Sierra Health and Life Molecular Oncology Coverage Update | OpenPayer
Currentsierra health and lifePolicy 2026T0588MM
Molecular Oncology Testing for Solid Tumor Cancer Diagnosis, Prognosis, and Treatment Decisions
Policy governing coverage of molecular and gene expression profiling tests for diagnosis, prognosis, and treatment decisions in solid tumor cancers for UnitedHealthcare Commercial and Individual Exchange plans.
Policy Summary
Payersierra health and life
PolicyMolecular Oncology Testing for Solid Tumor Cancer Diagnosis, Prognosis, and Treatment Decisions
Policy CodePolicy 2026T0588MM
Change TypeMinor update — no material clinical or coverage changes
Effective DateJan 1, 2026
Next Review DateN/A
Key ActionDocument clinical records to show the test meets specified clinical criteria (e.g., timing, nodal status, cytology category) and that results will influence management.
No material clinical or coverage changes in this revision.
6Breast GEP window (months)
10Prostate life expectancy (years)
50NGS gene-count threshold
~120Approx. codes listed
46%MINDACT avoided chemo
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Breast Cancer Gene Expression Profiling (GEP) is proven and medically necessary when used to inform treatment decisions in the following scenarios.
Newly diagnosed invasive breast cancer: Test performed within 6 months of diagnosis AND lymph node negative (including micrometastases ≤2 mm) OR 1–3 positive ipsilateral axillary lymph nodes AND no distant metastases AND hormone receptor–positive AND HER2 receptor–negative AND adjuvant chemotherapy is not precluded by other factors (e.g., advanced age/comorbidities).6 months
Applies to MammaPrint, Oncotype DX Breast, Prosigna (PAM50), Breast Cancer Index (BCI), EndoPredict.
Decision about extended adjuvant hormonal therapy: Individual currently receiving adjuvant hormonal therapy AND hormone receptor–positive AND HER2 receptor–negative AND treating physician and individual discussed potential test results prior to testing and will use results to guide decision regarding extended adjuvant hormonal therapy.
BCI may be used for extended endocrine therapy evaluation even if prior GEP was done for adjuvant chemotherapy decision.
Lung cancer — Covered indications
Non-small cell lung cancer (NSCLC) multigene molecular profiling is proven and medically necessary when used to identify actionable genomic alterations to guide targeted therapy.
NSCLC multigene profiling: Multigene molecular profiling using targeted NGS panels (preferably multiplex panel-based testing) is indicated to identify actionable genomic alterations to guide targeted therapy; plasma cfDNA/ctDNA testing may be used when tissue is unavailable or patient is unfit for biopsy, but negative plasma results should be followed by tissue testing if clinical suspicion remains.prefer panel-based NGS (may exceed 50 genes when consistent with guideline/companion diagnostic use)
Multiplexed panels preferred over single-gene assays; cfDNA has prognostic associations but is not a substitute for tissue when tissue testing feasible.
ctDNA prognostic/serial assessment: Serial ctDNA/cfDNA testing may provide prognostic information (baseline negativity or early clearance associated with improved PFS), but heterogeneity in the evidence limits routine use for prognostic-only decisions; use primarily to identify actionable alterations or when tissue is unavailable.
Additional serial ctDNA studies recommended; interpret in clinical context.
Prostate GEP — Covered indications
Prostate cancer gene expression profiling tests are proven and medically necessary when used to assist treatment decision-making in untreated, localized adenocarcinoma under the following conditions.
Initial risk stratification (GPS/Prolaris/Decipher biopsy): Test ordered by a physician specializing in organ-confined prostate cancer (urology/surgical oncology, radiation oncology, or medical oncology) AND individual is treatment‑naïve and a candidate for active surveillance or definitive therapy AND life expectancy > 10 years AND risk group is Very Low, Low, or Favorable Intermediate‑Risk (per guideline definitions).life expectancy >10 years
Applicable to Genomic Prostate Score (GPS)/Oncotype DX Prostate, Prolaris, Decipher biopsy; Decipher may include additional risk groups in some settings.
Post‑prostatectomy / adverse pathology (Decipher RP): Decipher post‑prostatectomy genomic classifier used to inform adjuvant therapy decisions when adverse pathological features are present (e.g., Gleason ≥8, extracapsular extension, positive margins, seminal vesicle invasion) OR PSA persistence/recurrence post‑prostatectomy.PSA > 0 or presence of adverse pathologic features
Decipher post‑RP use corresponds to NCCN category 2B evidence in specified contexts.
Thyroid molecular testing — Covered indications
Thyroid nodule molecular testing is proven and medically necessary when used as an adjunct to cytology and clinical assessment in specific indeterminate cases or when CGP is required for anaplastic thyroid cancer.
Indeterminate thyroid nodule testing (rule-out/management): Fine needle aspiration cytology is indeterminate (Bethesda III or IV) AND results of a validated molecular test will be used to inform the decision about further surgery (e.g., diagnostic lobectomy vs observation).Bethesda III/IV
Examples of covered tests include Afirma GSC, ThyroSeq v3, ThyGeNEXT/ThyraMIR; Afirma Xpression Atlas and some other listed tests are not supported for all indications.
Anaplastic thyroid cancer — CGP: Comprehensive genomic profiling (CGP) of confirmed anaplastic thyroid cancer is indicated to identify targetable alterations for systemic therapy or clinical trial enrollment.
CGP intended for confirmed anaplastic histology to inform targeted treatment options.
Uveal melanoma GEP — Covered indications
Uveal melanoma gene expression profiling (GEP) is proven and medically necessary when used to inform prognostication and follow‑up planning in primary localized disease.
Uveal melanoma prognostic GEP: Individual has primary, localized uveal melanoma AND no evidence of metastatic disease AND testing (e.g., DecisionDx-UM/15‑GEP) will be used to inform follow‑up intensity or surveillance strategy AND individual has not previously had the same test for the current diagnosis.
Tumor size and other clinicopathologic features should be considered alongside GEP classification; biopsy risks and benefits must be documented and discussed.
This section lists CPT/PLA/HCPCS codes and brief descriptions of molecular and genomic oncology tests referenced by the policy.
Code catalog overview: Enumerated PLA (U), CPT and HCPCS codes correspond to specific oncology molecular tests (targeted NGS panels, GEP assays, ctDNA/MRD assays, methylation assays, etc.) as described in adjacent code descriptions; see code table for the full list and test descriptions.
This catalog is a reference; coverage determinations for tests are specified in the related coverage criteria sections.
Breast cancer molecular assay coverage evidence
Evidence summaries and clinical utility findings for breast cancer gene expression assays inform coverage considerations.
General evidence summary for breast GEPs: Multiple commercial GEAs (Oncotype DX, MammaPrint, Prosigna/PAM50, BCI, EndoPredict) have evidence supporting prognostic capability in specific patient subsets; Oncotype DX has the strongest evidence for predicting chemotherapy benefit based on large prospective trials and meta-analyses.
Evidence includes MINDACT, TAILORx and multiple prospective-retrospective validations; applicability varies by menopausal and nodal status.
MammaPrint evidence (MINDACT): MINDACT randomized trial (n=6693) showed MammaPrint can identify clinically high-risk but genomically low-risk patients who may safely omit chemotherapy with a small absolute reduction in 5‑year DMFS; trial evidence supports use in selected early-stage patients and informed the non-inferiority margin used in clinical decision-making.MINDACT non-inferiority boundary: 92% five-year DMFS lower 95% CI
Effect size and age dependence noted; benefit concentrated in younger women in subgroup analyses.
Selected evidence-based conclusions and implied coverage considerations from trials and assessments.
Prospective trial-derived conclusions: MINDACT and other randomized/prospective trials provide context for identifying patients who may avoid chemotherapy based on genomic risk; retrospective and prospective-retrospective studies support prognostic validity for several assays but have limitations in generalizability and subgroup applicability.
Trials often use specific eligibility windows and node-status groupings; interpretation should follow trial-specified populations.
Guideline-aligned use: Professional guidelines (ASCO, ESMO, NCCN, NICE) support selective use of GEPs when clinical/pathologic uncertainty remains and when testing will influence management decisions; use should be within intended purpose and laboratory QA frameworks.
ASCO supports Oncotype DX, MammaPrint, BCI, EndoPredict in specific postmenopausal/node scenarios; NCCN prefers Oncotype DX for predictive use.
Limitations and need for documentation: Evidence limitations (retrospective analyses, limited diversity, manufacturer involvement) and absence of demonstrated long-term outcome benefit in some settings imply that testing should be documented as intended to alter management, with specimen adequacy and lab QA noted.
Evidence-based coverage considerations
Evidence-based coverage considerations and guideline-constrained application constraints summarized for clinical use.
When GEPs are appropriate: GEPs may be used when clinical/pathologic assessment leaves uncertainty regarding adjuvant chemotherapy or extended endocrine therapy and when the individual falls within guideline-specified populations (e.g., postmenopausal or age >50, node-negative or 1–3 positive nodes for selected assays).node-negative or 1–3 positive nodes; age/menopausal status per guideline
Use should be shared‑decision driven and within intended assay use and laboratory QA participation.
Assay selection and preference: NCCN prefers the 21-gene Oncotype DX for prognostic and predictive use in pN0 and selected pN1 contexts; other assays (MammaPrint, Prosigna, EndoPredict, BCI) provide prognostic information with varying predictive evidence and may be used where guideline recommendations apply.
NICE constrains MammaPrint use in certain node-positive contexts and recommends menopausal-status limitations for some assays.
Documentation and lab requirements:
Guideline-constrained use
Guideline-constrained use — professional society recommendations that constrain appropriate application of molecular tests.
NCCN guidance — breast GEPs: Gene expression assays provide prognostic and therapy‑predictive information complementary to TNM and biomarker data; 21‑gene Oncotype DX is preferred for prognosis and prediction of chemotherapy benefit in pN0 and selected pN1 cases.pN0 or select pN1 (1–3 nodes)
Other assays may be prognostic but have variable predictive evidence; interpret per NCCN categories.
ASCO/ESMO/NICE constraints: ASCO and ESMO endorse selective use of Oncotype DX, MammaPrint, BCI, and EndoPredict in postmenopausal or >50 individuals with ER+, HER2- disease who are node‑negative or have 1–3 positive nodes; NICE places menopausal and nodal limitations (e.g., MammaPrint not for guiding chemo in 1–3 node premenopausal women).menopausal status and nodal status dependent
Shared decision-making and lab QA participation emphasized.
Breast cancer — Gene expression profiling
GEP for breast cancer: Covered when used to inform adjuvant systemic therapy decisions consistent with guideline‑specified indications.
Oncotype DX (preferred) for invasive breast cancer: Oncotype DX 21‑gene Recurrence Score used to provide prognostic and predictive information to guide adjuvant chemotherapy decisions in invasive ER+/HER2- breast cancer in pN0 and selected pN1 (1–3 positive nodes) patients, consistent with NCCN preference and supporting RCT evidence.pN0 or select pN1 (1–3 nodes)
Integration with clinicopathologic factors (RSClin) can improve prognostic accuracy; randomized data (TAILORx, Kalinsky et al.) inform predictive use in subgroups.
NICE-specific breast cancer coverage nuance
NICE-specific breast cancer coverage nuance.
NICE recommendations (selected): EndoPredict, Oncotype DX, or Prosigna may be used with clinical risk factors to guide adjuvant chemotherapy decisions for ER/PR‑positive, HER2‑negative early breast cancer with 1–3 positive lymph nodes in postmenopausal individuals; MammaPrint should not be used to guide adjuvant chemotherapy decisions for 1–3 node positive premenopausal women and MammaPrint/IHC4+C not recommended for LN‑negative guidance in some contexts.menopausal status and nodal status dependent
Testing should be within intended purpose, labs should participate in external QA, and shared decision-making documented.
Non-small cell lung cancer — Molecular/genomic testing
NSCLC molecular testing: Covered when used to identify actionable genomic alterations to guide targeted therapy.
Broad panel NGS testing for NSCLC: Broad panel‑based NGS testing is preferred when feasible to identify actionable alterations that inform targeted therapy selection; multiplexed panels are preferred over single‑gene assays.panel-based approach preferred; panel size per guideline/companion diagnostic use
Plasma ctDNA testing may be used when tissue is insufficient or invasive sampling not feasible; negative plasma should prompt tissue testing if suspicion remains.
ctDNA as prognostic marker in NSCLC
ctDNA prognostic use in NSCLC — evidence summary relevant to coverage considerations (prognostic associations but heterogenous evidence).
ctDNA prognostic association in NSCLC: Baseline negative ctDNA or early reduction/clearance after treatment is associated with improved progression‑free survival in pooled analyses, but high heterogeneity and publication bias limit certainty; serial ctDNA studies are recommended to further define utility.baseline negative or early reduction
Interpretation should account for study heterogeneity; use primarily to identify actionable alterations or as adjunct when tissue limited.
Prostate cancer — Genomic prognostic testing
Genomic classifiers in prostate cancer — evidence supporting prognostic association and selective clinical application.
GPS prognostic associations: Higher Genomic Prostate Score (GPS) is associated with increased risk of distant metastases and biochemical recurrence in localized prostate cancer; pooled analyses report substantially higher hazard ratios in high vs low GPS groups and per 20‑unit GPS increments.per 20‑unit GPS increase
Evidence derives from meta-analyses and cohort studies; quality assessed as variable by systematic assessments.
Decipher and Prolaris evidence: Decipher GC has multiple retrospective, registry and trial‑ancillary analyses showing independent prognostic value and potential utility in intermediate‑risk and post‑prostatectomy contexts; Prolaris (CCR) associated with selection/durability of active surveillance in low‑risk cohorts.
Prospective randomized outcome data remain limited; selective use recommended when results will change management.
Evidence summary and implied coverage considerations
Summary of evidence and implied coverage considerations for genomic classifiers in prostate cancer.
Evidence summary for genomic classifiers: Systematic reviews and assessments find genomic classifiers (GPS, Decipher, Prolaris) are independently prognostic for outcomes such as biochemical recurrence, metastasis and disease‑specific mortality in multiple cohorts; evidence quality ranges from low to moderate and prospective utility data are limited in some populations.
Guideline panels recommend selective, not routine, use—particularly when results are likely to affect management.
Limitations influencing coverage: Hayes and other assessments note very low to low quality evidence in certain indications and insufficient prospective trial data demonstrating improved long‑term outcomes when decisions are guided by these assays; coverage is therefore selective and tied to anticipated management impact.
Documentation that testing will influence management is advised.
Selective coverage when results influence management
Selective coverage is supported when assay results are likely to affect management decisions and align with guideline recommendations.
Initial risk stratification (prostate): Decipher, Oncotype DX Prostate (GPS), and Prolaris may be considered for men with low or favorable intermediate‑risk localized prostate cancer and life expectancy ≥10 years to guide decisions such as active surveillance versus definitive therapy.life expectancy >=10 years
NCCN and ASCO endorse selective offering when results will affect management.
Post‑prostatectomy and unfavorable risk: Decipher and Prolaris may be considered for risk stratification in unfavorable intermediate and high‑risk disease; Decipher may be used to inform adjuvant therapy decisions after radical prostatectomy (NCCN category 2B).
Use should be reserved for situations where results will change management; routine use not recommended absent prospective outcome data.
Adjunctive urine/blood markers: Urine- or serum-based adjunctive markers (e.g., ExoDx/EPI, MyProstateScore) may be used selectively when they would influence the decision to proceed with biopsy or repeat biopsy.
Prostate cancer — when tests may be considered
Prostate cancer — contexts where tests may be considered per guideline recommendations.
When prostate molecular assays may be considered: Decipher, Oncotype DX Prostate (GPS), and Prolaris may be considered in men with low or favorable intermediate‑risk prostate cancer with life expectancy ≥10 years for initial risk stratification; Decipher and Prolaris may be considered in unfavorable intermediate and high‑risk disease and Decipher may inform adjuvant therapy post‑prostatectomy and in PSA persistence/recurrence contexts.life expectancy >= 10 years
NCCN categorizes some post‑RP uses as category 2B; selection should be based on likelihood of management change.
Thyroid nodules — evidence and limitations
Thyroid nodules — evidence and limitations for molecular testing in indeterminate cytology.
Performance and limitations: Systematic reviews and meta-analyses report high sensitivity and NPV for ThyroSeq v3 and Afirma GSC in Bethesda III/IV nodules but specificity/PPV vary and many studies lack surgical confirmation for benign results; evidence quality limitations and need for prospective outcome data noted.
Hayes found overall evidence quality variable and recommended further high‑quality studies; test selection should consider institutional malignancy rates.
Thyroid nodule molecular testing — covered indications when results will alter management for indeterminate cytology.
Adjunctive molecular testing for indeterminate cytology: Molecular testing may be considered for nodules with nondiagnostic cytology, AUS/FLUS (Bethesda III), or follicular neoplasm/suspicious for follicular neoplasm (Bethesda IV) when results will change the decision about diagnostic surgery versus surveillance; testing should be interpreted with clinical, imaging, and cytologic features and institutional prevalence in mind.Bethesda III/IV
Examples of covered tests include Afirma GSC, ThyroSeq v3; multiple tests and versions have varying evidence quality.
Cutaneous melanoma molecular testing
Cutaneous melanoma molecular testing — evidence and conditional coverage considerations.
Prognostic GEP for melanoma (31‑GEP): Prognostic 31‑GEP testing may aid risk stratification (Class 1 vs Class 2) in select T1‑T2/AJCC I–II patients and could influence sentinel lymph node biopsy decisions, but studies have limitations (funding, follow‑up, heterogeneous designs) and routine prognostic use outside defined contexts is not established.
Prospective studies show potential to reduce SLNBs in selected populations but require cautious interpretation.
Diagnostic adjuncts (PLA/tape‑stripping): Pigmented Lesion Assay (PLA) and tape‑stripping tests may reduce unnecessary biopsies in some settings but evidence quality is low, real‑world discrepancies exist, and clinical utility for outcome improvement is unproven.
Guidelines recommend adjunctive use only with expert dermatopathologic interpretation and caution.
Routine prognostic GEP discouraged: Professional guidance (AAD, NCCN) discourages routine molecular prognostic testing for cutaneous melanoma until better use criteria and prospective evidence of clinical utility are available.
Coverage statements and evidence-based guidance
Coverage statements and evidence-based guidance for melanoma, uveal melanoma, cutaneous SCC, and CUP.
Adjunct diagnostic molecular techniques (melanoma): Ancillary molecular techniques (CGH, FISH, GEP, NGS) may be used as adjuncts for equivocal melanocytic neoplasms when interpreted with clinical and expert dermatopathologic examination.
Diagnostic adjunct use acceptable; prognostic use remains limited pending further evidence.
Uveal melanoma prognostic testing: When biopsy is performed for prognostic purposes in uveal melanoma, molecular/chromosomal testing is preferred over cytology and may be considered to stratify follow‑up intensity; risks/benefits of biopsy must be discussed and documented.
Hayes judged DecisionDx‑UM evidence insufficient for definitive 5‑year metastasis risk claims; tumor size remains an independent prognostic factor.
Cutaneous SCC — 40‑GEP: 40‑GEP testing may be used to further stratify metastatic risk in high‑risk cSCC and can be considered to inform adjuvant radiation therapy decisions within multidisciplinary planning, recognizing retrospective design and potential bias in current evidence.
CUP - Mixed/insufficient evidence
Cancers of unknown primary (CUP) — mixed/insufficient evidence regarding routine use of molecular testing to guide site‑specific therapy.
CUP — diagnostic yield vs outcome evidence: Molecular tests (GEP, DNA sequencing, CGP) can resolve the tissue‑of‑origin in a subset of CUP cases and identify potentially actionable alterations, but randomized trials have not demonstrated consistent survival benefit from site‑specific therapy guided by GEP and evidence is insufficient to support routine use for directing site‑specific therapy.
Use may be considered when multidisciplinary justification exists and when results will change management or enable targeted/trial options.
Colorectal cancer - Insufficient evidence for many molecular tests
Colorectal cancer — evidence and coverage considerations for molecular tests used in screening, prognostication, and tumor biomarker testing.
CRC screening (mSEPT9): Methylated SEPT9 (Epi proColon/ColoHealth) has limited sensitivity and evidence quality and is not a replacement for standard screening; it may be considered only for average‑risk individuals who would otherwise refuse standard screening modalities.
ACG recommends against routine use; Hayes rates evidence low‑quality.
Tumor testing for therapy selection (MMR/MSI, KRAS/NRAS, BRAF, HER2): Universal MMR/MSI testing is recommended for individuals with colon or rectal cancer; determination of KRAS/NRAS, BRAF, and HER2 status is recommended to guide targeted therapy and NGS is the preferred methodology when feasible.
NCCN endorses universal MMR/MSI for CRC; tumor biomarker testing may be done as single genes or via panels.
Oncotype DX Colon Recurrence Score and other multigene panels: Multigene recurrence scores provide prognostic information in stage II/III colon cancer but evidence for routine clinical utility to change management is limited and further validation is needed.
Coverage stance and clinical criteria
Coverage stance and clinical criteria derived from guideline recommendations and evidence summaries across tumor types.
Septin 9 / mSEPT9 screening stance: mSEPT9 (Epi proColon/ColoHealth) testing has limited sensitivity and overall low‑quality evidence; professional guidance does not recommend routine use for CRC screening and it may be considered only for individuals who refuse standard screening modalities.
ACG recommends against routine use; Hayes rates evidence low‑quality.
Tumor molecular testing (CRC and others): Tumor molecular testing for established therapeutic biomarkers (e.g., MMR/MSI, KRAS/NRAS, BRAF, HER2) is recommended per guidelines; NGS is preferred methodology when feasible for comprehensive genotyping to inform therapy and trial eligibility.
NCCN recommends universal MMR/MSI for colon/rectal cancer and targeted testing to guide therapy.
Pancreatic cyst and tumor testing: Targeted NGS testing of pancreatic cyst fluid (e.g., PancreaSeq) or TTNB/EUS‑FNB samples may aid in diagnosing mucinous cysts and detecting advanced neoplasia in select clinical contexts where results would change management, though some tests (e.g., PancraGEN) lack sufficient peer‑reviewed evidence.
Coverage considerations and evidence-based stance
Coverage considerations and evidence‑based stance for emerging assays (multi‑cancer detection, NavDx, pancreatic cyst testing, tumor‑informed MRD).
Multi‑cancer detection (MCD) tests: Current evidence does not support routine population screening with multi‑cancer detection (MCD) assays (e.g., Galleri); professional societies have not recommended routine use and prospective trials to demonstrate impact on late‑stage cancer incidence and mortality are ongoing.
Published studies show high specificity but variable sensitivity by stage and cancer type; use only in research or trial settings pending validation.
NavDx (TTMV‑HPV DNA): Evidence for NavDx is limited and primarily observational; while it may add incremental diagnostic or surveillance value in HPV‑related cancers, clinical utility data demonstrating improved outcomes are lacking and routine coverage is not established.
Hayes and ECRI assessments identify limited evidence and call for prospective validation studies.
Tumor‑informed MRD assays (Signatera) and broad MRD use: Tumor‑informed ctDNA MRD assays can detect minimal residual disease and are prognostic in multiple cohorts, but evidence demonstrating that routine MRD monitoring changes outcomes is insufficient; routine surveillance use is not supported outside clinical trials or defined contexts.
General coverage determinations (MRD, broad sequencing)
General coverage determinations for MRD ctDNA assays and whole‑exome/genome/transcriptome tumor profiling.
Tumor‑informed/naive MRD assays: Current evidence is insufficient to support routine clinical use of ctDNA MRD assays (tumor‑informed or tumor‑naive) for surveillance or to guide adjuvant therapy decisions outside clinical trials; consideration may be given within prospective study protocols or when management will demonstrably change based on results.
Hayes concluded insufficient evidence for routine use; multiple trials ongoing.
Whole exome/genome/transcriptome sequencing (WES/WGS/WTS): Whole exome/genome/transcriptome tumor profiling currently lacks sufficient peer‑reviewed evidence to support routine clinical use for informing treatment decisions in solid tumors; identification of potentially actionable findings does not by itself establish improved outcomes.
Evidence shows potential actionable findings but inadequate outcome data linking testing to benefit.
Evidence summaries (prognostic vs. actionable)
Evidence summaries (prognostic associations vs. actionable utility) relevant to MRD and ctDNA — contextual findings for coverage consideration.
Prognostic associations of ctDNA MRD: Multiple cohort studies show ctDNA MRD positivity after definitive therapy is strongly associated with higher recurrence risk and worse survival across tumor types, indicating prognostic value but not yet established clinical utility for routine decision‑making.
Examples include Reinert et al., Loupakis et al., Magbanua et al.; further prospective outcome‑driven trials needed.
Impact on management uncertain: Retrospective analyses report that a minority of ctDNA MRD tests led to an immediate change in clinical management (e.g., ~16% in some series), underscoring the current uncertainty about how test results translate into beneficial management changes.
Additional high‑quality trials required to establish standardized clinical pathways and benefit.
All molecular testing for solid tumor cancers that is not explicitly identified as proven and medically necessary in this policy is considered unproven and not medically necessary. Examples include, but are not limited to, NGS panels >50 genes or comprehensive genomic profiling (CGP) unless otherwise specified, measurable residual disease (MRD) assays in solid tumors (tumor‑informed or tumor‑naïve), multi‑cancer early detection tests, and the proprietary assays and categories listed in the policy (e.g., Afirma XA, CancerTYPE ID, Guardant Shield™, Galleri®, PancraGEN®, Signatera™, NavDx®, and others).
Within the portions of the source excerpt referenced here there are no additional explicit exclusions listed beyond the general statement that non‑specified molecular tests are unproven and not medically necessary; coverage decisions are defined elsewhere in the policy for specific assays and clinical indications.
Note: the Prosigna (PAM50) assay is not intended for individuals with N2 disease (four or more positive lymph nodes); Prosigna’s prognostic use is described for postmenopausal women with HR+, N0 or N+ (stage II) disease.
In the provided excerpts there are no further test‑specific exclusions beyond those stated for individual assays (for example, Prosigna’s N2 limitation); other assays’ applicability and limitations are described in their evidence sections rather than as categorical exclusions.
ASCO guidance states that no gene expression assays are recommended for individuals with HER2‑positive or triple‑negative breast cancer, i.e., GEAs are not indicated to guide adjuvant systemic therapy decisions in these receptor‑defined subgroups.
NICE guidance includes nuanced recommendations: EndoPredict, Oncotype DX, or Prosigna may be used with clinical risk factors for postmenopausal individuals (or others depending on hormonal profile) to guide adjuvant chemotherapy decisions, but MammaPrint should not be used to guide adjuvant chemotherapy decisions for ER/PR‑positive, HER2‑negative early breast cancer with 1–3 positive lymph nodes; NICE also specifies age/menopausal and nodal considerations and intended‑use constraints for these assays.
Systematic assessments (Hayes) and guideline summaries note that evidence is insufficient to conclude that GPS or Decipher definitively improve long‑term clinical outcomes in some populations; the quality of evidence is low or very low for certain indications, and this uncertainty limits routine use where outcome benefit has not been demonstrated.
Oncology, 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.
0012M
Oncology (urothelial), mRNA, gene expression profiling by real-time quantitative PCR of five genes (MDK, HOXA13, CDC2 [CDK1], IGFBP5, and CXCR2), utilizing urine, algorithm reported as a risk score for having urothelial carcinoma.
0013M
Oncology (urothelial), mRNA, gene expression profiling by real-time quantitative PCR of five genes (MDK, HOXA13, CDC2 [CDK1], IGFBP5, and CXCR2), utilizing urine, algorithm reported as a risk score for having recurrent urothelial carcinoma.
0016M
Oncology (bladder), mRNA, microarray gene expression profiling of 219 genes, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as molecular subtype.
0020M
Oncology (central nervous system), analysis of 30000 DNA methylation loci by methylation array, utilizing DNA extracted from tumor tissue, diagnostic algorithm reported as probability of matching a reference tumor subclass.
0005U
Oncology (prostate) gene expression profile by real-time RT-PCR of 3 genes (ERG, PCA3, and SPDEF), urine, algorithm reported as risk score.
0018U
Oncology (thyroid), microRNA profiling by RT-PCR of 10 microRNA sequences, utilizing fine needle aspirate, algorithm reported as a positive or negative result for moderate to high risk of malignancy.
0019U
Oncology, RNA, gene expression by whole transcriptome sequencing, formalin-fixed paraffin-embedded tissue or fresh frozen tissue, predictive algorithm reported as potential targets for therapeutic agents.
0022U
Targeted genomic sequence analysis panel, non-small cell lung neoplasia, DNA and RNA analysis, 23 genes, interrogation for sequence variants and rearrangements, reported as presence or absence of variants and associated therapy(ies) to consider.
0026U
Oncology (thyroid), DNA and mRNA of 112 genes, next-generation sequencing, fine needle aspirate of thyroid nodule, algorithmic analysis reported as a categorical result ("Positive, high probability of malignancy" or "Negative, low probability of malignancy").
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1/3
Applicable CPT/PLA/HCPCS Codesmixed
0022U
Targeted genomic sequence analysis panel, non-small cell lung neoplasia, DNA and RNA analysis, 23 genes
0026U
Oncology (thyroid), DNA and mRNA of 112 genes, NGS, fine needle aspirate
0036U
Exome (somatic), paired FFPE tumor and normal specimen, sequence analyses
0037U
Targeted genomic sequence analysis, solid organ neoplasm, DNA 324 genes, includes MSI and TMB
0045U
Oncology (breast DCIS), mRNA, gene expression profiling by RT-PCR of 12 genes, recurrence score
0047U
Oncology (prostate), mRNA, gene expression profiling by RT-PCR of 17 genes, risk score
0048U
Oncology (solid), DNA targeted sequencing of 468 genes, includes somatic mutations and MSI
0069U
Oncology (colorectal), microRNA, RT-PCR profiling of miR-31-3p
0089U
Oncology (melanoma), gene expression profiling, PRAME and LINC00518, adhesive patch
0090U
Oncology (cutaneous melanoma), mRNA profiling by RT-PCR of 23 genes
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1/12
Applicable CPT/HCPCS Codesmixed
81524
Oncology (central nervous system tumor), DNA methylation analysis of at least 10,000 methylation sites, algorithm(s) reported as probability of matching a reference tumor family and class, and MGMT promoter methylation status, if performed.
81525
Oncology (colon), mRNA, gene expression profiling by real-time RT-PCR of 12 genes (7 content and 5 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a recurrence score.
81529
Oncology (cutaneous melanoma), mRNA, gene expression profiling by real-time RT-PCR of 31 genes (28 content and 3 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as recurrence risk, including likelihood of sentinel lymph node metastasis.
81540
Oncology (tumor of unknown origin), mRNA, gene expression profiling by real-time RT-PCR of 92 genes (87 content and 5 housekeeping) to classify tumor into main cancer type and subtype, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a probability of a predicted main cancer type and subtype.
81541
Oncology (prostate), mRNA gene expression profiling by real-time RT-PCR of 46 genes (31 content and 15 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a disease-specific mortality risk score.
Oncology (thyroid), mRNA, gene expression analysis of 10,196 genes, utilizing fine needle aspirate, algorithm reported as a categorical result (e.g., benign or suspicious).
81551
Oncology (prostate), promoter methylation profiling by real-time PCR of 3 genes (GSTP1, APC, RASSF1), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a likelihood of prostate cancer detection on repeat biopsy.
81552
Oncology (uveal melanoma), mRNA, gene expression profiling by real-time RT-PCR of 15 genes (12 content and 3 housekeeping), utilizing fine needle aspirate or formalin-fixed paraffin-embedded tissue, algorithm reported as risk of metastasis.
81599
Unlisted multianalyte assay with algorithmic analysis.
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No explicit CPT/HCPCS/ICD codes in these chunksmixed
No codes listed
No CPT/HCPCS/ICD codes listed in this excerptmixed
No codes listed
Referenced molecular tests (no codes provided)mixed
not listed
Document references tumor gene testing (KRAS/NRAS, BRAF, HER2, MSI/MMR) but provides no billing codes in this excerpt.
Pancreatic cyst NGS panels (no codes provided)mixed
not listed
PancreaSeq (74-gene NGS panel) referenced; no billing codes provided in this excerpt.
NGS panel gene-count thresholdNGS panels >50 genes are generally considered unproven and not medically necessary unless explicitly specified or used consistent with FDA-cleared/approved companion diagnostic policy
Covered small-to-moderate panelsPanels of 5-50 genes are described in code definitions (e.g., CPT 81445/81449) and are acceptable for indicated uses
Exception for companion diagnostics/liquid biopsyPanels >50 genes may be acceptable when used per the FDA Cleared or Approved Companion Diagnostic Testing policy or for validated cfDNA/ctDNA liquid biopsy contexts
inv-67: Gene count thresholds referenced in code descriptions (examples of gene counts in code text)
Prior authorization — link testing to management decision
Prior authorization: Providers should be aware that prior authorization may apply for genomic tests (e.g., GEP, NGS) depending on the member's benefit plan and intended use. When prior authorization is required, requests should clearly link the ordered test to a specific management decision (for example: to inform adjuvant chemotherapy, active surveillance vs definitive therapy, or extended endocrine therapy). Documentation should demonstrate how the test result will change patient management.
Tie test order to a management decision (e.g., chemotherapy vs no chemotherapy, selection for targeted therapy, decision for extended endocrine therapy).
Provide clinical context: timing, nodal status, receptor status, life expectancy, prior treatments, and whether shared decision-making occurred.
If ordering NGS or broad panels, explain why results cannot be obtained via single-gene testing when relevant.
Prior Authorization
Prior authorization considerations for GEP and NGS
For GEP and tumor NGS, prior authorization considerations include demonstrating clinical utility for the specific clinical scenario. Authorization reviewers may require evidence that the assay is being used within its intended purpose (e.g., Oncotype DX for ER+/HER2- early breast cancer to inform adjuvant chemo decisions; NCCN/ASCO-endorsed indications for prostate GEP).
Not Covered / Unproven Tests and Indications
The following categories of tests are listed as not covered (unproven / not medically necessary) in the policy unless a specific exception is stated: proprietary assays and diagnostic platforms shown in the source (examples include Afirma XA, CancerTYPE ID, Guardant Shield™, Galleri®, NavDx®, PancraGEN®, Percepta GSC, and similar), measurable residual disease (MRD) ctDNA assays in solid tumors, multi‑cancer early detection tests, and broadly, NGS panels >50 genes or CGP unless otherwise specified.
The combined use of BluePrint with MammaPrint is described as having insufficient evidence to support clinical utility at this time; BluePrint’s complementary classification of molecular subtype has not been demonstrated to add validated, actionable benefit when used together with MammaPrint in routine clinical decision‑making.
Other breast profiling assays not specifically listed among the validated platforms (for example, Theros H/I, DCISionRT, Oncotype DX DCIS, 41‑gene and 76‑gene signatures) are noted to lack sufficient evidence of clinical utility and therefore are not supported for routine coverage.
NICE explicitly restricts use of MammaPrint for certain subgroups: MammaPrint should not be used to guide adjuvant chemotherapy decisions for ER‑ or PR‑positive, HER2‑negative early breast cancer with one to three positive lymph nodes, and NICE details additional intended‑use constraints and quality assurance expectations for other assays.
Consensus guidance cautions that tumor mutation burden (TMB) alone should not be used to select patients with advanced NSCLC for immune checkpoint inhibitors because evidence is insufficient to support TMB as a standalone selection biomarker.
CGH definitionComparative Genome Hybridization (CGH) detects genomic copy number variations by hybridizing labeled tumor and reference DNA and measuring intensity differences on arrays
Primary applicationUsed to identify copy number changes across the genome useful for distinguishing CNV patterns in tumors versus benign tissue
Platform noteCGH platforms may use diverse probes or SNPs and report relative gain/loss intensity compared with reference DNA
CGP definitionComprehensive Genomic Profiling (CGP) is an NGS-based test able to detect all classes of genomic alterations (mutations, copy number changes, fusions, MSI, TMB) from a single sample to identify cancer biomarkers
Use case
Eligibility Requirements & Pre-conditions
Eligibility criteria for covered molecular and gene expression tests are specified elsewhere in this policy in the detailed criteria sets for each indication (breast, lung, prostate, thyroid, uveal melanoma, etc.).
See the respective covered‑indication sections for condition‑specific eligibility requirements and documentation expectations.
Prior testing, pathology, imaging, cytology category, and intended management impact are among elements used to determine eligibility per indication.
Clinical specialty involvement (e.g., oncology, urology, endocrinology) and life‑expectancy or performance status criteria are referenced in the indication‑specific rules.
Specimen type and adequacy (FFPE, core biopsy, FNA, plasma) are relevant to test acceptability and are documented in test‑specific guidance.
Tests intended to guide adjuvant systemic therapy in breast cancer should generally be performed within the clinically specified time window referenced in the full criteria.
For prostate genomic assays, ordering by clinicians experienced in organ‑confined prostate cancer management and documentation of life expectancy and risk group are expected.
Thyroid molecular testing eligibility is tied to indeterminate cytology categories (Bethesda III/IV) and the expectation that results will inform surgical decision‑making.
NGS panel coverage in NSCLC is constrained by panel size thresholds and companion‑diagnostic alignment per policy; broad panels >50 genes are generally unproven unless a specified exception applies.
Background
Gene expression profiling (GEP) and comprehensive genomic profiling (CGP) are tools used to inform prognosis and treatment decisions across multiple solid tumors. GEP assays produce an expression‑based risk score or classifier that may aid prognosis or predict benefit from specific therapies in well‑validated, indication‑specific contexts (for example, certain breast, prostate, thyroid, uveal melanoma, and NSCLC scenarios). CGP and targeted NGS panels are used to detect actionable somatic genomic alterations to guide targeted therapy selection and clinical‑trial eligibility. The policy distinguishes assays and uses with demonstrated clinical validity and utility from a large group of other molecular tests and broad NGS panels that remain unproven or have insufficient evidence of outcome benefit; tests without demonstrated clinical utility are not covered for routine care.
Quick Provider Summary (Actionable Highlights)
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Revision History
2026-01-01policy_effective_dateLatest
Policy effective date set to January 1, 2026 (policy number 2026T0588MM).
Policy Summary
Payersierra health and life
PolicyMolecular Oncology Testing for Solid Tumor Cancer Diagnosis, Prognosis, and Treatment Decisions
Policy CodePolicy 2026T0588MM
Change TypeMinor update — no material clinical or coverage changes
Effective DateJan 1, 2026
Next Review DateN/A
Key ActionDocument clinical records to show the test meets specified clinical criteria (e.g., timing, nodal status, cytology category) and that results will influence management.
Adjunctive markers for biopsy decision-making: Urine- or blood-based adjunctive markers (e.g., ExoDx/EPI, MyProstateScore) may be used selectively to influence the decision to proceed with prostate biopsy when results would change management.
AUA/SUO endorse selective use when results will affect biopsy decisions; evidence quality varies by test.
Oncotype DX (21-gene) provides a Recurrence Score that adds prognostic and predictive information; randomized and large observational data support use to guide adjuvant chemotherapy decisions in pN0 and selected pN1 contexts with RS‑based cutoffs informing benefit assessment.
RS-based categories per cited trials
Integration with clinicopathologic factors (RSClin) improves prognostic accuracy.
EndoPredict and BCI evidence: EndoPredict (EPclin) and BCI offer prognostic information and may influence treatment decisions (including extended endocrine therapy for BCI) in selected populations, but prospective validation and applicability to premenopausal women remain limited; further studies recommended.
Hayes assessments cite limited-to-moderate evidence and note need for broader prospective data.
Provider documentation of rationale and how results will change management supports coverage decisions.
Tests should be used within intended purpose, laboratories should participate in external QA schemes, and provider documentation should indicate how results will influence management decisions to support coverage.
NICE recommends lab external QA and shared decision-making documentation; specimen source and QC should be documented.
AUA/SUO conditional recommendations support selective adjunctive use.
Use primarily in research or well‑defined multidisciplinary contexts where results will meaningfully influence management.
Evidence evolving; use in multidisciplinary decision‑making when results influence management.
CUP — diagnostic/CGP role: RNA/DNA‑based molecular testing (GEP, NGS/CGP) can assist tissue‑of‑origin diagnosis in CUP when clinicopathologic workup is inconclusive, and CGP may identify actionable alterations for targeted therapy or trial eligibility, but randomized data showing outcome benefit are lacking and routine use to direct site‑specific therapy is not established.
SUPER and other studies show diagnostic yield but insufficient trial evidence of survival benefit for site‑directed therapy.
Recurrence score cutoffs per assay (e.g., <30, 30–40, ≥41)
Use primarily in contexts where results would change adjuvant therapy decisions and within guideline recommendations.
Singhi and others report high sensitivity/specificity in select cohorts; broader validation recommended.
Hayes assessment found limited clinical‑utility evidence; ongoing trials may clarify utility.
Examples of gene-count code categories
Codes describe panels of 5-50 genes (e.g., 81445/81449) and 51+ genes (e.g., 81455/81456) as distinct categories
Large panel examples in PLA/U codesPLA/other entries reference panels with exact counts including 257, 324, 468, 505, 521, 600+ genes in specific code descriptions
Breast assay gene-count examplesBreast assays include 11-gene (81518), 21-gene (81519), 58/70-gene descriptions (81520/81521/81523) as enumerated examples
inv-68: Node status groups relevant to GEP applicability (pN0, pN1)
Node groups referenced for GEP applicabilitypN0 (node-negative) and pN1 (1–3 positive ipsilateral axillary lymph nodes) are specified as eligible contexts for breast GEP use
NCCN preference contextsNCCN indicates GEP consideration in pN0 and selected pN1 (1-3 nodes) with distinctions by menopausal status and evidence level
Prosigna limitationProsigna is prognostic for pN0 and pN1 but is not intended for N2 (≥4 positive nodes) disease per policy text
inv-69: Example test cut points and performance (EPI, MyProstateScore)
EPI (ExoDx) predefined cut-pointsValidated EPI cut-points cited include 15.6 (and alternative cut-point 20) with reported NPV around 89% and biopsy reduction estimates of 26%-40% depending on threshold
MyProstateScore threshold and performanceMyProstateScore threshold of 10 reported with 97% sensitivity and 98% NPV for grade group ≥2 disease
Impact on unnecessary biopsiesUsing EPI/MyProstateScore cut points could avoid an estimated 26%-40% of unnecessary biopsies in cited studies
inv-70: NCCN prostate cancer risk group definitions (clinical parameters)
NCCN prostate risk group parametersRisk groups are defined by combinations of cT stage, Grade Group, PSA thresholds (e.g., <10, 10-20, >40 ng/mL), percent positive cores, and PSA density (<0.15) per NCCN definitions
Very low/Low/Favorable intermediate distinctionsVery low/low/favorable intermediate groups include cT stage and biopsy core percent criteria and Grade Group 1–2 specifications
Implication for GEP useNCCN recommends considering Decipher, GPS, or Prolaris in low or favorable intermediate risk men with life expectancy ≥10 years and for select post-RP adverse-feature contexts
inv-71: Uveal melanoma tumor thickness thresholds linked to class/risk
Uveal melanoma thickness thresholds linked to riskClass 2 tumors with thickness ≥7.0 mm are associated with increased metastasis risk; Class 1 tumors with thickness ≥9.0 mm also show increased metastasis risk in cited analyses
GEP class and metastasis ratesClass 2 tumors demonstrate substantially higher 5‑year metastasis risk (example five-year MFS ~47.5% in class 2 in cited cohort) versus class 1
Tumor size adds prognostic valueTumor thickness contributed independent prognostic information beyond GEP class in multivariable analyses
Oncotype DX Colon Recurrence Score cutoffsRecurrence Score categories: <30 = low, 30–40 = intermediate, ≥41 = high (used to stratify recurrence risk in stage II/III colon cancer)
Clinical implicationsHigh Recurrence Score stage II risk approximates recurrence risk of some stage III low-risk cases; used for prognostic stratification in cited cohorts
Intended assay contextAssay performed on FFPE primary tumor tissue to estimate recurrence risk and inform adjuvant considerations in research and select clinical settings
Document that the assay is being used as recommended by professional guidelines (NCCN, ASCO, ESMO, NICE) when applicable.
For NGS panels >50 genes or CGP, note that these are listed as unproven/not medically necessary in many contexts unless specifically indicated.
If ordering liquid biopsy (cfDNA) instead of tissue, document tissue unavailability or patient unfitness for biopsy per guideline rationale.
Denial Risk
Unproven tests — denial risk
Unproven tests and indications are at high risk for denial. Tests listed as unproven or not medically necessary in the policy (including many MCD tests, MRD assays, broad CGP/NGS >50 genes for routine use, and specific named assays) should not be assumed to be covered without explicit benefit language or prior authorization approval.
Examples of tests commonly considered unproven or not medically necessary: multi-cancer early detection tests (e.g., Galleri), tumor-informed MRD assays (e.g., Signatera) for routine surveillance, NavDx, many large NGS/CGP panels unless indication-specific.
Ordering multiple overlapping molecular profiles for the same indication (e.g., more than one GEP for breast cancer) is considered unproven and may be denied.
Documentation Required
Documentation-related denial risk
Medical record documentation may be required for prior authorization and claims review. Lack of adequate clinical documentation (timing, node status, receptor status, intended management change, specimen source/adequacy) increases the risk of denial.
Include tumor histology, staging (T/N/M), receptor status (ER/PR/HER2 where relevant), date of diagnosis, and intended treatment decision tied to testing.
Document specimen source and adequacy (e.g., CNB concordance, sample age/QC), and if using cfDNA, rationale for tissue infeasibility.
Attach notes from shared decision-making discussions when results will guide patient choices (e.g., extended endocrine therapy).
Note
No explicit authorization or coverage pathway stated
No explicit, uniform administrative prior authorization or coverage pathway is stated in these policy excerpts for many tests — coverage depends on member benefits and clinical criteria. Providers should check member-specific benefits and submit clinical rationale when plans do not specify automatic coverage.
If prior authorization processes are not defined in the benefit plan, submit clinical records and guideline citations supporting intended test use.
When policy states 'unproven' or 'not medically necessary' for an indication, expect denials absent compelling documentation or clinical-trial context.
Documentation Required
Laboratory and intended-use requirements
Laboratory and intended-use requirements: Use assays within their validated/intended purpose and prefer labs participating in external quality assurance (e.g., CLIA/CAP) when applicable. Tests should be performed and reported consistent with manufacturer and guideline intended uses.
Document that the laboratory is CLIA-certified and that the assay is validated for the intended specimen (e.g., FNA, FFPE, plasma).
For cfDNA/cell-free HPV assays and other plasma-based tests, note validation per CLIA/CAP and intended clinical context (diagnosis, MRD, monitoring).
Avoid using broad WES/WGS/WTS for routine decision-making unless specifically indicated and supported by evidence.
Denial Risk
Evidence insufficiency — potential denial trigger
Evidence insufficiency may trigger denial. Tests or indications lacking prospective, high-quality evidence of clinical utility (impact on management and outcomes) are frequently considered not medically necessary.
Hayes and other assessments flag many assays with low or insufficient evidence (e.g., DecisionDx-UM, NavDx, Signatera, various prostate and melanoma adjunct tests).
When evidence is limited, emphasize ongoing clinical trial enrollment or cite randomized/prospective data if available to support coverage requests.
Note
Guideline cautions — melanoma and DecisionDx-UM
Guideline cautions and specific test limitations should be documented when relevant. For example, dermatology and melanoma guidance discourage routine prognostic molecular GEP outside research; DecisionDx-UM has very low-quality evidence per Hayes.
If ordering prognostic melanoma GEP or DecisionDx tests, document why the result would change management and consider noting that AAD discourages routine prognostic molecular testing outside trials.
Reference Hayes assessments where appropriate to support requests or to acknowledge limits of clinical utility.
Note
NCCN and ACG guidance — impact on authorization/coverage
NCCN/ACG implications: Use guideline-based indications when possible. NCCN does not recommend certain multigene assays or post-surgical ctDNA to guide adjuvant therapy in colon cancer; ACG recommends against Septin 9 for CRC screening.
For colon cancer, document that NCCN does not support routine use of postsurgical ctDNA or multigene assays to guide adjuvant therapy — cite trial or guideline rationale if seeking coverage.
For screening tests (e.g., SEPT9), note ACG guidance that the assay is not recommended for CRC screening.
Step Therapy
Stepwise use and pancreatic cyst fluid sequencing
Sequencing and stepwise testing considerations: follow recommended sequencing where specified (e.g., perform clinical staging before ordering GEP-directed adjuvant radiation decisions such as 40-GEP for cSCC; consider preoperative NGS of pancreatic cyst fluid only when results will change surgical planning).
Document prior clinical staging and why molecular testing is needed to alter management (e.g., 40-GEP to inform adjuvant radiotherapy decisions after staging).
For pancreatic cysts, indicate that preoperative cyst fluid NGS may be useful if results will influence surgical decisions; include sample adequacy/QC data.
Denial Risk
NavDx, Signatera and MRD assays — limited evidence
NavDx and MRD assays: limited evidence for clinical utility. Tests such as NavDx and many tumor-informed MRD assays (e.g., Signatera) have limited supporting data; include rationale and any trial enrollment if requesting coverage for surveillance or actionable decision-making.
Hayes and ECRI assessments found limited evidence for NavDx and insufficient evidence for routine Signatera use to guide surveillance or change management.
If ordering for experimental or investigational use, indicate that testing is within a clinical trial or include protocol details.
Hayes and systematic assessments indicate limitations in the evidence supporting Genomic Prostate Score (GPS) for changing long‑term outcomes in some settings; accordingly, coverage for GPS may be limited where evidence of clinical utility is insufficient (e.g., certain lower‑risk or unvalidated populations).
Select urine‑ or tissue‑based prostate assays such as Select mdx and Confirm mdx are identified as having a very low or insufficient evidence base; these tests are therefore not supported for routine clinical decision‑making to rule out the need for biopsy or to direct management.
Hayes assessments found evidence limitations for certain thyroid diagnostic panels (e.g., ThyGeNEXT/ThyraMIR and ThyroSeq v3 assessments highlighted concerns about insufficient reference‑standard data and follow‑up), indicating these tests have evidence limitations that constrain routine clinical use for some intended claims.
Several diagnostic and prognostic tests for cutaneous lesions (e.g., Pigmented Lesion Assay [PLA], tape‑stripping tests, myPath, and some GEP prognostic assays) are described as having insufficient evidence of clinical utility. The policy notes concerns about study design, follow‑up of negative results, and heterogeneous quality, supporting noncoverage for routine management decisions where outcome benefit has not been shown.
DecisionDx‑UM (uveal melanoma prognostic GEP) is judged by Hayes to have insufficient evidence to support identifying 5‑year metastasis risk with demonstrable impact on outcomes; routine use for prognostic‑directed management is therefore not supported.
CancerTYPE ID and similar tissue‑of‑origin GEP assays have been evaluated and found to lack sufficient evidence that their use to identify tissue of origin leads to improved outcomes from site‑specific therapy; therefore they are not supported for routine guidance of site‑specific treatment absent stronger outcome data.
Professional guideline assessments advise against routine use of SEPT9 blood testing for colorectal cancer screening; the ACG recommends against Septin‑9 testing and the USPSTF does not include serum tests for CRC screening, supporting noncoverage for routine SEPT9 screening outside narrowly defined contexts.
Hayes concluded there is insufficient evidence to support PancraGEN for pancreatic cyst cancer risk assessment. While targeted NGS of pancreatic cyst fluid (e.g., PancreaSeq) shows promising diagnostic performance in some studies, PancreaGEN lacks peer‑reviewed evidence demonstrating clinical utility for routine use.
Both PancraGEN and multi‑cancer detection (MCD) assays are described as lacking sufficient evidence for routine population screening or risk stratification; MCD tests and PancraGEN are not supported for routine coverage pending prospective validation and demonstration of clinical benefit.
The policy states that routine use of individualized tumor‑informed assays such as Signatera for surveillance, treatment‑response monitoring, or routine clinical decision‑making is not supported by current evidence, and that comprehensive whole exome/genome/transcriptome sequencing likewise lacks sufficient evidence to inform routine clinical care.
Pre‑symptomatic ctDNA multi‑cancer early detection assays are recommended to be offered only in prospective clinical trials and should not replace established screening methods in asymptomatic individuals until clinical validity and utility are demonstrated.
CGP is intended to identify potentially actionable alterations for targeted therapy selection or trial eligibility
Relation to panel sizeCGP often involves broad panels that may exceed 50 genes and are contrasted with smaller targeted panels in policy coding
inv-139: Liquid Biopsy definition
Liquid biopsy definitionLiquid Biopsy uses bodily fluids (commonly plasma) to detect tumor-derived cells or circulating tumor DNA/RNA for detection, therapy selection, or monitoring (ctDNA/cfDNA)
Clinical contextsUsed as an alternative or adjunct to tissue profiling in settings such as NSCLC when tissue is insufficient or patient unfit for biopsy; ctDNA should be followed by tissue testing when negative and suspicion remains
Evidence caveatPrognostic associations (e.g., baseline negative ctDNA predicting improved PFS) are reported but heterogeneity and need for further validation noted
inv-140: Prostate cancer risk group definitions
Prostate risk-group definitions (summary)Risk groups (very low, low, favorable/unfavorable intermediate, high, very high) are defined by combinations of cT stage, Grade Group, PSA thresholds, percentage of positive cores and PSA density per NCCN
Examples of thresholdsVery low: PSA <10, Grade Group 1, <3 cores positive and PSA density <0.15; High/Very high include cT3-T4, Grade Group 4–5, PSA >20–40 ng/mL
Implication for testingGEP test consideration tied to these risk groups (e.g., GPS/Decipher/Prolaris considered for low/favorable intermediate with life expectancy ≥10 years)
Genomic/molecular oncology assays (PLA/814xx/815xx)Assays include targeted DNA/RNA panels, gene expression classifiers, methylation assays, microRNA profiling and multianalyte algorithmic tests represented in CPT/PLA codes (e.g., 814xx, 815xx)
Scope of contentThese assays interrogate DNA/RNA alterations, copy number, fusions, MSI/TMB, expression signatures and provide algorithmic interpretations relevant to diagnosis, prognosis, or therapy selection
Coding linkPolicy maps specific test types to PLA/CPT/HCPCS codes in code catalog (multiple entries enumerated) for billing/reference
Expression signature / recurrence score definitionA defined combination of gene expression results reported as a score, classifier, or probability used for prognosis or prediction of therapy benefit
ExamplesApplied in assays like Oncotype DX (recurrence score), PAM50 ROR, MammaPrint index, EndoPredict EPclin
Clinical useIntended to complement clinicopathologic factors to inform adjuvant therapy or surveillance decisions
inv-144: PAM50 ROR score definition
PAM50 ROR score definitionROR (risk of recurrence) score derived from the PAM50 assay (Prosigna) associated with ten-year distant recurrence risk
Intended useUsed for prognostication in postmenopausal HR+ early-stage breast cancer (N0/N1) to estimate recurrence risk
LimitationsNot predictive for radiotherapy benefit in cited subgroup analysis; not intended for N2 disease per policy notes
inv-145: MammaPrint (70-gene) definition
MammaPrint (70-gene) definitionMammaPrint is a 70-gene expression signature classifying tumors as low- or high-risk for distant recurrence to assist adjuvant treatment decisions
Sample typesAssay analyzes tumor tissue from fresh, frozen or FFPE specimens
Complementary test noteBluePrint is complementary (80-gene) but combined clinical utility with MammaPrint is currently insufficient per policy
inv-146: BluePrint (80-gene) definition
BluePrint (80-gene) definitionBluePrint is an 80-gene molecular subtyping assay used adjunctively with MammaPrint to classify tumors into molecular subtypes (e.g., Luminal A/B, HER2, Basal)
Clinical utility caveatEvidence for added clinical utility of BluePrint when combined with MammaPrint is insufficient at this time
Sample and usePerformed on tumor tissue; used for molecular subtyping to inform prognosis and potential therapy response
inv-147: EndoPredict definition
EndoPredict definitionEndoPredict is a 12-gene assay combining gene expression with clinical features (nodal status, tumor size) to produce an EPclin Risk Score estimating ten-year distant recurrence risk
Score rangeEPclin numeric score reported between ~1.1 and 6.2
Evidence noteLimited but positive evidence for prognostic ability in ER+, HER2- N0/N1 disease; prospective validation limited
inv-148: EPclin Risk Score definition
EPclin Risk Score definitionA numeric score (approximately 1.1–6.2) generated by EndoPredict that incorporates gene expression plus tumor size and nodal status to estimate recurrence risk
Clinical useUsed to aid adjuvant therapy decisions in ER+/HER2- early breast cancer when combined with clinicopathologic features
Evidence limitationProspective outcome data limited; applicability to premenopausal women unclear
inv-149: Breast Cancer Index (BCI) definition
Breast Cancer Index (BCI) definitionBCI is a combined gene-expression prognostic score derived from the HOXB13:IL17BR ratio (H/I) and Molecular Grade Index (MGI) to estimate risk of late (5–10 years) and overall (0–10 years) distant recurrence
Intended useBCI may help predict benefit from extended endocrine therapy in select postmenopausal/node-negative patients per evidence summaries
Evidence caveatStudies mainly in postmenopausal populations; further validation recommended
inv-150: DCISionRT Decision Score (DS) definition
DCISionRT Decision Score (DS) definitionDCISionRT combines molecular (7 genes) and clinicopathologic factors to produce a 0–10 Decision Score intended to stratify ten‑year DCIS recurrence risk and potential radiotherapy benefit (scores 0–3 low, 3–10 elevated)
Clinical applicationAims to guide post-BCS radiotherapy decisions but evidence quality and impact on outcomes remain under evaluation
Score interpretationScores 0–3 considered low risk; 3–10 considered elevated risk
GEA abbreviationGEA = Gene Expression Assay (or Gene Expression Profiling) used to provide prognostic or predictive gene-expression based scores or classifiers
ScopeEncompasses assays like Oncotype DX, MammaPrint, Prosigna, BCI, EndoPredict and others for tumor prognostication/therapy prediction
Policy noteNCCN and guideline references distinguish between GEAs based on evidence for predictive benefit
inv-152: ctDNA / cfDNA definition
ctDNA / cfDNA definitionctDNA/cfDNA refers to tumor-derived cell-free DNA fragments in plasma used in liquid biopsy testing for detection, therapy selection, prognostic assessment, or monitoring (e.g., MRD)
Use contextsUsed for plasma-based NGS in NSCLC when tissue is limited, for MRD assays, and for investigational multi-cancer detection tests; clinical utility varies by indication
Evidence caveatPrognostic associations reported but heterogeneous; tissue confirmation often recommended when clinically indicated
inv-153: NGS broad panel definition
NGS broad panel definitionNGS broad panel testing refers to multi-gene assays (often >50 genes) used to comprehensively genotype tumors for actionable alterations
Preferred contextsNCCN prefers broad panel-based NGS in NSCLC and for tumor profiling when seeking multiple actionable biomarkers
Policy restrictionBroad NGS panels >50 genes are considered unproven/not medically necessary unless specified or consistent with companion diagnostic policies
inv-154: Decipher genomic classifier definition
Decipher genomic classifier definitionDecipher is a genomic classifier (22-gene biopsy model or whole-transcriptome RP-based) used to predict risk of progression, metastasis, and prostate cancer-specific mortality
Clinical contextsValidated in multiple retrospective and trial-ancillary cohorts; used for risk stratification and post‑prostatectomy adjuvant decision-making (NCCN category 2B in some settings)
Sample typesMeasured on biopsy or prostatectomy tissue (FFPE) depending on test version
inv-155: Genomic Prostate Score (GPS) definition
Genomic Prostate Score (GPS) definitionGPS (Oncotype DX Prostate) is a 17-gene expression assay measured on biopsy tissue to predict adverse pathology and inform risk stratification in localized prostate cancer
Clinical associationsGPS is associated with adverse pathology, biochemical recurrence and metastasis risk in cohort studies and meta-analyses
Intended useUsed to assist treatment decisions (active surveillance vs definitive therapy) in specified risk groups per guidelines
inv-159: GPS / Oncotype DX Prostate label
GPS / Oncotype DX Prostate labelGPS is marketed as Oncotype DX Prostate and represents a 17-gene assay used on biopsy tissue for prognostic prediction and to aid decision-making in localized prostate cancer
Evidence noteValidated in prospectively enrolled cohorts and assessed in meta-analyses; evidence quality variable across indications
Clinical orderingGuidelines recommend consideration by treating specialists for selected patients with life expectancy ≥10 years
inv-157: Prolaris / CCP / CCR definition
Prolaris / CCP / CCR definitionProlaris (Cell Cycle Progression, CCP) provides a molecular CCP score; CCR combines CCP with clinical variables to estimate risk and inform selection (e.g., active surveillance)
Clinical useCCR associated with selection and durability of active surveillance in low-risk cohorts; evidence includes multicenter observational studies
LimitationsProspective randomized outcome data limited; evidence derived largely from observational cohorts
inv-158: ExoDx / EPI definition
ExoDx / EPI definitionExoDx Prostate IntelliScore (EPI) is a urine exosome gene expression assay designed to assess risk for high‑grade prostate cancer and inform biopsy decisions
Cut-points and impactValidated cut‑points (e.g., 15.6, 20) reported with NPV ~89% and potential biopsy reduction; prospective utility and assay failure rates noted in studies
Sample typeUrine collected without prior digital rectal exam in most studies; used pre‑biopsy
inv-159: MyProstateScore definition
MyProstateScore definitionMyProstateScore is a urine-based model combining serum PSA, PCA3 and TMPRSS2:ERG to predict grade group ≥2 prostate cancer; threshold of 10 reported with 97% sensitivity and 98% NPV in a validation study
Intended useIntended to inform decision to proceed with prostate biopsy in men with elevated PSA or clinical suspicion
Evidence noteLarge validation cohorts reported high sensitivity/NPV but additional long-term outcome data recommended
inv-160: Decipher label
Decipher labelDecipher is labeled as a 22-gene genomic classifier for prostate cancer used to predict metastasis risk and inform post‑prostatectomy adjuvant therapy discussions
Guideline contextNCCN recognizes Decipher for post-RP decision-making (category 2B) and for risk stratification in localized disease
Sample typesAvailable as biopsy or prostatectomy (RP) based assays depending on version
inv-161: Oncotype DX Prostate (GPS) label
Oncotype DX Prostate (GPS) labelOncotype DX Prostate (GPS) is a 17-gene expression assay available for biopsy tissue to predict adverse pathology and assist risk stratification
Regulatory/marketing noteReferred to in guidelines as GPS/Oncotype DX Prostate with supporting cohort and validation studies
Clinical interpretationResults intended to be used alongside clinicopathologic factors to inform active surveillance vs treatment decisions
inv-162: Prolaris label
Prolaris labelProlaris (CCP) is a cell cycle progression gene expression assay used for prostate cancer risk stratification and combined as CCR with clinical variables
Use contextUsed to support selection of active surveillance and prognostic stratification in low-risk cohorts; evidence from observational studies supports associations with outcomes
LimitationsProspective randomized outcome data limited; interpret in clinical context
Indeterminate thyroid cytology definitionBethesda III (AUS/FLUS) and Bethesda IV (follicular neoplasm/suspicious for follicular neoplasm) cytology categories where molecular testing may supplement malignancy risk assessment
Policy roleMolecular testing considered when results would alter surgical decision-making; tests are adjunctive to clinical and sonographic features
Evidence caveatNo single molecular test definitively rules in/out malignancy for all indeterminate cases; institutional malignancy rates affect interpretation
31-GEP definition (cutaneous melanoma)31-GEP is a 31-gene expression classifier used to stratify cutaneous melanoma into Class 1 (low risk) and Class 2 (high risk) to aid prognostication and sentinel lymph node biopsy decisions
Clinical applicationsMay influence SLNB decision-making in T1–T2/AJCC I–II tumors though prospective outcome data and utility remain under evaluation
Evidence notesProspective studies (e.g., DECIDE) show impact on SLNB rates but limitations include lack of long‑term outcomes and potential confounding
inv-166: 31-gene expression classifier (Class 1 vs Class 2) definition
31-gene expression classifier (Class 1 vs Class 2)Classifies cutaneous melanoma tumors as Class 1 (low risk) or Class 2 (high risk) with associated differences in recurrence-free and distant metastasis‑free survival in validation cohorts
Prognostic performanceReported five-year RFS and DMFS differ substantially between classes in cited studies (e.g., RFS 88% vs 52% for class 1 vs 2)
Use cautionClinical utility to change long-term outcomes not definitively established; interpret with clinicopathologic factors
inv-167: 15-GEP definition for uveal melanoma
15-GEP (uveal melanoma) definitionA 15-gene expression profile designed to predict five-year metastatic risk in uveal melanoma and classify tumors into low/intermediate/high risk groups
Prognostic associationClass 2 (high-risk) associated with higher metastasis and mortality; registry and meta-analytic data support prognostic separation
Clinical contextGEP may guide surveillance intensity and follow-up when biopsy is performed and results will influence management
inv-168: 40-GEP (DecisionDx-SCC) definition for cSCC
40-GEP (DecisionDx-SCC) definition40-GEP is a 40-gene expression profile for cutaneous squamous cell carcinoma that classifies metastatic risk into Class 1, 2A, and 2B to aid prognostication and adjuvant therapy discussions
Guideline contextMultidisciplinary consensus suggests 40-GEP may inform adjuvant radiation therapy decisions when used with staging systems and clinical factors
Evidence limitationsEvidence primarily retrospective and some industry-funded; multidisciplinary decision-making recommended
CGP definition (restate)Comprehensive Genomic Profiling (CGP) is broad NGS‑based tumor profiling assessing mutations, MSI, TMB, fusions and other alterations to identify potential targeted therapy options or clinical trial eligibility
Evidence caveatCGP can identify actionable alterations in many tumors but policy treats many broad CGP panels (>50 genes) as unproven unless specified; utility depends on clinical context
Sample typesPerformed on tumor FFPE tissue or cell‑free DNA depending on assay and indication
inv-170: GEP definition (tissue of origin classifiers)
GEP (tissue of origin classifiers) definitionGene expression profiling for tissue‑of‑origin uses tumor RNA expression patterns (microarray, NanoString, RT‑PCR) to predict primary cancer type/subtype in CUP cases
Diagnostic yieldGEP can provide high‑confidence predictions in known metastatic cancers but resolves a subset of clinicopathologically unresolved CUPs; DNA sequencing may add diagnostic value
Clinical utilityEvidence insufficient to routinely guide site‑specific therapy with GEP alone; integration with clinicopathologic data recommended
inv-171: Epi proColon / ColoHealth definition
Epi proColon / ColoHealth definitionEpi proColon (ColoHealth) is a plasma real‑time PCR assay that qualitatively detects methylated SEPT9 DNA (mSEPT9) as a blood‑based colorectal cancer screening option for average‑risk adults who decline traditional screening
Evidence noteHayes rated overall evidence low quality; sensitivity increases with stage and test is not a replacement for standard screening
Intended useConsidered only for individuals who would otherwise refuse screening; not recommended for routine replacement of established tests
inv-172: MMR/MSI testing definition
MMR/MSI testing definitionMismatch repair deficiency (MMR) / microsatellite instability (MSI) testing identifies defects in DNA MMR and is recommended universally for individuals with colon or rectal cancer to detect Lynch syndrome and guide immunotherapy decisions
Clinical useUsed for hereditary risk assessment (Lynch), informing immunotherapy in metastatic disease, and assisting stage II adjuvant decisions per NCCN
MethodologiesCan be performed via IHC, PCR‑based MSI testing or NGS panels depending on laboratory capabilities
Oncotype DX Colon Recurrence Score definitionA 12-gene assay producing a Recurrence Score categorized as low (<30), intermediate (30–40), or high (≥41) to estimate recurrence risk in stage II/III colon cancer
Clinical interpretationHigh-risk stage II Recurrence Score may approximate recurrence risk seen in some stage III low-risk cases; used for prognostic stratification
Sample typeAssay performed on FFPE primary tumor tissue
Tumor-informed MRD assay definitionTumor‑informed MRD assays (example: Signatera) sequence tumor tissue (often via WES) to design patient‑specific ctDNA targets for postoperative monitoring of molecular residual disease
Intended useUsed to detect minimal residual disease and early recurrence in a personalized manner; current evidence insufficient to support routine clinical utility for surveillance
Process noteRequires tumor tissue sequencing to identify individualized somatic targets prior to plasma testing
inv-175: Multi-cancer detection (MCD) test definition
Multi‑cancer detection (MCD) test definitionMCD tests are blood‑based assays measuring cell‑free nucleic acid signals (e.g., methylation patterns) to detect signals from multiple cancer types and potentially predict tissue of origin
Evidence statusCurrently investigational for population screening; professional societies do not recommend routine use pending prospective trials assessing impact on late‑stage cancer occurrence and mortality
ExamplesExamples include Galleri and other cfDNA methylation‑based MCED assays discussed in policy
inv-176: TTMV-HPV DNA (NavDx) definition
TTMV‑HPV DNA (NavDx) definitionNavDx detects tumor tissue‑modified viral HPV DNA in plasma to confirm HPV genotype, monitor treatment response, detect MRD, and potentially identify recurrence in HPV‑related cancers
Evidence caveatSystematic reviews report high pooled sensitivity/specificity in small studies but standardization and prospective validation are needed before routine adoption
Intended applicationsUsed in surveillance and monitoring contexts for HPV+ OPSCC in investigational/limited clinical settings
WGTA/WES/WGS/WTS definitionWhole exome/genome/transcriptome sequencing (WES/WGS/WTS/WGTA) are comprehensive sequencing approaches that profile coding exons, entire genomes, or transcriptomes to detect somatic variations across the tumor genome/transcriptome
Policy notePolicy considers routine use of WES/WGS/WTS for informing clinical decision‑making in solid tumors as unsupported by current peer‑reviewed evidence
Use casesUsed in research, discovery, or comprehensive profiling contexts; may identify actionable alterations but clinical utility remains to be proven for routine care
MRD and multi‑cancer detection testing are generally limited to research or trial contexts and are not eligible for routine coverage under the policy.
Detailed prior‑authorization, documentation, and coding requirements—if applicable—are addressed in the provider actions and coding sections of the policy.
Local institutional malignancy rates and specimen quality metrics should be considered when interpreting thyroid and other diagnostic molecular tests.
When molecular testing is used as an adjunct to guide therapy, the treating clinician should document how results will change management to support medical necessity.
Coverage and eligibility decisions remain subject to the member’s benefit plan and applicable laws; clinical documentation may be requested to verify criteria.