NGS) of bisulfate converted DNA to detect the presence of Vimentin (mVIM) and CyclinA1 (mCCNA1) methylation signatures at 31 sites within those genes, to purportedly identify individuals with Barrett’s esophagus. o Esophageal String Test is designed to allow frequent, quantitative monitoring of an individual with eosinophilic esophagitis. A capsule containing a yard-long string is swallowed after one end of the string is taped to the individual’s cheek. The string passes through the gastrointestinal tract (stretching through the esophagus, stomach and the upper region of the small intestine) and becomes coated with digestive secretions. It is then removed and analyzed for See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

Multianalyte Assays with Algorithmic Analyses for Cancer Indications Effective Date: 12/14/2023 Revision Date: 12/14/2023 Review Date: 05/25/2023 Policy Number: HUM-0614-005 Page: 4 of 22 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. eosinophil-derived protein biomarkers that may indicate inflammation (eg, active eosinophilic esophagitis). o TissueCypher Barrett’s Esophagus Assay analyzes multiple protein-based biomarkers and tissue structure information along with whole slide digital imaging technology to identify if an individual with Barrett’s esophagus is at high risk for developing of esophageal cancer within 5 years of undergoing endoscopy.
• Liver Cancer o HeproDx-TM for hepatocellular carcinoma (HCC) incorporates levels of 161 genes, fresh hepatocellular carcinoma tumor tissue, α-fetoprotein (AFP) level and an algorithm to purportedly report a risk classifier related to HCC recurrence and metastasis.
• Lung Cancer o CyPath Lung is a noninvasive test for the early detection of lung cancer. The test evaluates sputum using flow cytometry and machine learning when an individual has a suspicious finding on computed tomography (CT).
o Nodify Lung testing consists of two blood-based proteomic tests (Nodify CDT and Nodify XL2) to purportedly aid in determining the risk of malignancy of a lung nodule.  Nodify CDT test is intended to detect early-stage lung cancer in an individual who is at moderate to high risk. The test measures the presence of 7 autoantibodies (CAGE, GBU4-5, HuD, MAGE A4, NY-ESO-1, p53 and SOX-2) that are asserted to be involved in early stages of lung cancer development. Results are to be used in conjunction with other clinical data to determine the appropriate diagnostic follow up.
 Nodify XL2 has been suggested to identify benign versus malignant pulmonary nodules using a mass spectrometric analysis of 2 proteins (galectin-3-binding protein [LGALS3BP] and scavenger receptor cysteine- rich type 1 protein M130) and 5 clinical risk factors (age, smoking status, See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

Multianalyte Assays with Algorithmic Analyses for Cancer Indications Effective Date: 12/14/2023 Revision Date: 12/14/2023 Review Date: 05/25/2023 Policy Number: HUM-0614-005 Page: 5 of 22 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. nodule diameter, nodule-spiculation status and nodule location) utilizing plasma and an algorithm reported as a categorical probability of malignancy. o PROphet NSCLC Test is a blood test that uses a proteomic pattern analysis tool to determine if an individual diagnosed with non-small cell lung cancer (NSCLC) will benefit from immunotherapy. o REVEAL Lung Nodule Characterization is an algorithm-based measurement of three clinical factors and three blood proteins associated with the presence of lung cancer to purportedly aid the evaluation of indeterminate pulmonary nodules (4mm – 30mm) in current smokers 25 years of age and older. The results, combined with other clinical risk factors may aid in the decision to perform a biopsy or consider routine monitoring. It is not intended as a screening or stand-alone diagnostic assay. o VeriStrat is a serum based mass spectrometric, eight proteins, including amyloid A, signature proteomic test. It is intended to aid in evaluating prognosis and predicting response to systemic or targeted therapies in an individual with advanced NSCLC. • Melanoma o DAWN IO Melanoma is a quantitative mass spectrometry test that uses artificial intelligence (AI) to analyze glycopeptides to purportedly determine benefit from immunotherapy for the treatment of melanoma.
• Neuroendocrine Tumors o NETest is a multianalyte algorithm, polymerase chain reaction (PCR)-based gene blood test that measures 51 neuroendocrine tumor specific gene transcripts in combination with molecular biomarkers which purportedly allows monitoring of neuroendocrine tumor gene activity levels.
• Oral Cancer See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

Multianalyte Assays with Algorithmic Analyses for Cancer Indications Effective Date: 12/14/2023 Revision Date: 12/14/2023 Review Date: 05/25/2023 Policy Number: HUM-0614-005 Page: 6 of 22 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. o SaliMark OSCC – Oral Cancer Salivary Diagnostic Test is a molecular DNA biomarker test performed on saliva when suspicious lesions are observed to purportedly aid in the early detection of oral squamous cell carcinoma. • Ovarian Cancer o OvaSuite is a collection of blood tests (Ova1 Plus [Ova1 and Overa] and OvaWatch) proposed to assess risk of ovarian cancer in an individual diagnosed with an adnexal mass. Proprietary algorithms are applied, along with an individual’s features as well as the levels of certain biomarkers. These biomarkers include apolipoprotein A1 (Apo A-1), beta-2 microglobulin (B2M), CA-125, follicle stimulating hormone (FSH), human epididymis protein (HE4), prealbumin and transferrin (TRF). Each test has a specific indication:  Ova1 Plus is comprised of Ova1 and Overa. Ova1, an FDA-approved test, is performed for an individual with adnexal mass when surgery has been scheduled. If an individual has an intermediate risk result, Overa is automatically reflexed (performed in succession of original test).
 OvaWatch is indicated for an individual diagnosed with adnexal mass when the initial clinical assessment is classified as benign or indeterminate.
o Risk of Ovarian Malignancy Algorithm (ROMA) is an FDA-approved blood test that measures HE4 and CA-125 to evaluate an individual with an adnexal mass to purportedly determine the likelihood of ovarian cancer.
• Pancreatic Cancer o IMMray PanCan-d measures 9 serum biomarkers (C5, C4, cystatin C, factor B, osteoprotegerin, gelsolin, IGFBP3, CA125 and multiplex electrochemiluminescent immunoassay (ECLIA) for CA19-9) combined with an algorithm to purportedly detect pancreatic ductal adenocarcinoma with a result of high-risk signature present, negative high-risk signature or borderline. See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

Multianalyte Assays with Algorithmic Analyses for Cancer Indications Effective Date: 12/14/2023 Revision Date: 12/14/2023 Review Date: 05/25/2023 Policy Number: HUM-0614-005 Page: 7 of 22 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. o PancraGEN (formerly PathFinderTG) is a topographic genotyping test that purportedly assesses the risk of malignancy in an individual with a pancreatic cyst.
• Solid Organ Tumors o LC-MS/MS Targeted Proteomic Assay is a liquid chromatography (LC) mass spectrometric analysis of 30 protein targets that uses formalin-fixed, paraffin- embedded (FFPE) tissue of solid organ tumors. The results are intended to be used as a prognostic and predictive algorithm reported as likely, unlikely or uncertain benefit for treatment of 39 chemotherapy and targeted therapeutic oncology agents.
Test MAAA testing for noncancer indications MAAA testing for prostate cancer Tumor markers Medical Coverage Policy Multianalyte Assays with Algorithmic Analyses for Noncancer Indications Laboratory Analysis for Prostate Cancer Emerging Tumor Markers for Diagnosis and Monitoring of Cancer Coverage Determination Humana members may NOT be eligible under the Plan for the following MAAAs including, but may not be limited to: • ACC adrenal mass panel (0015M) • CyPath Lung (0406U) • DAWN IO Melanoma (0357U) • DCISionRT (0295U) • Envisage (0386U) • EsoGuard (0114U) • Esophageal String Test (0095U) • Esopredict (0398U) • HeproDx-TM (0006M) • IMMray PanCan-d (0342U) • Immunoscore (0261U) • LC-MS/MS Targeted Proteomic Assay (0174U) • NETest (0007M) See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

Multianalyte Assays with Algorithmic Analyses for Cancer Indications Effective Date: 12/14/2023 Revision Date: 12/14/2023 Review Date: 05/25/2023 Policy Number: HUM-0614-005 Page: 8 of 22 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. • Nodify Lung including: o Nodify CDT (0360U) o Nodify XL2 (0080U) • Oncuria including: o Oncuria Detect (0365U) o Oncuria Monitor (0366U) o Oncuria Predict (0367U) • OvaSuite including:
o Ova1 (81503) o Ova1 Plus o OvaWatch (0375U) o Overa (0003U)
• PancraGEN (formerly PathFinder TG) (84999, 81599) • PreciseDx Breast Biopsy Test (0418U) • PreciseDx Breast Cancer Test (0220U) • PROphet NSCLC Test (0436U) • REVEAL Lung Nodule Characterization (0092U) • ROMA (81500) • SaliMark OSCC – Oral Cancer Salivary Diagnostic Test • TissueCypher Barrett’s Esophagus Assay (0108U) • Veristrat (81538) These are considered experimental/investigational as they are not identified as widely used and generally accepted for the proposed uses as reported in nationally recognized peer-reviewed medical literature published in the English language. Background Additional information about conditions addressed in this policy may be found from the following websites: • American College of Obstetricians and Gynecologists See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

Multianalyte Assays with Algorithmic Analyses for Cancer Indications Effective Date: 12/14/2023 Revision Date: 12/14/2023 Review Date: 05/25/2023 Policy Number: HUM-0614-005 Page: 9 of 22 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. • American Urological Association • National Comprehensive Cancer Network • National Library of Medicine Medical Alternatives Alternatives to mass spectrometric analysis to detect malignant pulmonary nodules include: • Low-dose computed tomography (LDCT) • Tumor markers (calretinin, carcinoembryonic antigen [CEA], lactate dehydrogenase [LDH], napsin A, thyroid transcription factor-1 [TTF-1])
Alternatives to molecular DNA biomarker testing to detect oral cancer include: • Brush biopsy • Exfoliative cytology • Fluorescence staining
• Toluidine blue stain
Alternatives to mRNA expression testing for hepatocellular carcinoma include: • Alpha-fetaoprotein (AFP) • Computed tomography • Hepatic ultrasound Alternatives to multianalyte algorithm PCR-based gene testing for neuroendocrine tumor include: • Chromogranin A (CGA) and thyroid transcription factor-1 (TTF-1) Alternatives to multianalyte assays for the evaluation of Barrett’s esophagus include: • Upper endoscopy Alternatives to multianalyte assays for the evaluation of pelvic masses include: See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

Multianalyte Assays with Algorithmic Analyses for Cancer Indications Effective Date: 12/14/2023 Revision Date: 12/14/2023 Review Date: 05/25/2023 Policy Number: HUM-0614-005 Page: 10 of 22 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. • AFP, beta-HCG, CA-125 and LDH testing
Alternatives to multianalyte assays for the evaluation of urothelial cancer include: • Cystoscopy Alternatives to proteomic testing for non-small cell lung cancer (NSCLC) include, but may not be limited to: • EGFR gene testing Alternatives to topographic genotyping for pancreatic cancer include, but may not be limited to: • Conventional diagnostic methods such as cytology, histology and immunohistochemistry (IHC) Physician consultation is advised to make an informed decision based on an individual’s health needs.
Humana may offer a disease management program for this condition. The member may call the number on his/her identification card to ask about our programs to help manage his/her care. Provider Claims Codes Any CPT, HCPCS or ICD codes listed on this medical coverage policy are for informational purposes only. Do not rely on the accuracy and inclusion of specific codes. Inclusion of a code does not guarantee coverage and or reimbursement for a service or procedure. CPT® Code(s) 81500 Description Oncology (ovarian), biochemical assays of two proteins (CA-125 and HE4), utilizing serum, with menopausal status, algorithm reported as a risk score Comments Not Covered See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

Multianalyte Assays with Algorithmic Analyses for Cancer Indications Effective Date: 12/14/2023 Revision Date: 12/14/2023 Review Date: 05/25/2023 Policy Number: HUM-0614-005 Page: 11 of 22 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. 81503 81538 Oncology (ovarian), biochemical assays of five proteins (CA-125, apolipoprotein A1, beta-2 microglobulin, transferrin, and pre- albumin), utilizing serum, algorithm reported as a risk score Oncology (lung), mass spectrometric 8-protein signature, including amyloid A, utilizing serum, prognostic and predictive algorithm reported as good versus poor overall survival Not Covered Not Covered 81599 Unlisted multianalyte assay with algorithmic analysis 84999 Unlisted chemistry procedure 0003U 0006M 0007M 0015M Oncology (ovarian) biochemical assays of five proteins (apolipoprotein A-1, CA 125 II, follicle stimulating hormone, human epididymis protein 4, transferrin), utilizing serum, algorithm reported as a likelihood score Oncology (hepatic), mRNA expression levels of 161 genes, utilizing fresh hepatocellular carcinoma tumor tissue, with alpha-fetoprotein level, algorithm reported as a risk classifier Oncology (gastrointestinal neuroendocrine tumors), real-time PCR expression analysis of 51 genes, utilizing whole peripheral blood, algorithm reported as a nomogram of tumor disease index Adrenal cortical tumor, biochemical assay of 25 steroid markers, utilizing 24-hour urine specimen and clinical parameters, prognostic algorithm reported as a clinical risk and integrated clinical steroid risk for adrenal cortical carcinoma, adenoma, or other adrenal malignancy Not Covered if used to report any test outlined in Coverage Determination section Not Covered if used to report any test outlined in Coverage Determination section Not Covered Not Covered Test Obsolete/No Longer Available Not Covered Not Covered See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

Multianalyte Assays with Algorithmic Analyses for Cancer Indications Effective Date: 12/14/2023 Revision Date: 12/14/2023 Review Date: 05/25/2023 Policy Number: HUM-0614-005 Page: 12 of 22 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. 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 0092U Oncology (lung), three protein biomarkers, immunoassay using magnetic nanosensor technology, plasma, algorithm reported as risk score for likelihood of malignancy Inflammation (eosinophilic esophagitis), ELISA analysis of eotaxin-3 (CCL26 [C-C motif chemokine ligand 26]) and major basic protein (PRG2 [proteoglycan 2, pro eosinophil major basic protein]), specimen obtained by swallowed nylon string, algorithm reported as predictive probability index for active eosinophilic esophagitis Gastroenterology (Barrett's esophagus), whole slide-digital imaging, including morphometric analysis, computer-assisted quantitative immunolabeling of 9 protein biomarkers (p16, AMACR, p53, CD68, COX-2, CD45RO, HIF1a, HER-2, K20) and morphology, formalin-fixed paraffin-embedded tissue, algorithm reported as risk of progression to high-grade dysplasia or cancer Gastroenterology (Barrett's esophagus), VIM and CCNA1 methylation analysis, esophageal cells, algorithm reported as likelihood for Barrett's esophagus Oncology (solid tumor), mass spectrometric 30 protein targets, formalin-fixed paraffin-embedded tissue, prognostic and predictive algorithm reported as likely, unlikely, or uncertain benefit of 39 chemotherapy and targeted therapeutic oncology agents Oncology (breast cancer), image analysis with artificial intelligence assessment of 12 histologic and immunohistochemical features, reported as a recurrence score 0095U 0108U 0114U 0174U 0220U Not Covered Not Covered Not Covered Not Covered Not Covered Not Covered Not Covered See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

Multianalyte Assays with Algorithmic Analyses for Cancer Indications Effective Date: 12/14/2023 Revision Date: 12/14/2023 Review Date: 05/25/2023 Policy Number: HUM-0614-005 Page: 13 of 22 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. 0261U 0295U 0342U 0357U 0360U 0365U 0366U Oncology (colorectal cancer), image analysis with artificial intelligence assessment of 4 histologic and immunohistochemical features (CD3 and CD8 within tumor- stroma border and tumor core), tissue, reported as immune response and recurrence-risk score Oncology (breast ductal carcinoma in situ), protein expression profiling by immunohistochemistry of 7 proteins (COX2, FOXA1, HER2, Ki-67, p16, PR, SIAH2), with 4 clinicopathologic factors (size, age, margin status, palpability), utilizing formalin-fixed paraffin-embedded (FFPE) tissue, algorithm reported as a recurrence risk score Oncology (pancreatic cancer), multiplex immunoassay of C5, C4, cystatin C, factor B, osteoprotegerin (OPG), gelsolin, IGFBP3, CA125 and multiplex electrochemiluminescent immunoassay (ECLIA) for CA19-9, serum, diagnostic algorithm reported qualitatively as positive, negative, or borderline Oncology (melanoma), artificial intelligence (AI)-enabled quantitative mass spectrometry analysis of 142 unique pairs of glycopeptide and product fragments, plasma, prognostic, and predictive algorithm reported as likely, unlikely, or uncertain benefit from immunotherapy agents Oncology (lung), enzyme-linked immunosorbent assay (ELISA) of 7 autoantibodies (p53, NY-ESO-1, CAGE, GBU4-5, SOX2, MAGE A4, and HuD), plasma, algorithm reported as a categorical result for risk of malignancy Oncology (bladder), analysis of 10 protein biomarkers (A1AT, ANG, APOE, CA9, IL8, MMP9, MMP10, PAI1, SDC1 and VEGFA) by immunoassays, urine, algorithm reported as a probability of bladder cancer Oncology (bladder), analysis of 10 protein biomarkers (A1AT, ANG, APOE, CA9, IL8, MMP9, MMP10, PAI1, SDC1 and VEGFA) by immunoassays, urine, algorithm reported as a probability of recurrent bladder cancer Not Covered Not Covered Not Covered Not Covered New Code Effective 01/01/2023 Not Covered New Code Effective 01/01/2023 Not Covered New Code Effective 04/01/2023 Not Covered New Code Effective 04/01/2023 See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

Multianalyte Assays with Algorithmic Analyses for Cancer Indications Effective Date: 12/14/2023 Revision Date: 12/14/2023 Review Date: 05/25/2023 Policy Number: HUM-0614-005 Page: 14 of 22 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. 0367U 0375U 0386U 0398U 0406U 0418U 0436U Oncology (bladder), analysis of 10 protein biomarkers (A1AT, ANG, APOE, CA9, IL8, MMP9, MMP10, PAI1, SDC1 and VEGFA) by immunoassays, urine, diagnostic algorithm reported as a risk score for probability of rapid recurrence of recurrent or persistent cancer following transurethral resection Oncology (ovarian), biochemical assays of 7 proteins (follicle stimulating hormone, human epididymis protein 4, apolipoprotein A-1, transferrin, beta-2 macroglobulin, prealbumin [ie, transthyretin], and cancer antigen 125), algorithm reported as ovarian cancer risk score Gastroenterology (Barrett’s esophagus), P16, RUNX3, HPP1, and FBN1 methylation analysis, prognostic and predictive algorithm reported as a risk score for progression to high-grade dysplasia or esophageal cancer Gastroenterology (Barrett esophagus), P16, RUNX3, HPP1, and FBN1 DNA methylation analysis using PCR, formalin-fixed paraffin-embedded (FFPE) tissue, algorithm reported as risk score for progression to high-grade dysplasia or cancer Oncology (lung), flow cytometry, sputum, 5 markers (meso- tetra [4-carboxyphenyl] porphyrin [TCPP], CD206, CD66b, CD3, CD19), algorithm reported as likelihood of lung cancer Oncology (breast), augmentative algorithmic analysis of digitized whole slide imaging of 8 histologic and immunohistochemical features, reported as a recurrence score Oncology (lung), plasma analysis of 388 proteins, using aptamer-based proteomics technology, predictive algorithm reported as clinical benefit from immune checkpoint inhibitor therapy Not Covered New Code Effective 04/01/2023 Not Covered New Code Effective 04/01/2023 Not Covered New Code Effective 04/01/2023 Not Covered New Code Effective 07/01/2023 Not Covered New Code Effective 10/01/2023 Not Covered New Code Effective 10/01/2023 Not Covered New Code Effective 01/01/2024 CPT® Category III Code(s) No code(s) identified Description Comments See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

Multianalyte Assays with Algorithmic Analyses for Cancer Indications Effective Date: 12/14/2023 Revision Date: 12/14/2023 Review Date: 05/25/2023 Policy Number: HUM-0614-005 Page: 15 of 22 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. HCPCS Code(s) No code(s) identified Description Comments References

7. American College of Gastroenterology (ACG). Diagnosis and management of Barrett’s esophagus: an updated ACG guideline. https://www.gi.org. Published April 2022. Accessed June 4, 2023.
   American College of Obstetricians and Gynecologists (ACOG). Committee Opinion. The role of the obstetrician-gynecologist in the early detection of epithelial ovarian cancer in women at average risk. https://www.acog.org. Published September 2017. Updated 2021. Accessed April 19, 2023. American College of Obstetricians and Gynecologists (ACOG). Practice Bulletin. Evaluation and management of adnexal masses. https://www.acog.org. Published November 2016. Updated 2021. Accessed April 19, 2023. American Gastroenterological Association (AGA). AGA Institute and the Joint Task Force on allergy-immunology practice parameters clinical guidelines for the management of eosinophilic esophagitis. https://www.gastro.org. Published May 2020. Accessed June 4, 2023.
   American Gastroenterological Association (AGA). American Gastroenterological Association medical position statement on the management of Barrett's esophagus. https://www.gastro.org. Published March 2011. Accessed June 4, 2023.
   American Gastroenterological Association (AGA). Clinical practice update on new technology and innovation for surveillance and screening in Barrett’s esophagus: expert review. https://www.gastro.org. Published July 2022. Accessed June 4, 2023. American Society for Gastrointestinal Endoscopy (ASGE). ASGE guideline on screening and surveillance of Barrett’s esophagus. https://www.asge.org. Published November 2019. Accessed June 4, 2023. See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

   Multianalyte Assays with Algorithmic Analyses for Cancer Indications Effective Date: 12/14/2023 Revision Date: 12/14/2023 Review Date: 05/25/2023 Policy Number: HUM-0614-005 Page: 16 of 22 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

9. American Urological Association (AUA). Diagnosis and treatment of non- muscle invasive bladder cancer: AUA/SUO guideline. https://www.auanet.org. Published 2016. Updated 2020. Accessed April 20, 2023.
   American Urological Association (AUA). Microhematuria: AUA/SUFU guideline. https://www.auanet.org. Published 2020. Accessed April 20, 2023.
10. American Urological Association (AUA). Treatment of non-metastatic muscle- invasive bladder cancer: AUA/ASCO/ASTRO/SUO. https://www.auanet.org. Published 2020. Accessed April 20, 2023.
11. 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. https://www.ncbi.nlm.nih.gov/pmc. Accessed April 6, 2023.
12. Chen R, Pagano I, Sun Y, et al. A diagnostic gene expression signature for bladder cancer can stratify cases into prescribed molecular subtypes and predict outcome. Diagnostics (Basel). 2022;12(8):1801. https://www.ncbi.nlm.nih.gov/pmc. Accessed January 20, 2023.
13. ECRI Institute. Clinical Evidence Assessment. Esophageal string test (EnteroTrack, LLC) for monitoring pediatric eosinophilic esophagitis. https://www.ecri.org. Published June 28, 2021. Accessed May 29, 2023.
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