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    v1.0.28
    OpenPayerPolicy UpdatesGenetic & Molecular TestingHMSA Liquid Biopsy Coverage Policy | OpenPayer
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    CurrentHawaii Medical Service Association (HMSA)Policy G2054

    Liquid Biopsy

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    Coverage criteria for liquid biopsy testing, including cfDNA/ctDNA, circulating tumor cell, urinary, cerebrospinal fluid, and other tumor-derived biomarker testing for HMSA members.

    Policy Summary
    PayerHawaii Medical Service Association (HMSA)
    PolicyLiquid Biopsy
    Policy CodePolicy G2054
    Change TypeNo material change
    Effective DateFebruary 1, 2026
    Next Review DateN/A
    Key ActionObtain precertification according to the GTM Utilization Review Matrix before requesting coverage.
    SourceLink
    POLICY UPDATE CHANGES

    No material clinical or coverage changes in this revision.

    3Cancer settings with specified cfDNA/ctDNA coverage criteria
    10Recommended NSCLC biomarkers listed for molecular assessment
    AnnuallyTesting frequency when qualifying criteria are met
    5Explicitly non-covered liquid biopsy situations
    60–80%Reported liquid biopsy sensitivity range
    20Applicable CPT/HCPCS procedure codes

    Coverage Criteria

    NSCLC cfDNA/ctDNA testing

    Covered when the individual has NSCLC and at least one of the following situations applies.

    • Qualifying NSCLC situation

      • Tissue testing infeasible: Tissue-based testing is infeasible because the tissue quantity is insufficient or invasive biopsy is medically contraindicated.
      • Insufficient tissue after diagnosis: In the initial diagnostic setting, pathological confirmation of NSCLC has occurred but there is insufficient tissue for broad molecular analysis. If no oncogenic driver is identified, follow-up tissue-based analysis should be considered.
      • Incomplete tissue biomarker assessment: In the initial diagnostic setting, tissue-based molecular analysis does not completely assess all recommended biomarkers because of tissue quantity or available testing methodologies.
    Policy Summary
    PayerHawaii Medical Service Association (HMSA)
    PolicyLiquid Biopsy
    Policy CodePolicy G2054
    Change TypeNo material change
    Effective DateFebruary 1, 2026
    Next Review DateN/A
    Key ActionObtain precertification according to the GTM Utilization Review Matrix before requesting coverage.
    SourceLink
    On This Page
    Coverage CriteriaCovered Disease-Specific IndicationsEligibility RequirementsNot Covered ServicesApplicable CPT and HCPCS CodesProvider Requirements and Action ItemsLiquid Biopsy BackgroundDefinitions and Abbreviations

    Recommended biomarkers include ALK, BRAF, EGFR, ERBB2/HER2, KRAS, MET exon 14 skipping, NTRK1/2/3, RET, ROS1, and PD-L1 expression levels.

  1. Treatment-selection biomarker evaluation: Testing is used to aid biomarker evaluation for treatment selection in the initial diagnostic setting when the feasibility of timely tissue-based testing is uncertain.

    2. Breast cancer PIK3CA testing

    Covered when both the diagnosis and treatment-selection context are present.

    HR-positive/HER2-negative breast cancer: The individual has HR-positive/HER2-negative breast cancer, is being considered for targeted therapy, and requests cfDNA/ctDNA testing for PIK3CA.

    Castration-resistant prostate cancer testing

    Covered when the individual has castration-resistant prostate cancer and the testing is for one of the specified treatment-selection purposes.

    CRPC cfDNA/ctDNA testing

    • Covered CRPC biomarker purpose

      • AR-V7 testing: Testing for androgen receptor variant 7 (AR-V7) is requested to guide therapy selection in the postabiraterone/enzalutamide metastatic CRPC setting.
      • BRCA1/BRCA2 testing: Somatic analysis of BRCA1 and BRCA2 is requested to select patients for rucaparib treatment.

    Annual testing frequency

    For individuals meeting one of the specified disease-specific criteria, testing is covered annually.

    Annual repeat testing: The individual meets one of the policy's covered disease-specific criteria and cfDNA/ctDNA testing is performed annually.Annually

    NSCLC liquid biopsy

    For NSCLC, plasma ctDNA testing may be used in specific circumstances.

    NSCLC plasma testing circumstance: The individual has NSCLC and is not medically fit for invasive tissue sampling, or there is insufficient tissue for molecular analysis.

    If an oncogenic driver is not identified, follow-up tissue-based analysis should be performed; plasma testing does not replace histologic tissue diagnosis.

    Breast cancer biomarker testing

    Liquid biopsy may be considered for selected breast cancer biomarker evaluation.

    Breast cancer biomarker evaluation

    • PIK3CA evaluation: The individual has recurrent or progressive HR-positive, HER2-negative breast cancer and alpelisib plus fulvestrant is being considered; liquid biopsy may be used to assess PIK3CA.
    • ESR1 evaluation: The individual has ER-positive, HER2-negative metastatic breast cancer with recurrence or progression on endocrine therapy and ESR1 testing is performed on blood or tissue.

      Blood-based ctDNA is preferred because of greater sensitivity. If tumor or ctDNA remains ESR1 wild-type, retesting at subsequent progression may be warranted.

    • Recurrent stage IV profiling: The individual has recurrent stage IV breast cancer and tumor tissue or plasma ctDNA is used for comprehensive genomic profiling to identify candidates for additional targeted therapies.

      If one specimen is negative for actionable biomarkers, testing of the alternative specimen may be considered.

    Prostate cancer liquid or urine biomarkers

    Selected liquid biopsy or urine biomarker uses are described for prostate cancer.

    Prostate cancer testing

    • ARV7 testing in circulating tumor cells is used to help guide therapy selection in the post-abiraterone/enzalutamide metastatic castration-resistant prostate cancer setting.
    • BRCA1/BRCA2 analysis: Circulating DNA analysis of BRCA1 and BRCA2 is used to select patients for rucaparib treatment.
    • SelectMDx is considered in an individual who has never undergone biopsy.

      The cited prostate guidelines describe an additional serum or urine biomarker test as a weak biopsy-indication option when PSA is 3–20 ng/mL and digital rectal examination is normal.

    Analytic validation and laboratory standards

    Where liquid biopsy is used, testing should be analytically and clinically validated.

    Validated assay and processing: The test uses a clinically validated platform and standardized procedures for specimen collection, handling, and processing.

    For advanced NSCLC, plasma ctDNA testing should generally use a clinically validated NGS platform. A negative single-gene test is not considered complete; additional actionable biomarker testing must be pursued. For specified esophageal, esophagogastric junction, and gastric cancers, validated NGS-based genomic profiling may be performed in a CLIA-approved laboratory.

    Liquid biopsy testing for screening, detection, or monitoring of any malignancy or tumor does not meet coverage criteria when the situation is not specifically described in the covered indications. This includes testing such as GRAIL Galleri.

    PD-L1 analysis by liquid biopsy does not meet coverage criteria for situations not otherwise addressed by the policy.

    Urinary liquid biopsy using urinary cell-free DNA (UcfDNA) or urine-derived circulating tumor DNA does not meet coverage criteria when used for cancer screening, detection, or diagnosis. This includes tests such as SelectMDX.

    Liquid biopsy testing on cerebrospinal fluid (CSF) does not meet coverage criteria.

    Cell capture-enumeration assays of circulating tumor cells do not meet coverage criteria. This includes assays such as CELLSEARCH CTC.

    Cell-free or circulating tumor DNA testing should not be used in place of histologic tissue diagnosis. Liquid biopsy may be considered in selected circumstances, but it does not replace the diagnostic information provided by tissue evaluation.

    A negative plasma ctDNA result does not eliminate the need for tissue-based testing when an oncogenic driver has not been identified. When feasible, tissue-based testing with re-biopsy material is strongly recommended.

    Cell-free or circulating tumor DNA testing should not be used in lieu of histologic tissue diagnosis. A liquid biopsy result does not replace tissue diagnosis when tissue assessment is clinically indicated.

    For colon cancer, the NCCN reports insufficient data to recommend multigene assays, Immunoscore, or post-surgical ctDNA to estimate recurrence risk or determine adjuvant therapy.

    ASCO recommends against using circulating biomarkers as a routine surveillance strategy for recurrence after curative-intent treatment of stage I–III non-small cell lung cancer or small cell lung cancer.

    There is insufficient evidence to support circulating cell-free plasma DNA molecular methods or circulating tumor cell molecular analysis as established testing for diagnosis of primary lung adenocarcinoma, identification of EGFR or other mutations, or identification of EGFR T790M at EGFR tyrosine kinase inhibitor resistance.

    Situations not specifically described as covered do not meet coverage criteria because published scientific literature confirming that the testing is required and beneficial for diagnosis or treatment is lacking.

    HMSA has determined that services not covered under this Medical Policy will generally be considered not medically necessary under Hawaii law, subject to applicable member contract language.

    Covered Disease-Specific Indications

    NSCLC cfDNA/ctDNA testing when tissue testing is infeasible or inadequate

    Covered for NSCLC treatment-selection biomarker evaluation when tissue-based testing cannot adequately provide the needed molecular information.

    NSCLC cfDNA/ctDNA treatment-selection testing

    • Qualifying tissue or timing circumstance

      • Tissue testing infeasible: Tissue-based testing is infeasible because tissue quantity is insufficient or invasive biopsy is medically contraindicated.
      • Insufficient tissue: After pathological confirmation of NSCLC, there is insufficient tissue for broad molecular analysis.

        If no oncogenic driver is identified, follow-up tissue-based analysis should be considered.

      • Incomplete biomarker assessment: Tissue-based molecular analysis does not completely assess the recommended biomarkers because of tissue quantity or available testing methodologies.
      • Timely tissue testing uncertain: In the initial diagnostic setting, the feasibility of timely tissue-based testing is uncertain.

    PIK3CA testing in HR-positive/HER2-negative breast cancer

    Covered when PIK3CA testing is being used to inform targeted treatment selection.

    PIK3CA cfDNA/ctDNA testing: The individual has HR-positive/HER2-negative breast cancer, targeted therapy is being considered, and cfDNA/ctDNA testing is requested to assess PIK3CA.

    AR-V7 testing in metastatic CRPC

    Covered in the specified metastatic CRPC treatment-selection setting.

    AR-V7 testing: The individual has metastatic castration-resistant prostate cancer, has received abiraterone or enzalutamide, and AR-V7 testing by cfDNA/ctDNA or circulating tumor cell analysis is requested to help guide therapy selection.

    BRCA1/BRCA2 analysis in CRPC

    Covered when BRCA status is being used to select treatment with rucaparib.

    Somatic BRCA1/BRCA2 analysis: The individual has castration-resistant prostate cancer and somatic BRCA1 and BRCA2 analysis using a circulating tumor DNA sample is requested to select patients for rucaparib treatment.

    Selected NSCLC patients eligible for plasma ctDNA testing

    Plasma ctDNA testing may be used for selected NSCLC patients when invasive tissue testing is not feasible or tissue is insufficient.

    Qualifying NSCLC patient

    • Medically unfit for invasive sampling: The patient is not medically fit for invasive tissue sampling.
    • Insufficient tissue: There is insufficient tissue for molecular analysis after pathological confirmation of NSCLC.

      Follow-up tissue-based analysis should be planned if no oncogenic driver is identified.

    Breast cancer biomarker evaluation at recurrence or progression

    Covered for selected recurrent or progressive breast cancer biomarker evaluation.

    Breast cancer biomarker application

    • ESR1 testing: The individual has ER-positive, HER2-negative metastatic breast cancer with recurrence or progression on endocrine therapy and ESR1 testing is performed on blood or tissue.

      Blood-based ctDNA is preferred because of greater sensitivity.

    • PIK3CA testing: The individual has HR-positive, HER2-negative breast cancer and alpelisib plus fulvestrant is being considered; liquid biopsy is used to assess PIK3CA.
    • Comprehensive genomic profiling: The individual has recurrent stage IV breast cancer and tumor tissue or plasma ctDNA is used for comprehensive genomic profiling to identify candidates for additional targeted therapies.

      If one specimen is negative for actionable biomarkers, testing of the alternative specimen may be considered.

    Selected prostate cancer applications

    Covered for selected prostate cancer treatment-selection or biopsy-indication applications.

    Covered prostate cancer application

    • ARV7 in CTCs: ARV7 testing in circulating tumor cells is requested after abiraterone or enzalutamide in metastatic castration-resistant prostate cancer to help guide therapy selection.
    • Circulating BRCA1/BRCA2 analysis: Circulating DNA analysis of BRCA1 and BRCA2 is requested for rucaparib treatment selection.
    • SelectMDx is considered for an individual who has never undergone biopsy.

      The cited guidelines describe an additional serum or urine biomarker test as a weak biopsy-indication option when PSA is 3–20 ng/mL and digital rectal examination is normal.

    Selected molecular profiling and cfDNA applications

    Selected molecular profiling or cfDNA applications may be considered in the following disease settings; use and evidentiary support vary by disease.

    Selected disease-specific application

    • Pancreatic adenocarcinoma: Cell-free DNA testing may be considered when tumor tissue is not available.

      The cited guidance describes this use as under investigation and does not establish liquid biopsy screening as a covered indication.

    • Biliary tract cancer: A cfDNA test may be considered to identify gene mutations.

      Depending on the panel and specific partner gene, cfDNA may not reliably identify gene fusions or rearrangements.

    • Esophageal, esophagogastric junction, or gastric cancer: Validated NGS-based genomic profiling performed in a CLIA-approved laboratory may be considered.

      A negative result should be interpreted with caution because it does not exclude tumor mutations or amplifications.

    Eligibility Requirements

    For an individual with NSCLC, tissue-based testing may be infeasible when the available tissue is insufficient for molecular analysis or when invasive biopsy is medically contraindicated. Plasma cfDNA/ctDNA testing may also be considered when tissue-based molecular analysis does not assess all recommended biomarkers because of tissue quantity or available testing methods, or when the feasibility of timely tissue testing for treatment-selection biomarker evaluation is uncertain. If no oncogenic driver is identified, a plan for follow-up tissue-based analysis should be documented.

    Not Covered Services

    Liquid biopsy testing for screening, detection, or monitoring outside the policy’s specified covered indications is not covered. Other excluded uses include PD-L1 analysis outside addressed situations, urinary UcfDNA or urine-derived ctDNA for screening, detection, or diagnosis, CSF testing, and cell capture-enumeration assays of circulating tumor cells.

    Applicable CPT and HCPCS Codes

    Applicable CPT/HCPCS Procedure CodesCPT
    81162BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full sequence analysis and full duplication/deletion analysis (ie, detection of large gene rearrangements).
    81163BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full sequence analysis.
    81164BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (ie, detection of large gene rearrangements).
    Applicable CPT/HCPCS Procedure CodesCPT
    81194NTRK (neurotrophic receptor tyrosine kinase 1, 2, and 3) (eg, solid tumors) translocation analysis.
    81210BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s).
    81235EGFR (epidermal growth factor receptor) (eg, non-small cell lung cancer) gene analysis, common variants (eg, exon 19 LREA deletion, L858R, T790M, G719A, G719S, L861Q).
    81275KRAS (Kirsten rat sarcoma viral oncogene homolog) (eg, carcinoma) gene analysis; variants in exon 2 (eg, codons 12 and 13).
    81276KRAS (Kirsten rat sarcoma viral oncogene homolog) (eg, carcinoma) gene analysis; additional variant(s) (eg, codon 61, codon 146).
    81309Additional variant(s) (eg, codon 61, codon 146) PIK3CA (phosphatidylinositol-4, 5-biphosphate 3-kinase, catalytic subunit alpha) (eg, colorectal and breast cancer) gene analysis, targeted sequence analysis (eg, exons 7, 9, 20).
    81405Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally.
    81406Targeted cytogenomic array analysis.
    81462Solid organ neoplasm, genomic sequence analysis panel, cell-free nucleic acid (eg, plasma), interrogation for sequence variants; DNA analysis or combined DNA and RNA.
    81479Unlisted molecular pathology procedure.
    Applicable CPT/HCPCS Procedure CodesCPT
    86152Cell enumeration using immunologic selection and identification in fluid specimen (eg, circulating tumor cells in blood).
    86153Cell enumeration using immunologic selection and identification in fluid specimen (eg, circulating tumor cells in blood); physician interpretation and report, when required.
    0011MOncology, prostate cancer, mRNA expression assay of 12 genes (10 content and 2 housekeeping), RT-PCR test utilizing blood plasma and urine, algorithms to predict high-grade prostate cancer risk. Proprietary test: NeoLAB Prostate Liquid Biopsy, NeoGenomics Laboratories.
    0091UOncology (colorectal) screening, cell enumeration of circulating tumor cells, utilizing whole blood, algorithm, for the presence of adenoma or cancer, reported as a positive or negative result. Proprietary test: FirstSightCRC, CellMax Life.
    Applicable CPT/HCPCS Procedure CodesCPT
    0177UOncology (breast cancer), DNA, PIK3CA gene analysis of 11 gene variants utilizing plasma, reported as PIK3CA gene mutation status. Proprietary test: therascreen PIK3CA RGQ PCR Kit.
    0179UOncology (non-small cell lung cancer), cell-free DNA, targeted sequence analysis of 23 genes (single nucleotide variations, insertions and deletions, fusions without prior knowledge of partner/breakpoint, copy number variations), with report of significant mutation(s). Proprietary test: Resolution ctDx Lung.
    0229UBCAT1 and IKZF1 (eg, colorectal cancer) promoter methylation analysis. Proprietary test: Colvera, Clinical Genomics Pathology Inc.
    0317UOncology (lung cancer), four-probe FISH (3q29, 3p22.1, 10q22.3, 10cen) assay, whole blood, predictive algorithm-generated evaluation reported as decreased or increased risk for lung cancer. Proprietary test: LungLB, LungLife AI.
    0332UOncology (pan-tumor), genetic profiling of 8 DNA-regulatory (epigenetic) markers by quantitative polymerase chain reaction (qPCR), whole blood, reported as a high or low probability of responding to immune checkpoint-inhibitor therapy. Proprietary test: EpiSwitch CiRT, Next Bio-Research Services, LLC.
    0333UOncology (liver), surveillance for hepatocellular carcinoma (HCC) in high-risk patients, analysis of methylation patterns on circulating cell-free DNA (cfDNA) plus measurement of serum AFP/AFP-L3 and oncoprotein des-gamma-carboxyprothrombin (DCP), algorithm reported as normal or abnormal result. Proprietary test: HelioLiver, Fulgent Genetics, LLC.
    Applicable CPT/HCPCS Procedure CodesCPT
    0337UOncology (plasma cell disorders and myeloma), circulating plasma cell immunologic selection, identification, morphological characterization, and enumeration of plasma cells based on differential CD138, CD38, CD19, and CD45 protein biomarker expression, peripheral blood. Proprietary test: CELLSEARCH Circulating Multiple Myeloma Cell Test, Menarini Silicon Biosystems, Inc.
    0338UOncology (solid tumor), circulating tumor cell selection, identification, morphological characterization, detection and enumeration based on differential EpCAM, cytokeratins 8, 18, and 19, and CD45 protein biomarkers, and quantification of HER2 protein biomarker-expressing cells, peripheral blood. Proprietary test: CELLSEARCH HER2 Circulating Tumor Cell Test.
    Applicable CPT/HCPCS Procedure CodesCPT
    0177UOncology (breast cancer), DNA, PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) gene analysis of 11 gene variants utilizing plasma, reported as PIK3CA gene mutation status. Proprietary test: therascreen® PIK3CA RGQ PCR Kit.
    0179UOncology (non-small cell lung cancer), cell-free DNA, targeted sequence analysis of 23 genes (single nucleotide variations, insertions and deletions, fusions without prior knowledge of partner/breakpoint, copy number variations), with report of significant mutation(s). Proprietary test: Resolution ctDx Lung™.
    0229UBCAT1 (Branched chain amino acid transaminase 1) and IKZF1 (IKAROS family zinc finger 1) (eg, colorectal cancer) promoter methylation analysis. Proprietary test: Colvera®. Lab/Manufacturer: Clinical Genomics Pathology Inc.
    0317UOncology (lung cancer), four-probe FISH (3q29, 3p22.1, 10q22.3, 10cen) assay, whole blood, predictive algorithm-generated evaluation reported as decreased or increased risk for lung cancer. Proprietary test: LungLB®. Lab/Manufacturer: LungLife AI®.
    0332UOncology (pan-tumor), genetic profiling of 8 DNA-regulatory (epigenetic) markers by quantitative polymerase chain reaction (qPCR), whole blood, reported as a high or low probability of responding to immune checkpoint-inhibitor therapy. Proprietary test: EpiSwitch® CiRT (Checkpoint-inhibitor Response Test). Lab/Manufacturer: Next Bio-Research Services, LLC.
    0333UOncology (liver), surveillance for hepatocellular carcinoma (HCC) in high-risk patients, analysis of methylation patterns on circulating cell-free DNA (cfDNA) plus measurement of serum AFP/AFP-L3 and oncoprotein des-gamma-carboxyprothrombin (DCP), algorithm reported as normal or abnormal result. Proprietary test: HelioLiver™ Test. Lab/Manufacturer: Fulgent Genetics, LLC.
    0337UOncology (plasma cell disorders and myeloma), circulating plasma cell immunologic selection, identification, morphological characterization, and enumeration of plasma cells based on differential CD138, CD38, CD19, and CD45 protein biomarker expression, peripheral blood. Proprietary test: CELLSEARCH® Circulating Multiple Myeloma Cell (CMMC) Test. Lab/Manufacturer: Menarini Silicon Biosystems, Inc.
    0338UOncology (solid tumor), circulating tumor cell selection, identification, morphological characterization, detection and enumeration based on differential EpCAM, cytokeratins 8, 18, and 19, and CD45 protein biomarkers, and quantification of HER2 protein biomarker-expressing cells, peripheral blood. Proprietary test: CELLSEARCH® HER2 Circulating Tumor Cell (CTC-HER2) Test.
    0343UOncology (prostate), exosome-based analysis of 442 small non-coding RNAs (sncRNAs) by quantitative reverse transcription polymerase chain reaction (RT-qPCR), urine, reported as molecular evidence of no-, low-, intermediate- or high-risk of prostate cancer. Proprietary test: miR Sentinel™ Prostate Cancer Test.
    0368UOncology (colorectal cancer), evaluation for mutations of APC, BRAF, CTNNB1, KRAS, NRAS, PIK3CA, SMAD4, and TP53, and methylation markers (MYO1G, KCNQ5, C9ORF50, FLI1, CLIP4, ZNF132 and TWIST1), multiplex quantitative polymerase chain reaction (qPCR), circulating cell-free DNA (cfDNA), plasma, report of risk score for advanced adenoma or colorectal cancer. Proprietary test: ColoScape™ Colorectal Cancer Detection.
    1–10 of 20
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    Provider Requirements and Action Items

    Prior Authorization

    Precertification and Benefit Review

    Review benefit coverage and precertification requirements before ordering liquid biopsy testing. Coverage depends on the member’s benefit at the time of the request; refer to the GTM Utilization Review Matrix for precertification requirements and applicable Medicare or Medicaid provisions.

    • Confirm the member’s applicable benefit and line of business: HMO, PPO, QUEST Integration, Medicare, or FEP.
    • Obtain precertification when required before the service is performed.
    • Benefit determinations remain subject to the member contract; contract language controls if it conflicts with this policy.
    Documentation Required

    Clinical Indication and Medical Necessity

    Document the diagnosis, clinical setting, intended treatment or biomarker-selection purpose, specimen source, and clinical rationale supporting cfDNA/ctDNA testing. For covered NSCLC use, explain why tissue testing is infeasible, insufficient, incomplete, or unlikely to be timely.

    • Document pathological confirmation of NSCLC when applicable.
    • Identify the specimen being tested and the biomarkers or treatment decision at issue.
    • For HR-positive/HER2-negative breast cancer, document consideration of targeted therapy and the PIK3CA-testing rationale.
    • For castration-resistant prostate cancer, document the treatment-selection purpose and applicable AR-V7 or BRCA1/2 indication.
    Documentation Required

    NSCLC Tissue-Testing Documentation

    For NSCLC, document tissue feasibility and the reason plasma testing is needed. Record whether tissue quantity is insufficient, invasive biopsy is medically contraindicated, tissue testing cannot assess all recommended biomarkers, or timely tissue testing is uncertain.

    • After pathological confirmation, document insufficient tissue for broad molecular analysis when applicable.
    • If tissue-based molecular analysis is incomplete, identify the unassessed recommended biomarkers, including ALK, BRAF, EGFR, ERBB2/HER2, KRAS, MET exon 14, NTRK1/2/3, RET, ROS1, and PD-L1.
    • If an oncogenic driver is not identified in plasma, plan or arrange follow-up tissue-based analysis.
    Documentation Required

    Clinical Rationale and Follow-Up Tissue Plan

    When plasma testing is selected because tissue is unavailable, insufficient, or difficult to obtain, document the clinical rationale and establish a tissue follow-up plan. Plasma testing may help identify actionable biomarkers, but a negative result does not exclude a tumor alteration.

    • Consider scheduling tissue biopsy concurrently with the plasma-testing referral when clinically appropriate.
    • Plan tissue re-biopsy or other tissue-based testing after a negative plasma result or when no oncogenic driver is identified.
    • Document that tissue-based testing generally has greater sensitivity and that plasma testing may better reflect tumor heterogeneity in some situations.

    Unsupported block type: documentation

    Unsupported block type: documentation

    Note

    Documentation for Reconsideration

    If the treating physician disagrees with HMSA’s medical-necessity determination, submit a physician reconsideration request with supporting clinical documentation for the case.

    • Include the diagnosis, benefit information, clinical indication, relevant pathology and tissue-testing results, assay and laboratory details, and the rationale for medical necessity.
    • Address any policy criterion or denial condition at issue.
    Denial Risk

    Unspecified Malignancy Screening or Monitoring

    Liquid biopsy testing for screening, detecting, or monitoring malignancy outside the specifically covered situations does not meet coverage criteria. This includes uses for an unspecified malignancy or tumor that are not otherwise addressed by the policy.

    • Examples include broad cancer screening such as GRAIL Galleri and other unlisted screening, detection, or monitoring uses.
    • Document a covered indication before ordering the test.
    Denial Risk

    PD-L1 Liquid Biopsy Outside Covered Criteria

    PD-L1 analysis by liquid biopsy does not meet coverage criteria when performed outside the specifically covered situations described in the policy.

    • Do not assume that a liquid-biopsy PD-L1 result is covered solely because PD-L1 may be relevant to treatment selection.
    • Document the applicable covered clinical indication and testing method.
    Denial Risk

    Urinary Liquid Biopsy

    Urinary liquid biopsy for cancer screening, detection, or diagnosis does not meet coverage criteria when it uses cell-free DNA or circulating tumor DNA obtained from urine.

    • Affected uses include UcfDNA, urine-derived ctDNA, and related tests such as SelectMDX when used for screening, detection, or diagnosis.
    Denial Risk

    CSF Liquid Biopsy

    Liquid biopsy testing performed on cerebrospinal fluid (CSF) does not meet coverage criteria under this policy.

    • This denial condition applies to liquid biopsy testing using CSF specimens, including ctDNA or CTC analysis.
    Denial Risk

    CTC Enumeration Assays

    Cell capture-enumeration assays for circulating tumor cells do not meet coverage criteria.

    • This includes CTC enumeration assays such as CELLSEARCH® CTC.
    • Do not treat cell enumeration as equivalent to covered plasma ctDNA genotyping.
    Documentation Required

    Do Not Substitute for Tissue Diagnosis

    Do not use cfDNA/ctDNA testing in lieu of histologic tissue diagnosis. A negative plasma result has limited sensitivity and may be falsely negative; tissue diagnosis and appropriate tissue-based molecular follow-up remain necessary.

    • Obtain histologic confirmation of NSCLC when clinically feasible.
    • If plasma testing is negative or does not identify an oncogenic driver, perform or plan tissue-based testing with re-biopsy material when appropriate.
    • Plasma testing may be considered when the patient is medically unfit for invasive sampling or tissue is insufficient for molecular analysis, but follow-up tissue analysis should be planned.
    Denial Risk

    Insufficient Evidence for Routine Surveillance or Monitoring

    Do not use liquid biopsy routinely for surveillance, therapy-response monitoring, early diagnosis, recurrence assessment, or screening when the policy does not specifically cover the use. Current evidence is insufficient for many of these applications, and negative or discordant results require cautious interpretation.

    • Do not use circulating biomarkers as a surveillance strategy for recurrence after curative-intent treatment of stage I–III NSCLC or SCLC.
    • Routine ctDNA or CTC monitoring of treatment response in metastatic breast cancer is not supported by sufficient evidence.
    • Post-surgical ctDNA for recurrence-risk estimation or adjuvant-therapy decisions in colorectal cancer lacks sufficient evidence for routine use.
    • Liquid biopsy for screening or early cancer diagnosis, and CTC or ctDNA use for recurrence or therapy monitoring outside covered indications, should not be ordered as routine practice.
    Denial Risk

    CTC or ctDNA Use in Breast Cancer Management

    Do not use CTC or ctDNA results to guide systemic-therapy decisions in breast cancer unless the use is specifically supported by the coverage criteria. CTCs may be prognostic but are not predictive of clinical benefit for selecting systemic therapy, and routine ctDNA or CTC monitoring is not supported for metastatic breast cancer.

    • Do not use CTCs to guide adjuvant systemic therapy decisions in early-stage invasive breast cancer.
    • Do not use CTCs as an adjunctive assessment to guide systemic therapy in metastatic breast cancer.
    • Covered liquid-biopsy use remains distinct: PIK3CA testing may meet criteria for HR-positive/HER2-negative breast cancer when targeted therapy is being considered.
    • Blood-based ctDNA may be used for guideline-supported ESR1 or PIK3CA treatment-selection testing at recurrence or progression when clinically indicated; this does not establish coverage for routine surveillance or response monitoring.
    Denial Risk

    Services Outside Policy Coverage

    Services that do not meet this policy’s coverage criteria will generally be considered not medically necessary under applicable Hawaii law. Providers may still offer clinically appropriate care, but coverage and payment remain subject to the member contract and HMSA’s determination.

    • If the treating physician disagrees with a medical-necessity determination, request reconsideration with supporting documentation.
    • The medical policy is a coverage guide and does not replace the physician’s clinical judgment.
    Note

    NSCLC Molecular Profiling and Clinical-Trial Counseling

    For NSCLC, pursue broad molecular profiling to identify rare driver mutations for which effective targeted therapies may be available and to support appropriate clinical-trial counseling. Consider plasma or tissue-based broad profiling at progression for T790M and other genomic-resistance mechanisms, while arranging tissue follow-up when plasma testing is negative.

    • Assess guideline-recommended biomarkers broadly rather than relying on an incomplete single-gene approach when clinically feasible.
    • Counsel eligible patients regarding clinical-trial availability when rare drivers or resistance mechanisms are identified or when standard options are limited.
    • Use a clinically validated NGS platform when feasible; if a limited assay is negative, pursue serial or additional testing for other actionable biomarkers.
    • Do not use plasma ctDNA in place of histologic diagnosis.

    Liquid Biopsy Background

    Liquid biopsy analyzes blood or another bodily fluid for circulating tumor cells, cell-free tumor DNA, or other tumor-derived molecules. It can provide a less invasive means of tumor characterization for treatment selection, monitoring, or recurrence assessment, but it has lower sensitivity and more false-negative results than tissue biopsy. Tissue biopsy remains relevant when liquid biopsy does not identify an oncogenic driver or when additional tissue-based assessment is needed.

    Definitions and Abbreviations

    Liquid biopsy
    DefinitionA test performed on blood, urine, or another bodily fluid to detect cancer cells or DNA, RNA, or other molecules released by tumor cells.
    SpecimensBlood, urine, or another bodily fluid may be used.
    AnalytesLiquid biopsy may examine circulating tumor cells, cell-free tumor DNA, RNA, or other tumor-derived molecules.
    cfDNA
    Full termCell-free tumor deoxyribonucleic acid.
    DefinitionTumor DNA detected in a bodily fluid, especially blood or plasma.
    Relationship to liquid biopsycfDNA fragments may be shed into the bloodstream from existing tumors and detected in blood.
    ctDNA
    Full termCirculating tumor deoxyribonucleic acid.
    DefinitionTumor DNA released from tumor cells into the bloodstream.
    Common specimenctDNA may be measured in a blood or plasma specimen.
    Circulating tumor cells
    DefinitionCells shed from a primary tumor into the vasculature.
    Clinical significanceCirculating tumor cells may contribute to metastatic growth.
    DetectionCTCs can be detected in bodily fluids, including blood.
    CRPC
    AbbreviationCRPC.
    Full termCastration-resistant prostate cancer.
    Policy contextThe policy addresses selected circulating biomarker testing in the metastatic CRPC setting.
    NSCLC
    AbbreviationNSCLC.
    Full termNon-small cell lung cancer.
    Policy contextThe policy addresses plasma ctDNA testing for selected NSCLC circumstances.
    CTCs
    Full termCirculating tumor cells.
    DefinitionTumor cells present in a bodily fluid, including blood or cerebrospinal fluid.
    UseCTCs may be analyzed for disease-related information.
    cfDNA
    DefinitionDNA circulating outside intact cells.
    Tumor-derived cfDNATumor-derived cell-free DNA may be analyzed from blood or other liquid specimens.
    SpecimensCell-free DNA is not necessarily confined to blood; other liquid media may be used.
    Exosomes
    DefinitionVesicles found in bodily fluids.
    Transport functionExosomes can protect and transport RNA, DNA, proteins, lipids, oligosaccharides, and metabolites.
    RNA analysisNucleic acids in exosomes can be isolated and the entire transcriptome examined.
    InDels
    Full termInsertions and deletions.
    DefinitionSequence alterations involving the addition or loss of nucleotides.
    Assay contextInDels are among the molecular alterations that liquid biopsy platforms may analyze.
    ctDNA
    DefinitionCirculating tumor DNA or cell-free tumor DNA measured in a body-fluid specimen, commonly plasma.
    PurposectDNA may be measured to detect tumor-associated genomic alterations.
    Clinical limitationctDNA testing should not be used in lieu of histologic tissue diagnosis; plasma testing may produce false-negative results.
    Circulating tumor cells (CTCs)
    DefinitionTumor cells isolated, identified, characterized, or enumerated from a fluid specimen such as peripheral blood.
    SpecimenPeripheral blood is an example of a fluid specimen used for CTC testing.
    Testing activitiesCTC assays may select, identify, characterize, detect, or enumerate tumor cells.
    Liquid biopsy methodology
    DefinitionA group of methodologies for analyzing circulating analytes.
    Most studied approachPlasma circulating tumor DNA is the most extensively studied and widely adopted alternative to tissue tumor genotyping in solid tumors.
    Clinical applicationLiquid biopsy methodologies may be used to evaluate circulating tumor DNA and other circulating analytes.
    Laboratory-developed test (LDT)
    DefinitionA test performed and validated in-house by a laboratory.
    CMS and CLIA statusLDTs are regulated by CMS as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA '88).
    FDA contextLDTs are not approved or cleared by the U.S. Food and Drug Administration; FDA clearance or approval is not currently required for clinical use according to the document.
  2. Acute myeloid leukemia: Morphologically detectable circulating leukemic blasts from peripheral blood may be used to detect molecular abnormalities.
  3. Primary CNS lymphoma: Cerebrospinal fluid analysis may possibly include gene rearrangement evaluation.
  4. Leptomeningeal metastasis: ctDNA or circulating tumor cells in cerebrospinal fluid may be assessed to increase sensitivity of tumor-cell detection and assess response to treatment.