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Genetic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Advanced Cancer

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Defines coverage and clinical considerations for genetic biomarker testing (tumor tissue and circulating tumor DNA/liquid biopsy) to guide targeted therapy in individuals with unresectable, recurrent, relapsed, refractory, advanced, or metastatic cancer.

Policy Summary

Payerblue cross blue shield - kansas

PolicyGenetic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Advanced Cancer

Policy CodePolicy N/A

Change TypeMultiple additions and coding updatesctDNA expandednew gene-specific indications

Effective DateMar 10, 2022

Last ReviewFeb 26, 2026

Next Review DateFeb 26, 2026

Key ActionVerify member benefits and any prior authorization requirements with BCBSKS and document that the test and intended FDA-approved therapy will be used consistent with the drug's label.

SourceLink

POLICY UPDATE CHANGES

Added policy sections for NTRK gene fusion testing, ALK testing, and BRAF testing as medically necessary in specified clinical contexts.

Updated coding section with numerous CPT/PLA additions and nomenclature updates (including adding 0242U, 0338U and PLA codes) and removal of some prior codes.

ESR1 testing via Guardant360 CDx may be considered medically necessary to predict response to elacestrant in ER+/HER2- advanced/metastatic breast cancer after progression on endocrine therapy.

Added or expanded sections for many genes (ALK, BRAF, BRCA1/2, CLDN18, EGFR, ESR1, EZH2, FGFR2/3, FLT3, FOLR1, HER2, HRR, HRD, HLA, IDH1/2, KIT, MET exon 14, MMR/MSI, NTRK, PDGFRA, PIK3CA, PD-L1, RAS, RET, ROS1, TP53, TMB) and expanded circulating tumor DNA coverage.

Language changed from 'predict treatment response to' to 'select treatment with' for multiple sections; tissue-preferred language for some tests was removed or clarified.

Circulating Tumor DNA (liquid biopsy) coverage expanded as an alternative to tissue for many specific biomarkers when using FDA‑approved companion diagnostic plasma tests; specified certain plasma tests as experimental (e.g., RET via plasma).

Guidance added that repeat genomic testing (tissue or liquid) may be useful at progression to identify acquired resistance variants; tissue is recommended when available but liquid biopsy may be acceptable in specific situations.

Noted that extensive evidence review is not included for somatic tests of individual genes associated with FDA-approved therapies with NCCN ≥2A; somatic tests without such therapies are considered investigational.

Removed prior text stating testing for individual genes tied to FDA-approved therapeutics are not subject to extensive evidence review, and removed specific guidance and a CPT code (0211U).

30+genes/biomarkers discussed

advanced/metastaticpopulation

MultiplectDNA permitted

Severalinvestigational uses

11/01/2025FDA list currency

Coverage Criteria and Medical Necessity

General coverage criteria for biomarker testing

Covered when ALL of the following are met

Population and purpose: Individual has unresectable, recurrent, relapsed, refractory, advanced, or metastatic cancer AND testing is performed to identify actionable oncogenic driver variants to inform consideration of an FDA‑approved targeted therapy consistent with the labeled indication.

Supported by policy scope and objective statements

FDA-linked companion diagnostic coverage

Covered when the listed FDA-cleared/approved companion diagnostic corresponds to the indicated drug and biomarker in the specified cancer type

Linkage requirement: Companion diagnostic must be the FDA-listed test (diagnostic name/manufacturer) associated with the specific drug NDA/BLA for the cancer indication.

See Table 1 (FDA companion diagnostics list current to 11/01/2025)

Biomarker-specific criteria: Biomarker result meets the indicated definition required by the listed companion diagnostic (e.g., MSI‑High by Idylla CDx; BRCA1/2 alterations by FoundationOne Liquid CDx; PIK3CA mutations by therascreen PIK3CA RGQ PCR Kit).see specific diagnostic entry

Biomarker specifics are enumerated per FDA-listed CDx entry

Regulatory companion diagnostic linkages (informational)

FDA‑cleared/approved companion diagnostics and their indicated biomarkers (administrative linkage rather than clinical eligibility criteria):

mCRPC plasma CDx: FoundationOne Liquid CDx (plasma) cleared for detection of BRCA1/BRCA2 (and ATM per specific supplements) to inform PARP inhibitor use in mCRPC.

P190032; PLA 0239U

mCRPC tissue CDx: FoundationOne CDx (tissue) cleared for detection of HRR genes (BRCA1/2, ATM, BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, RAD51 family, RAD54L) for selection of targeted therapies in mCRPC.

P170019/S015; PLA 0037U

NSCLC plasma/tissue CDx: Multiple FDA‑cleared plasma and tissue assays (e.g., cobas EGFR v2, FoundationOne Liquid CDx, Guardant360 CDx) cleared for EGFR (exon 19 deletions, exon 21 L858R), KRAS G12C, MET exon 14 skipping, ALK/ROS1 rearrangements and other actionable variants linked to corresponding targeted therapies.

Multiple PMA/510(k) entries and PLA codes

Regulatory-authorized companion diagnostics and biomarker definitions

Covered companion diagnostics and biomarker definitions as listed (no explicit coverage algorithm in these chunks):

CDx–drug–biomarker pair: Use of the FDA‑authorized diagnostic assay specified (e.g., Ventana ALK D5F3 CDx, cobas EGFR Mutation Test v2, FoundationOne CDx, FoundationOne Liquid CDx, Myriad myChoice CDx) to identify the biomarker listed (e.g., ALK rearrangement/expression, EGFR exon19 deletion/exon21 L858R, BRCA1/2 deleterious variant, NTRK fusion, MSI‑H, TMB ≥10) that corresponds to the linked FDA-approved drug is the regulatory basis for that test–therapy pairing.varies by biomarker; see diagnostic instructions

Mapping of authorized diagnostics to drug indications

ALK Testing (Medically Necessary)

ALK testing is covered when ALL of the following are met

ALK testing criteria: Analysis of tumor tissue for somatic ALK rearrangements to select an FDA‑approved ALK inhibitor for advanced lung adenocarcinoma or when an adenocarcinoma component cannot be excluded; patient must not have FDA‑labeled contraindications and therapy must be used consistent with FDA label.

See Ventana ALK D5F3 CDx entries and Policy Guidelines

BRAF Testing

BRAF testing is covered when ANY of the following are met

BRAF V600E for approved indications: Somatic testing of tumor tissue for BRAF V600E to select FDA‑approved BRAF and/or MEK inhibitor therapy in specified tumor types (advanced lung adenocarcinoma, colorectal cancer, glioma subsets, anaplastic thyroid cancer, unresectable/metastatic melanoma, resected stage III melanoma), used consistent with FDA label and without FDA‑labeled contraindications.

Pediatric low‑grade glioma: Testing for BRAF V600 variants or BRAF fusion rearrangements in relapsed or refractory pediatric low‑grade glioma to select tovorafenib.

BRAF testing experimental in other glioma: Testing for BRAF V600 variants or BRAF fusion rearrangements for all other individuals with glioma to select targeted treatment is considered experimental/investigational (not covered).

BRCA1 and BRCA2 Testing

BRCA1/2 testing criteria

Germline BRCA1/2: Germline BRCA1 or BRCA2 testing (whole blood) to select PARP inhibitor therapy for HER2‑negative metastatic and high‑risk early‑stage breast cancer, mCRPC, and advanced epithelial ovarian/fallopian tube/primary peritoneal cancer.

BRACAnalysis CDx listed as companion diagnostic

Somatic BRCA1/2 variant analysis on tumor tissue to select FDA‑approved targeted therapies in advanced epithelial ovarian/fallopian tube/primary peritoneal cancer, mCRPC, and prostate cancer.

Claudin 18 (CLDN18) Testing

CLDN18 testing criteria

CLDN18 testing: CLDN18 (CLDN18.2) testing of tumor tissue to select FDA‑approved targeted therapy in locally advanced unresectable or metastatic HER2‑negative gastric or gastroesophageal junction adenocarcinoma when tumor is CLDN18.2 positive by an FDA‑approved test.CLDN18 expression ≥75% TC staining as defined by CDx

See VENTANA CLDN18 RxDx assay entry

EGFR Testing

EGFR testing criteria

EGFR exons 18–21: Tumor tissue analysis for somatic variants in EGFR exons 18–21 (e.g., exon 19 deletions, exon 21 L858R) to select FDA‑approved EGFR therapies in appropriate NSCLC histologies, used consistent with FDA label and without FDA‑labeled contraindications.

cobas EGFR Mutation Test v2 and FoundationOne CDx entries

EGFR exon 20 insertions: Tumor tissue analysis for EGFR exon 20 insertion variants to select therapies (e.g., mobocertinib) when used consistent with FDA label.

EGFR in metastatic CRC: Somatic EGFR variant analysis using tumor tissue may be medically necessary to select FDA‑approved targeted therapies for metastatic colorectal cancer when used consistent with FDA label.

ESR1 Testing

ESR1 testing criteria

ESR1 testing: Tissue (or ctDNA per Policy Guidelines) analysis for somatic ESR1 variants to select elacestrant in ER+, HER2‑ advanced/metastatic breast cancer after progression following ≥1 line of endocrine therapy; both agent and test must be used consistent with FDA labels and no FDA‑labeled contraindications present.

Guardant360 CDx and related plasma CDx entries noted for ESR1

EZH2 Testing

EZH2 testing criteria

EZH2 testing: EZH2 variant testing of tumor tissue to select tazemetostat in relapsed/refractory follicular lymphoma when an EZH2 variant is detected by an FDA‑approved test and the individual has received ≥2 prior systemic therapies.

FGFR2 Testing

FGFR2 testing criteria

FGFR2 testing: FGFR2 fusion/rearrangement testing of tumor tissue to select pemigatinib in previously treated, unresectable locally advanced or metastatic cholangiocarcinoma when detected by an FDA‑approved test and agent use is label‑consistent.

FoundationOne CDx listed for FGFR2 fusions

FGFR3 Testing

FGFR3 testing criteria

FGFR3 testing of tumor tissue to select erdafitinib in locally advanced or metastatic urothelial carcinoma after progression on/after prior platinum‑containing chemotherapy, consistent with FDA label.

FLT3 Testing

FLT3 testing criteria

FLT3 testing: Somatic FLT3 variant or ITD testing using blood or bone marrow to select FDA‑approved targeted therapies for acute myeloid leukemia when detected by an FDA‑approved test and agent use is label‑consistent.

LeukoStrat CDx FLT3 Mutation Assay listed (PLA 0023U)

FOLR1 Testing

FOLR1 testing criteria

FOLR1 testing of tumor tissue to select FDA‑approved targeted therapies for platinum‑resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer in individuals who have received one to three prior systemic regimens, consistent with FDA label.

HER2 Testing

HER2 testing criteria

HER2 testing of tumor tissue to select FDA‑approved HER2‑targeted therapies in metastatic solid tumors when results meet companion diagnostic criteria and agent use is consistent with FDA label.

Multiple HER2 CDx assays referenced (PathVysion, PATHWAY 4B5, Ventana HER2 Dual ISH)

HRR Gene Testing

Homologous Recombination Repair (HRR) gene testing criteria

HRR gene testing: Somatic tissue testing for HRR gene variants (BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B/C/D, RAD54L) to select FDA‑approved targeted therapies for mCRPC when used consistent with FDA label and no FDA‑labeled contraindications exist.

FoundationOne CDx lists HRR genes for mCRPC

HRD Testing

Homologous Recombination Deficiency (HRD) testing criteria

HRD testing: HRD analysis of tumor tissue (e.g., BRCA1/2 deleterious variants and/or genomic instability score by an FDA‑authorized assay) to select FDA‑approved targeted therapies for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer when used per FDA label.Myriad myChoice criteria or CDx‑specified GIS threshold

Myriad myChoice CDx and FoundationFocus CDxBRCA referenced

Homologous Recombination Repair (HRR) Gene Testing (somatic, tissue)

Covered when ALL of the following are met

HRR tissue testing for mCRPC: Somatic tissue testing for HRR gene variants to select FDA‑approved targeted therapies in metastatic castration‑resistant prostate cancer is considered medically necessary when agent/test used per FDA label and no FDA‑labeled contraindications exist.

FoundationOne CDx tissue HRR listing (P170019/S015)

Homologous Recombination Deficiency (HRD) Testing (tissue)

Covered when ALL of the following are met

HRD testing for advanced ovarian/fallopian tube/primary peritoneal cancer: HRD analysis of tumor tissue to select FDA‑approved targeted therapies in advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer is considered medically necessary when used consistent with FDA labeling and companion diagnostic definitions.

Myriad myChoice CDx and FoundationFocus/FoundationOne CDxBRCA referenced

HLA Testing (tissue)

HLA testing for tebentafusp: HLA testing of tumor tissue to select tebentafusp‑tebn (Kimmtrak) for unresectable or metastatic uveal melanoma is considered medically necessary when used consistent with FDA label.

IDH1/IDH2 Testing

IDH testing indications: IDH1/IDH2 testing is considered medically necessary in glioma for vorasidenib candidacy and in selected AML/MDS/cholangiocarcinoma indications to select FDA‑approved therapies per labels.

Oncomine Dx Target Test entries (0022U) and related PMAs

KIT Testing

KIT testing for ASM: KIT gene variant testing in aggressive systemic mastocytosis without D816V or with unknown D816V status to select imatinib may be considered medically necessary when used consistent with FDA labeling.

MET Exon 14 Skipping Alteration (tissue or plasma)

MET exon 14 skipping for capmatinib: Tumor tissue analysis for alterations causing MET exon 14 skipping to select capmatinib in metastatic NSCLC is medically necessary when agent/test used per FDA label and no FDA‑labeled contraindications exist; plasma ctDNA testing using an FDA‑approved companion diagnostic is an accepted alternative when used per FDA label and Policy Guidelines.

FoundationOne CDx MET exon 14 entries; plasma CDx alternatives noted

Mismatch Repair / Microsatellite Instability (MMR/MSI) Testing

MMR/MSI for immune checkpoint inhibitors: Tumor tissue MMR/MSI testing to select FDA‑approved immune checkpoint inhibitors is medically necessary for unresectable or metastatic solid tumors when supported by NCCN (≥2A) and agent use is consistent with FDA label and no FDA‑labeled contraindications exist.MSI‑H or dMMR per CDx definition

Idylla CDx MSI Test and MMR IHC pharmDx entries

NTRK Gene Fusion Testing (tissue or plasma)

NTRK fusion testing indications: NTRK gene fusion testing of tumor tissue is medically necessary to select TRK inhibitor therapy in specified metastatic solid tumors and is medically necessary for recurrent unresectable or stage IV breast cancer as added by policy; plasma ctDNA testing with an FDA‑approved companion diagnostic is an alternative to tissue when used per FDA label and Policy Guidelines.

FoundationOne CDx / Liquid CDx entries for NTRK fusions

PDGFRA Testing

PDGFRA for avapritinib: Tumor tissue PDGFRA testing (e.g., D842V) to select avapritinib in unresectable or metastatic GIST is medically necessary when used consistent with FDA label.

therascreen PDGFRA RGQ PCR Kit referenced

PDGFRB Testing

PDGFRB rearrangements for imatinib: Tumor tissue testing for PDGFRB gene rearrangements (e.g., FIP1L1‑PDGFRα) to select imatinib in MDS/MPD is medically necessary when used consistent with FDA label.

PIK3CA Testing

PIK3CA for alpelisib: PIK3CA testing to select alpelisib in HR+/HER2‑ advanced/metastatic breast cancer after progression on or after an endocrine‑based regimen is medically necessary; tissue testing is preferred when available but plasma ctDNA (therascreen PIK3CA kit) is acceptable per Policy Guidelines.

therascreen PIK3CA RGQ PCR Kit (PLA 0155U/0177U) referenced

PD-L1 Testing

PD‑L1 testing for immune checkpoint inhibitors: PD‑L1 tumor tissue testing to select FDA‑approved immune checkpoint inhibitors is medically necessary for unresectable or metastatic solid tumors when NCCN gives a recommendation of ≥2A, no FDA‑labeled contraindications exist, and agent use is consistent with FDA label; assay‑specific thresholds (TPS or CPS) apply per companion diagnostic.assay‑specific (e.g., TPS ≥1% or ≥50%, CPS thresholds per indication)

PD‑L1 IHC 22C3 pharmDx and other assays referenced

RAS (KRAS/NRAS) Testing

KRAS/NRAS testing indications: (1) KRAS testing (e.g., G12C) in tumor tissue to select sotorasib for advanced lung adenocarcinoma when used per FDA label; (2) KRAS and NRAS testing of tumor tissue in metastatic colorectal cancer to guide anti‑EGFR and other targeted therapies when used per FDA label.

cobas KRAS, FoundationOne CDx entries referenced

RET Testing

RET testing for RET inhibitors: Tumor tissue testing for somatic RET alterations to select RET inhibitors (pralsetinib, selpercatinib) in advanced/metastatic NSCLC, CRC, medullary thyroid cancer or other indicated cancers is medically necessary when agent/test used per FDA label and no FDA‑labeled contraindications exist.

FoundationOne CDx RET entries referenced

ROS1 Testing

ROS1 rearrangement testing for ROS1 inhibitors: Tumor tissue testing for ROS1 rearrangements to select an FDA‑approved ROS1 inhibitor in advanced lung adenocarcinoma (or when adenocarcinoma component cannot be excluded) is medically necessary when agent/test used per FDA label and no FDA‑labeled contraindications exist.

TP53 (17p deletion) Testing

TP53 (17p deletion) testing for venetoclax: Tumor tissue or peripheral blood analysis for somatic deletion of chromosome 17p (TP53) to select venetoclax in CLL is medically necessary when used consistent with FDA label.

Vysis CLL FISH Probe Kit referenced

Tumor Mutational Burden (TMB) Testing

TMB testing for immune checkpoint inhibitors: Tumor tissue TMB testing to select FDA‑approved immune checkpoint inhibitors is medically necessary for unresectable or metastatic solid tumors when supported by NCCN (≥2A), no FDA‑labeled contraindications exist, and agent use is consistent with FDA label (TMB ≥10 mut/Mb where applicable).TMB ≥ 10 mutations/megabase where CDx specifies

FoundationOne CDx TMB entry

Circulating Tumor DNA (ctDNA) / Liquid Biopsy Testing

ctDNA testing allowances: Plasma ctDNA testing using an FDA‑approved companion diagnostic may be considered medically necessary as an alternative to tissue for specified biomarkers (ALK, BRAF V600E, EGFR exons 19–21 at diagnosis, EGFR T790M at progression when tissue not feasible, BRCA1/2 in ovarian cancer when tissue not feasible, ESR1 for elacestrant, PIK3CA for alpelisib, MET exon 14 skipping, NTRK fusions, KRAS/RAS including G12C) when used consistent with the FDA‑approved companion diagnostic labeling and Policy Guidelines.

See DD.1–DD.12 and EE.1 for specifics; plasma CDx examples include FoundationOne Liquid CDx, Guardant360 CDx, cobas EGFR v2

Medically necessary ctDNA/plasma testing

Covered uses of circulating tumor DNA (ctDNA) / plasma testing when ALL listed conditions for each indication are met as specified in individual items below.

BRCA1/2 in ovarian/fallopian tube/primary peritoneal cancer: ctDNA BRCA1/2 variant analysis may be considered medically necessary to select FDA‑approved targeted therapies when tumor tissue analysis is not clinically feasible and follow‑up tissue analysis is planned if no driver is found.

DD.3; EE.1

EGFR exons 19–21 at diagnosis in advanced NSCLC: At diagnosis, plasma ctDNA analysis for EGFR exons 19–21 using an FDA‑approved plasma CDx may be considered medically necessary as an alternative to tissue to select FDA‑approved EGFR therapy when agent/test used per FDA label.

DD.4; cobas EGFR v2 plasma CDx referenced

EGFR T790M at progression for osimertinib: At progression, plasma ctDNA testing for EGFR T790M with an FDA‑approved plasma CDx may be considered medically necessary to select osimertinib when tissue biopsy is not feasible and agent/test used per label.

DD.5

ESR1 for elacestrant in HR+/HER2- advanced breast cancer: ESR1 ctDNA testing may be considered medically necessary to predict response to elacestrant after progression on ≥1 endocrine therapy when agent/test used per FDA label.

DD.6; Guardant360 CDx and other plasma CDx referenced

BRCA1/2 and ATM for mCRPC: ctDNA testing for BRCA1, BRCA2, and ATM to select targeted therapies in mCRPC may be considered medically necessary when using FDA‑approved plasma CDx and agent use is label‑consistent.

DD.7; FoundationOne Liquid CDx entries

MET exon 14 skipping in NSCLC: Plasma ctDNA testing for alterations causing MET exon 14 skipping via an FDA‑approved plasma CDx may be considered medically necessary as an alternative to tissue to select MET inhibitors when agent/test used per FDA label.

DD.8

NTRK gene fusions across multiple tumor types: Plasma ctDNA testing for NTRK fusions using an FDA‑approved plasma CDx may be considered medically necessary as an alternative to tissue to select TRK inhibitors in specified metastatic solid tumors when agent/test used per FDA label.

DD.9; FoundationOne Liquid CDx referenced

PIK3CA in HR+/HER2- advanced breast cancer for alpelisib: PIK3CA ctDNA testing may be considered medically necessary to select alpelisib after progression on endocrine therapy; tissue testing preferred when available but not required.

DD.10; therascreen PIK3CA kit referenced

KRAS/RAS in metastatic CRC: Plasma ctDNA testing for KRAS/RAS variants using an FDA‑approved plasma CDx may be considered medically necessary as an alternative to tissue to select FDA‑approved therapy in metastatic CRC when agent/test used per FDA label.

DD.11

KRAS G12C for sotorasib in advanced lung adenocarcinoma: Plasma ctDNA testing for KRAS G12C via an FDA‑approved plasma CDx may be considered medically necessary as an alternative to tissue to select sotorasib when agent/test used per FDA label.

DD.12; Agilent/Resolution ctDNA assays referenced

ROS1 rearrangements in NSCLC: Plasma ctDNA testing for ROS1 rearrangements may be considered medically necessary as an alternative to tissue to select ROS1 inhibitor therapy when agent/test used per FDA label.

DD.14

Plasma testing when tissue insufficient: Plasma testing for oncogenic driver variants deemed medically necessary on tissue may be used when the individual lacks sufficient tissue for standard molecular testing AND follow‑up tissue‑based analysis is planned if plasma testing finds no driver variant.

EE.1

Experimental / Investigational

Not covered / investigational uses

RET gene somatic alterations via plasma: Plasma-based detection of somatic RET alterations to guide RET inhibitor therapy is considered experimental / investigational (not covered) as an alternative to tissue biopsy.

DD.13

All other ctDNA uses not listed: All other uses of somatic testing using circulating tumor DNA (liquid biopsy) to guide targeted cancer therapy that are not enumerated in the policy are considered experimental / investigational and not covered.

DD.15; FF.1

Testing to select FDA‑approved targeted therapies

Covered when ALL of the following are met

Primary criteria: Patient has unresectable, recurrent, relapsed, refractory, advanced, or metastatic cancer AND genetic biomarker testing of tumor tissue or circulating tumor DNA is being performed to inform selection of an FDA‑approved targeted therapy consistent with the labeled indication.

Based on evidence summary and PCO framework

ASCO Provisional Clinical Opinion–based coverage

Additional recommended scenarios

PCO scenarios: Genomic testing is recommended for metastatic/advanced solid tumor patients when (1) genomic biomarker‑linked therapies are approved for their cancer OR (2) when considering treatments with biomarker‑based contraindications/exclusions; fusion testing is recommended when fusion‑targeted therapies are approved (NTRK testing recommended when TRK inhibitors are a consideration).

ASCO Provisional Clinical Opinion guidance

Medical necessity criteria for genomic and fusion testing

Covered when criteria below are met per Provisional Clinical Opinions and policy additions

General genomic testing in advanced/metastatic solid tumors: Genomic testing should be performed for patients with metastatic or advanced solid tumors when there are genomic biomarker‑linked therapies approved for their cancer OR when considering treatments with known genomic biomarker‑based contraindications/exclusions; agents/tests must be used per FDA label and no FDA‑labeled contraindications should be present.

PCO framework and policy additions

Fusion testing: Perform fusion testing when fusion‑targeted therapies have regulatory approval for that specific disease; NTRK fusion testing is recommended when patients are candidates for TRK‑inhibitor therapy.

PCO 3.1–3.2

Repeat testing at progression: Repeat genomic testing (tissue or liquid) may be considered at progression or suspected acquired resistance when results would guide next‑line therapy.

ASCO suggestion; see Policy Guidelines

Medical necessity for somatic biomarker testing to select FDA‑approved targeted therapies

Covered when ALL of the following are met (examples by gene/biomarker):

General condition: Testing is performed to select treatment with an FDA‑approved targeted therapy and will be used consistently with the FDA‑approved label; the individual does not have any FDA‑labeled contraindications to the requested agent.

Applies across gene/biomarker sections

Tissue testing indicated for specific genes: Analysis of tumor tissue for specific somatic variants/fusions (e.g., ALK, BRAF V600E, BRCA1/2 somatic, CLDN18.2, EGFR, ESR1, EZH2, FGFR2, FGFR3, FLT3, FOLR1, HER2, HRR genes, HRD, HLA, IDH1/2, KIT, MET exon 14, MMR/MSI, NTRK fusions, PDGFRA, PIK3CA, PD-L1, KRAS/NRAS, RET, ROS1, TP53 17p deletion, TMB) may be medically necessary to select FDA‑approved therapies in specified tumor types when used per FDA label.

Each gene section includes tumor‑type specific indications

Plasma (ctDNA) alternative: Analysis of plasma (liquid biopsy) using an FDA‑approved companion diagnostic plasma test may be considered medically necessary as an alternative to tissue for specified biomarkers when tissue is insufficient or as allowed by FDA label and Policy Guidelines; some plasma uses are explicitly investigational (e.g., RET via plasma).

See ctDNA section and EE.1

Testing and coverage criteria

Covered when aligned with FDA approvals, guideline recommendations, and clinical utility:

Primary coverage principles: When tumor tissue is available, tissue testing is recommended for variants/biomarkers specified in this policy; circulating tumor DNA (liquid biopsy) may be an option in certain situations described in Policy Guidelines.

Tissue preferred but liquid biopsy acceptable in defined circumstances

When repeat testing is appropriate: Repeat genomic testing (tissue or liquid) may be considered at progression, particularly after targeted therapy, to detect acquired resistance variants if results would guide next‑line FDA‑approved therapy.

ASCO guidance cited

Evidence review scope: Extensive evidence review is not performed for somatic tests of individual genes (not gene panels) associated with FDA‑approved therapies with NCCN ≥2A; somatic tests of individual genes without FDA‑approved therapies are considered investigational.

Policy coding clarifications

Coverage determinations under this policy are subject to any plan or contract exclusions and applicable state or federal mandates; those provisions take precedence. Verify member benefits and prior authorization requirements with Blue Cross and Blue Shield of Kansas Customer Service before proceeding with testing.

The policy's FDA companion diagnostic table does not include all laboratory‑developed tests (LDTs). LDTs must be developed and validated in-house and performed in CLIA-certified high‑complexity laboratories, and their absence from the FDA list does not imply regulatory review or coverage. When an FDA‑approved companion diagnostic exists for a test–therapy pairing, the policy specifies use of that FDA‑authorized assay or an FDA‑approved plasma CDx where indicated.

Covered Indications and Biomarker-Drug Pairings

Coding, PLA and Regulatory Identifiers

Example PLA Codes from FDA companion diagnostics tableHCPCS

0023U

PLA code listed for LeukoStrat CDx FLT3 Mutation Assay (Invivoscribe Technologies, Inc.)

PLA Codes mentioned (example)CPT

0023U

PLA code associated with LeukoStrat CDx FLT3 Mutation Assay

PLA Codes mentionedCPT

0022U

PLA code associated with Oncomine Dx Target Test (listed for Anaplastic Thyroid Cancer and other tissue indications)

PLA Codes mentionedCPT

0239U	PLA code associated with Foundation One Liquid CDx (referenced for multiple plasma indications including PIK3CA/BRCA testing)
0326U	PLA code associated with Guardant360 CDx (referenced for ESR1 ctDNA testing)

PLA Codes mentionedCPT

0211U

PLA code associated with MI Cancer Seek (Caris Life Sciences) for PIK3CA and MSI-H related entries

PLA CodesHCPCS

0155U	PLA code associated with therascreen PIK3CA RGQ PCR Kit (QIAGEN) for tissue PIK3CA testing
0177U	PLA code associated with therascreen PIK3CA RGQ PCR Kit for plasma PIK3CA testing

Other PLA/CodesHCPCS

0037U	PLA/code associated with Foundation One CDx (listed for multiple tissue indications, e.g., colorectal, ovarian, NSCLC)
0211U	PLA/code associated with MI Cancer Seek (Caris) (appears in multiple tissue entries)
0523U	PLA/code associated with ONCO/Reveal Dx Lung & Colon Cancer Assay (Pillar Biosciences)
0471U	PLA/code associated with Idylla CDx MSI Test (Biocartis US, Inc.)

PMA / 510(k) identifiersmixed

P980024	PMA approval for PathVysion HER-2 DNA Probe Kit (Abbott) — 12/11/1998
P990081	PMA for PATHWAY anti-HER2/neu (4B5) antibody (Ventana) — 11/28/2000
P190001	PMA for therascreen PIK3CA kit — 05/24/2019
P190004	PMA supplement/clearance associated with therascreen PIK3CA — 05/24/2019

Examples of PLA/CPT codes listedCPT

0471U

PLA/CPT code referenced for Idylla CDx MSI Test (Colorectal Cancer)

Examples of PLA/CPT codes listedCPT

0473U

PLA/CPT code referenced for xT CDx (Tempus Labs) tissue/matching blood/saliva assay

Examples of PLA/CPT codes listedCPT

0037U

PLA/CPT code referenced for Foundation One CDx (listed for Low-Grade Glioma and other entries)

Examples of PLA/CPT codes listedCPT

0239U

PLA/CPT code referenced for Foundation One Liquid CDx (mCRPC plasma and other plasma indications)

PLA / Proprietary Laboratory Analyses codesCPT

0239U	PLA code referenced for Foundation One Liquid CDx (multiple plasma assays)
0037U	PLA code referenced for Foundation One CDx (tissue) and BRACAnalysis CDx (whole blood)
0326U	PLA code referenced for Guardant360 CDx (plasma)

Referenced PLA/Test Codesmixed

0037U	PLA code associated with Foundation One CDx referenced across multiple NSCLC and solid tumor entries
0022U	PLA code associated with Oncomine Dx Target Test referenced for multiple tissue indications
0523U	PLA code referenced for TruSight/ONCO panels in NSCLC/solid tumor contexts

PMA / 510(k) / Supplement Identifiersmixed

P170019	PMA identifier for Foundation One CDx (initial approval and supplements referenced)
P160045	PMA identifier for Oncomine Dx Target Test (and supplements)
P120022	PMA identifier for therascreen EGFR RGQ PCR Kit
P150013	PMA identifier for PD-L1 IHC 22C3 pharmDx
P140025	PMA identifier for Ventana ALK (D5F3) CDx Assay
P110027	PMA identifier referenced for therascreen KRAS RGQ PCR Kit

Listed PLA / Test Codesmixed

0239U	Foundation One Liquid CDx (plasma) - NTRK fusions and other plasma indications
0037U	Foundation One CDx (tissue) - listed for multiple solid tumor biomarkers (e.g., NTRK, MSI-H, TMB)
0211U	MI Cancer Seek (Caris) - PLA code referenced for MSI-H and other solid tumor entries
0543U	TruSight Oncology Comprehensive (Illumina) - PLA code listed for NTRK fusions and broad panels
0172U	Myriad myChoice CDx - PLA code associated with HRD (Myriad)

Regulatory/PLA codes citedmixed

0211U	PLA code referenced for MI Cancer Seek / Caris Life Sciences (MSI-H)
0543U	PLA code referenced for TruSight Oncology Comprehensive (NTRK fusions)
0037U	PLA code referenced for Foundation One CDx (various tissue indications)
0154U	PLA code referenced for FGFR testing (listed in regulatory entries)

Listed CPT/PLA and molecular pathology codesmixed

0037U	Targeted genomic sequence analysis, solid organ neoplasm, DNA analysis of 324 genes (FoundationOne CDx PLA)
0048U	Oncology DNA targeted sequencing of 468 genes (MSK-IMPACT PLA)
0155U	PIK3CA gene analysis (therascreen PIK3CA RGQ PCR Kit PLA)
0177U	PIK3CA gene analysis of 11 variants utilizing plasma (therascreen PIK3CA RGQ PCR Kit PLA)
0239U	Targeted genomic sequence analysis panel, cell-free DNA, analysis of 311+ genes (FoundationOne Liquid CDx PLA)
0242U	Targeted genomic sequence analysis panel, cell-free circulating DNA analysis of 55-74 genes (Guardant360 CDx PLA)
0338U	Circulating tumor cell selection/identification HER2 CTC (example PLA)
81162	BRCA1/BRCA2 full sequence and duplication/deletion analysis
81163	BRCA1/BRCA2 full sequence analysis
81164	BRCA1/BRCA2 duplication/deletion analysis

1–10 of 24

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Previously listed NTRK translocation CPT codes (removed per revisions)CPT

81191	NTRK1 translocation analysis
81192	NTRK2 translocation analysis
81193	NTRK3 translocation analysis
81194	NTRK1/2/3 translocation analysis

Example FDA‑approved companion diagnostic plasma tests (named examples)mixed

Guardant360 CDx	Example plasma companion diagnostic (Guardant360 CDx) referenced for EGFR, ESR1, and other plasma indications
FoundationOne Liquid CDx	Example plasma companion diagnostic (FoundationOne Liquid CDx) referenced for BRCA1/2, BRAF, NTRK fusions, EGFR, and other plasma indications

Updated Coding: Removed codesCPTNot Covered

0211U

Removed (previously listed PLA/CPT code)

Myriad MyChoice GIS threshold

AssayMyriad myChoice CDx (genomic instability score - GIS)

Positive criterionHRD-positive defined by pathogenic BRCA1/2 variant and/or GIS above Myriad-defined threshold

PurposeUsed to identify patients with ovarian (epithelial), fallopian tube, or primary peritoneal cancer eligible for HRD-directed therapy

High MSI definition

DefinitionHigh MSI (MSI‑H) defined as instability in ≥2 of 5 PCR microsatellite markers or >30% of tested biomarkers showing instability (panel-dependent)

Testing methodsMSI PCR panels (5-marker) or MMR IHC for MLH1, MSH2, PMS2, MSH6

Clinical implicationMSI‑H/dMMR identifies patients likely to respond to PD‑1/PD‑L1 immunotherapy

Myriad HRD positive criteria

HRD-positive (policy definition)Presence of a deleterious or suspected deleterious BRCA1 or BRCA2 mutation and/or genomic instability as assessed by an FDA‑approved assay (e.g., Myriad myChoice)

Assay exampleMyriad myChoice CDx assesses BRCA1/2 variants and computes a genomic instability score (GIS)

Clinical useDetermines eligibility for PARP inhibitor/HRD‑directed therapies in ovarian and related cancers

PD-L1 Combined Positive Score (CPS) examples

Example: Esophageal SCCPD‑L1 CPS ≥ 10 (PD‑L1 IHC 22C3 pharmDx) for pembrolizumab in ESCC

Example: Gastric/GEJPD‑L1 CPS ≥ 1 used in some gastric/GEJ adenocarcinoma indications

Scoring noteCPS combines PD‑L1 staining on tumor and immune cells per assay instructions

CLDN18 expression threshold (CLDN18.2)

ThresholdCLDN18 (claudin‑18.2) positive defined as ≥75% viable tumor cells staining (TC ≥75%)

Assay exampleVENTANA CLDN18 (43‑14A) RxDx Assay (Ventana) used for zolbetuximab selection

IndicationGastric or gastroesophageal junction (GEJ) adenocarcinoma

PD-L1 Tumor Proportion Score (TPS) thresholds

TPS ≥50% examplePD‑L1 Tumor Proportion Score (TPS) ≥50% — used in approvals requiring high tumor cell PD‑L1 expression (e.g., some PD‑1/PD‑L1 therapies)

TPS ≥1% examplePD‑L1 TPS ≥1% — used in other approvals with lower PD‑L1 expression thresholds

Assays referencedPD‑L1 IHC 22C3 pharmDx (TPS thresholds) and Ventana PD‑L1 assays with assay‑specific cutoffs

MET protein expression threshold

MET protein expression thresholdMET protein expression defined as ≥50% of tumor cells exhibiting strong membrane and/or cytoplasmic staining (3+)

Assay exampleVentana MET (SP44) RxDx Assay used in telisotuzumab vedotin (Emrelis) context

Clinical useThreshold used to identify patients for MET‑targeted therapy selection in NSCLC

Tumor mutational burden (TMB) threshold

TMB thresholdTumor mutational burden (TMB) ≥10 mutations per megabase

Assay exampleFoundationOne CDx (tissue) reports TMB and is used for certain immunotherapy indications

Clinical implicationTMB ≥10 mut/Mb used as companion diagnostic criterion for some immune checkpoint inhibitors

PD-L1 tumor cell staining (TC) examples

TC ≥50% examplePD‑L1 tumor cell staining (TC) ≥50% — used with some assays (e.g., SP263/SP142) to indicate high PD‑L1 tumor cell expression

TC ≥1% examplePD‑L1 tumor cell staining (TC) ≥1% — lower threshold used in other indications/assays (e.g., 22C3 for some agents)

Assay variabilityPD‑L1 thresholds are assay‑ and indication‑specific; reference the FDA‑cleared assay labeling

Panel gene counts (81445 vs 81455)

Panel size examplesCPT 81445: genomic sequence analysis panel, 5–50 genes; CPT 81455: genomic panel, 51+ genes

Use guidancePanel selection should align with intended biomarker detection and FDA companion diagnostic requirements

Coding noteMultiple PLA/CPT panel PLA codes (e.g., 0037U) correspond to specific multi‑gene assays such as FoundationOne CDx

Criteria for plasma testing when tissue insufficient

When allowedPlasma testing is allowed when the individual does not have sufficient tissue for standard molecular testing using FFPE tissue

Documentation requiredDocument insufficient tissue for standard molecular testing and that follow‑up tissue‑based analysis is planned if plasma testing identifies no driver variant

Intended usePlasma ctDNA tests used as alternative must be FDA‑approved companion diagnostic plasma tests and used consistent with the therapy's FDA label

Provider Responsibilities, Documentation, and Prior Authorization

Prior Authorization

Verify benefits / prior authorization

Verify member benefits and any prior authorization requirements with Blue Cross and Blue Shield of Kansas Customer Service before ordering testing; plan/member contract language takes precedence over this policy.

Contact BCBSKS Customer Service to confirm member coverage and any plan-specific prior authorization requirements.

Billing Rule

PLA code example — LeukoStrat CDx (FLT3)

When ordering an FDA companion diagnostic such as the LeukoStrat CDx FLT3 Mutation Assay, include the specific PLA code listed for that test (0023U) on submissions and billing where applicable.

LeukoStrat CDx FLT3 Mutation Assay — PLA code 0023U.

Documentation Required

Document companion diagnostic availability and CLIA status

Indicate on the order and prior authorization/claims whether an FDA‑cleared or -approved companion diagnostic is available for the intended targeted therapy and whether any laboratory‑developed test is performed in a CLIA high‑complexity laboratory.

Reference the FDA companion diagnostic listed in Table 1 when one exists.
If using an LDT, document that the laboratory is CLIA‑licensed for high‑complexity testing.

Billing Rule

Include listed PLA codes for tests (e.g., therascreen PIK3CA)

Use the PLA codes provided for specific companion diagnostics (for example, therascreen PIK3CA RGQ PCR Kit PLA codes 0155U or 0177U) when submitting prior authorization requests or claims for those tests.

therascreen PIK3CA RGQ PCR Kit — PLA codes 0155U and 0177U.

Billing Rule

Use FDA‑listed CPT/PLA codes on submissions

Include the FDA‑listed CPT/PLA code(s) associated with the companion diagnostic on prior authorization submissions and claims to support coverage determination.

Where Table 1 lists PLA/CPT codes for an FDA‑approved companion diagnostic, include those codes on PA requests and claims.

Billing Rule

Billing/code linkage examples for FDA companion diagnostics

When billing for FDA companion diagnostics, use the PLA identifiers cited in the policy for the named assays (examples include 0239U for FoundationOne Liquid CDx, 0037U for FoundationOne CDx, and 0326U for Guardant360 CDx).

FoundationOne Liquid CDx — PLA 0239U
FoundationOne CDx — PLA 0037U
Guardant360 CDx — PLA 0326U

Billing Rule

Reference test PLA/CPT identifiers on orders and claims

Reference the specific PLA/CPT identifiers listed for tissue companion diagnostics (e.g., 0037U, 0022U) when ordering, documenting, and billing those tests.

FoundationOne CDx and other tissue CDx — PLA 0037U
Oncomine Dx Target Test — PLA 0022U

Note

Prior authorization not specified in policy section (informational)

Informational: the policy section listing FDA‑approved companion diagnostics and PLA codes does not itself state payer prior authorization rules; verify plan-specific requirements separately.

Prior Authorization

Prior authorization may be required to establish label‑consistent use

Prior authorization may be required to demonstrate that testing is intended to select an FDA‑approved targeted therapy, will be used consistent with the agent's FDA label, and uses the appropriate specimen and test method.

PA may be requested to confirm label‑consistent intended use and that the individual has no FDA‑labeled contraindications.
Document specimen type (tissue, plasma, blood/bone marrow) and the specific FDA‑approved test when required.

Prior Authorization

PA may be required for ctDNA companion diagnostics

Prior authorization may be required for plasma (ctDNA) companion diagnostics used as alternatives to tissue biopsy; document that an FDA‑approved companion diagnostic plasma test is being used and the clinical justification for plasma testing.

When using plasma ctDNA as a tissue alternative, reference the FDA‑approved plasma CDx and document conformity with the test and drug labels.

Prior Authorization

Documentation expectations for PA of plasma ctDNA tests

Where plasma‑based ctDNA testing is used to select an FDA‑approved targeted therapy, prior authorization requests should document FDA‑label consistent intended use and, when applicable, that tissue biopsy is not feasible or is insufficient.

Document tissue infeasibility (insufficient tissue, no biopsy‑amenable lesion, contraindication) when plasma is substituted at progression or diagnosis.
Plan for follow‑up tissue analysis if plasma testing is negative, per policy guidance.

Note

Verify plan‑specific prior authorization requirements

Contextual note: the policy does not list a universal prior authorization mandate for all tests; verify member‑ and plan‑specific prior authorization requirements with BCBSKS.

Prior Authorization

Verify medical necessity and prior authorization for coded procedures

Procedure codes in the coding section are considered medically necessary only if the procedure is performed according to this policy and member benefits permit; verify medical necessity and any PA requirements before submitting claims.

Inclusion of a code in the policy does not guarantee member coverage—confirm benefits at time of service.

Prior Authorization

PA expectation for companion diagnostic testing

Prior authorization expectation: when an FDA‑approved companion diagnostic tissue or plasma test is specified for selecting an FDA‑approved targeted therapy, coverage is generally limited to the listed indications and to use consistent with the drug's FDA label.

Requests should reference the specific FDA‑approved companion diagnostic listed for the biomarker–drug pairing.

Prior Authorization

PA guidance for repeat and concurrent testing

For repeat or concurrent genomic testing, prior authorization requests should document the clinical rationale (e.g., progression or suspected acquired resistance) and how the results will guide next‑line FDA‑approved therapy.

Repeat testing may be considered at progression to identify acquired resistance variants when next‑line therapy decisions would be affected.

Prior Authorization

Benefit verification required

Verify member benefits with BCBSKS Customer Service because coverage may be preempted by state/federal mandates or specific member contract exclusions.

Confirm whether state law or contract provisions alter coverage before proceeding.

Note

Regulatory status — FDA list not comprehensive for LDTs

Regulatory status note: the policy lists FDA‑approved companion diagnostics but does not comprehensively enumerate laboratory‑developed tests (LDTs), which are subject to CLIA requirements rather than FDA listing.

Documentation Required

Document CDx availability and CLIA status on orders/PA

Documentation requirement: indicate whether an FDA‑cleared/approved companion diagnostic is available for the intended therapy and, if an LDT is used, document that the laboratory is CLIA high‑complexity certified.

Include the specific FDA‑cleared diagnostic name (e.g., Foundation One Liquid CDx, Foundation One CDx) and the biomarker(s) detected when submitting PA or claims.
If using an LDT, include CLIA high‑complexity laboratory certification documentation.

Note

PLA codes listed (informational)

Informational: numerous PLA codes are listed throughout the policy for reference; use the specific code(s) tied to the test being ordered when completing authorization or billing paperwork.

Documentation Required

Use regulatory listings to support PA/claims documentation

Use FDA regulatory listings (PMA/510(k)/PLA identifiers) cited in the policy to support documentation for prior authorization and claims when ordering an FDA‑approved companion diagnostic.

Reference PMA/510(k) or PLA identifiers as evidence that a tissue or plasma test is an FDA‑authorized companion diagnostic for a given drug–biomarker pairing.

Note

No step‑therapy rules specified

Informational: no step‑therapy requirements are specified in the policy excerpt; clinical sequencing requirements (other than the PIK3CA/alpelisib context) are not detailed here.

Documentation Required

Document prior endocrine therapy for alpelisib selection

For PIK3CA testing to select alpelisib, document that the patient progressed on or after an endocrine‑based regimen, as the policy specifies PIK3CA testing is used to select alpelisib in that clinical context.

Document prior endocrine therapy and progression when requesting testing for alpelisib selection.

Note

ASCO guidance — repeat genomic testing for acquired resistance

ASCO suggests repeat genomic testing for suspected acquired resistance when the results would guide next‑line therapy; include this rationale in prior authorization requests for repeat testing.

Use ASCO guidance to support PA for repeat testing when progression suggests acquired resistance that would change therapy.

Documentation Required

Document clinical context and intended FDA‑approved therapy

Documentation should support that the patient has unresectable, recurrent, relapsed, refractory, advanced, or metastatic cancer and that the test result will be used to select an FDA‑approved targeted therapy consistent with the labeled indication.

Include tumor type, clinical stage, and the intended FDA‑approved therapy in PA/claims documentation.

Denial Risk

Ensure testing is intended for label‑consistent use

Label‑consistent use required: testing must be intended to be used consistently with the agent's FDA label; testing intended for off‑label agent use or where the agent has FDA‑labeled contraindications may be denied.

Confirm and document that the requested test result will guide use of an FDA‑approved targeted therapy per its label and that no FDA‑labeled contraindications exist.

Denial Risk

Denial risk — missing follow‑up tissue plan or investigational ctDNA uses

Denial triggers: plasma testing may be denied if follow‑up tissue‑based analysis is not planned when plasma is used because tissue is insufficient; uses of somatic ctDNA testing not listed in the policy are considered experimental/investigational and may be denied.

If ordering plasma testing because tissue is insufficient, document plans for follow‑up tissue testing if plasma is negative.
Avoid using plasma ctDNA for indications the policy designates investigational (e.g., RET via plasma).

Denial Risk

Coverage contingent on member contract

Coverage of listed procedure codes is contingent on the member's contract; inclusion of a code in this policy does not guarantee coverage—verify contract benefits prior to ordering.

Confirm member contract terms at time of service to determine coverage and reimbursement.

Note

Check for state‑specific coverage mandates

Plans may need to modify local coverage to conform to applicable state law regarding biomarker testing; verify any state‑specific mandates that could affect coverage before ordering.

Denial Risk

Investigational risk for off‑label somatic tests without FDA‑approved therapies

Off‑label somatic tests of individual genes without associated FDA‑approved therapies are considered investigational and may be denied; ensure requested testing aligns with FDA‑approved companion diagnostic indications or guideline‑supported use.

If the requested test is for a gene without an FDA‑approved therapy, note that the policy considers such testing investigational.

Eligibility Requirements

Eligibility for testing is limited to individuals with unresectable, recurrent, relapsed, refractory, advanced, or metastatic cancer when testing is intended to inform selection of an FDA‑approved targeted therapy consistent with the agent's labeled indication. Providers should document the clinical context, intended therapy, and that the requested agent will be used per its FDA label.

Testing is intended for patients being considered for targeted therapy with an FDA‑approved drug consistent with its labeled indication. Use tissue testing when available; circulating tumor DNA (ctDNA) may be used as an alternative or concurrently in specific situations (see Policy Guidelines).

When ctDNA is used because tissue is not feasible, document why tissue biopsy is not possible (for example, insufficient tissue for standard FFPE molecular testing, no biopsy‑amenable lesion, or contraindication to biopsy) and plan for follow‑up tissue‑based analysis if no driver variant is identified via plasma testing.

Assay‑specific requirements: where the policy references an FDA‑cleared/approved companion diagnostic for a given biomarker–drug pairing, the named diagnostic and its authorized specimen type must be used to support selection of that targeted therapy (for example, specific PMA/PLA‑identified assays cited in Table 1).

Example — colorectal cancer (CRC): tests such as xT CDx (Tempus) and Idylla CDx MSI Test are cited with PMA/PLA identifiers for CRC biomarker evaluation (e.g., extended RAS and MSI) when used to select FDA‑approved therapies; follow the test's authorized biomarker definitions when documenting eligibility.

This policy does not address germline testing for inherited cancer risk (see related germline testing policies). Somatic testing described here focuses on selecting targeted therapies for advanced/metastatic disease and follows FDA companion diagnostic linkages and guideline frameworks.

Some entries in Table 1 reference IHC or ISH assays with PMA identifiers (for example PD‑L1 22C3 pharmDx) where specific biomarker thresholds (e.g., PD‑L1 Tumor Proportion Score definitions) are integral to eligibility; use the assay's defined thresholds when interpreting results for therapy selection.

Where the policy cites broad NGS companion diagnostics (e.g., FoundationOne CDx or FoundationOne Liquid CDx), those assays are listed for multiple tumor‑agnostic or tumor‑specific biomarkers (for example, NTRK fusions, RET fusions, MSI, TMB); use the named CDx and its reported biomarker definitions to establish eligibility for linked FDA‑approved therapies.

For select indications (for example, NTRK fusions, MET exon 14 skipping), plasma (ctDNA) companion diagnostic assays are allowed as alternatives to tissue when an FDA‑approved plasma CDx exists and the test and intended agent are used consistent with FDA labels; document that both the plasma test and therapy align with their FDA‑approved indications.

Plasma (ctDNA) testing examples: the policy permits ctDNA PIK3CA testing to select alpelisib in HR+/HER2‑ advanced/metastatic breast cancer after progression on endocrine therapy, and allows ctDNA BRCA1/2 testing in ovarian cancer when tissue testing is not feasible—only when performed with an FDA‑approved companion diagnostic and used per label.

Documentation requirements include tumor type, clinical indication, intended FDA‑approved targeted therapy, absence of any FDA‑labeled contraindications to the agent, and the specific diagnostic assay used (including manufacturer, PMA/510(k)/PLA identifiers where available) to support that the selected test matches the drug's companion diagnostic, if applicable.

When tissue is insufficient for standard molecular testing, plasma testing may be considered if the individual meets the policy's criteria for plasma testing when tissue is insufficient (insufficient FFPE tissue for standard testing and planned follow‑up tissue analysis if plasma testing is non‑informative).

Example — endometrial carcinoma and MSI/MMR: use the FDA‑approved MMR/MSI assays cited in the Table (e.g., Ventana MMR RxDx Panel) and document assay results according to the test's defined biomarker calls when selecting immunotherapy per labeled indications.

ASCO guideline recommendations are incorporated where relevant (for example, PIK3CA, germline BRCA1/2, PD‑L1, MSI‑H/dMMR, TMB, and NTRK fusions in metastatic breast cancer). Follow guideline‑recommended testing approaches and assay types when cited in those guidance statements.

The 'Plasma Testing When Tissue is Insufficient' subsection requires documentation that tissue is inadequate for standard molecular testing and that follow‑up tissue‑based analysis will be pursued if plasma testing does not identify a driver alteration.

Policy guidance emphasizes that when tumor tissue is available, tissue‑based testing is preferred for detecting variants and biomarkers in this policy, but concurrent tissue and liquid testing may be used to expedite results or for longitudinal monitoring if clinically justified.

Experimental, Investigational, and Not Covered Uses

No explicit test exclusions are listed in this extract; however, the policy notes that many other uses (including somatic tests without FDA‑approved therapies or lacking guideline support) are considered investigational and not covered. Verify member contract and applicable mandates.

Plasma‑based detection of somatic RET alterations to guide RET inhibitor therapy is explicitly designated as experimental / investigational and is not considered a medically necessary alternative to tissue in this policy.

Off‑label somatic tests performed to guide targeted therapy that lack an associated FDA‑approved therapy or do not have guideline support (for example, NCCN ≥2A) are considered investigational and are not supported for coverage under this policy.

Somatic tests of individual genes that do not have associated FDA‑approved therapies are treated as investigational per the Blue Cross and Blue Shield Association program and are not covered when used to select targeted treatments outside specified policy indications.

Tests that are not recommended by guideline panels or have insufficient evidence to guide therapy in specific settings (for example, routine tumor HRD testing to guide therapy in metastatic breast cancer; or PALB2 testing to select PARP therapy in MBC) are considered unsupported for routine coverage in those contexts.

When actionable genomic alterations lack approved biomarker‑linked therapies, the policy encourages enrollment in clinical trials and generally does not recommend off‑label targeted therapy selection outside a trial when trials are available.

Background and Definitions

Background: Genetic biomarker testing of tumor tissue and circulating tumor DNA (liquid biopsy) is used to identify actionable oncogenic driver variants and other molecular signatures (for example, PD‑L1, MSI/MMR, TMB, HRD) to select FDA‑approved targeted therapies for patients with unresectable, recurrent, relapsed, refractory, advanced, or metastatic cancers.

Definition — Liquid biopsy / ctDNA

DefinitionLiquid biopsy / circulating tumor DNA (ctDNA): tumor‑derived fragments of cell‑free DNA detectable in blood used for genomic characterization of tumors

PurposeUsed to detect somatic variants when tissue biopsy is not feasible or to monitor for resistance variants

Assay typesIncludes FDA‑approved plasma companion diagnostic assays (e.g., FoundationOne Liquid CDx, Guardant360 CDx)

Definition — Homologous recombination deficiency (HRD)

DefinitionHomologous recombination deficiency (HRD): loss of homologous recombination repair capacity leading to genomic instability

AssessmentAssessed by pathogenic BRCA1/2 variants and/or a genomic instability score (GIS) from assays such as Myriad myChoice

Clinical relevanceHRD is associated with ovarian and prostate cancers and can inform PARP inhibitor therapy selection

Definition — HRD-positive

DefinitionHRD‑positive: presence of a deleterious or suspected deleterious BRCA1/2 mutation and/or a genomic instability score above the assay‑defined threshold (e.g., Myriad myChoice)

Assay exampleMyriad myChoice CDx determines HRD‑positive status via BRCA1/2 variant detection and GIS

ImplicationDefines eligibility for HRD‑directed targeted therapies in ovarian cancer and related indications

Definition — dMMR / MSI-H

DefinitiondMMR / MSI‑H: mismatch repair deficiency (dMMR) or high microsatellite instability (MSI‑H) indicating defects in DNA repair genes

MarkersMMR IHC assesses MLH1, PMS2, MSH2, MSH6; MSI PCR uses 5 markers (MLH1, MSH2, MSH6, PMS1, PMS2)

MSI‑H thresholdMSI‑H defined as instability in ≥2 of 5 PCR markers or >30% unstable biomarkers depending on panel

Definition — ctDNA

DefinitionctDNA: circulating tumor DNA — tumor‑derived fragments of cell‑free DNA detectable in plasma used for tumor genomic profiling

SourceDerived from apoptotic/necrotic tumor cells from primary tumor, metastases, or circulating tumor cells

UseUsed as alternative to tissue biopsy for somatic variant detection and longitudinal monitoring

Definition — LDT must meet CLIA high-complexity standards

RequirementLaboratory‑developed tests (LDTs) must be developed/validated in‑house and performed in CLIA‑certified high‑complexity laboratories

Regulatory noteFDA has not required regulatory review of LDTs to date; LDTs are not comprehensively listed in the FDA companion diagnostic table

DocumentationProviders should document CLIA high‑complexity lab status when ordering LDTs

Definition — Companion diagnostic (FDA CDx)

DefinitionCompanion diagnostic (CDx): an FDA‑cleared or ‑approved diagnostic test linked to a specific targeted therapy (drug) and biomarker

ExamplesFoundationOne CDx, FoundationOne Liquid CDx, BRACAnalysis CDx, cobas EGFR Mutation Test v2

UsageWhen selecting an FDA‑approved targeted therapy, use the FDA‑listed companion diagnostic identified for that drug/biomarker pairing

Definition — PLA code

DefinitionPLA code: Proprietary Laboratory Analytic code used to identify specific FDA‑authorized laboratory tests (PLA/HCPCS codes like 0155U, 0177U)

PurposeInclude PLA codes on submissions/claims when billing for FDA‑cleared companion diagnostic assays

Exampletherascreen PIK3CA RGQ PCR Kit PLA codes 0155U (tissue) and 0177U (plasma)

Definition — MSI-H / dMMR and related proteins

DefinitionMSI‑H / dMMR: microsatellite instability‑high and deficient mismatch repair proteins (MLH1, PMS2, MSH2, MSH6) used to identify patients for immunotherapy

IHC vs PCRIHC assesses loss of MMR proteins; PCR assesses microsatellite marker instability — both identify MSI‑H/dMMR status

Clinical relevanceMSI‑H/dMMR status indicates potential responsiveness to PD‑1/PD‑L1 inhibitors

Definition — cfDNA/plasma companion diagnostic (e.g., Foundation One Liquid CDx)

DefinitioncfDNA/plasma companion diagnostic: plasma‑based (liquid biopsy) assays (e.g., FoundationOne Liquid CDx, Guardant360 CDx) cleared to detect tumor alterations in ctDNA

ExamplesFoundationOne Liquid CDx (PLA 0239U) for BRCA1/2 in mCRPC; FoundationOne Liquid CDx for NTRK fusions

Use caseMay be used as alternative to tissue when FDA‑approved companion diagnostic exists and tissue is not feasible

Definition — Companion diagnostic (CDx) (additional)

DefinitionCompanion diagnostic (CDx): FDA‑cleared/approved diagnostic assay (tissue, plasma, or whole blood) used to identify biomarker alterations for selection of associated targeted therapies

DocumentationPolicy lists PMA/510(k)/PLA identifiers for CDx assays — providers should reference the specific CDx when documenting testing rationale

Regulatory linkageCoverage tied to use consistent with the FDA‑approved CDx and drug label

Definition — PD-L1 TPS

DefinitionPD‑L1 TPS (Tumor Proportion Score): percentage of tumor cells with PD‑L1 membrane staining; thresholds include ≥1% and ≥50% depending on assay and indication

AssaysPD‑L1 IHC 22C3 pharmDx (TPS ≥1% or ≥50% per indication); Ventana PD‑L1 assays have assay‑specific cutoffs

Clinical implicationTPS thresholds used in FDA approvals to select patients for PD‑1/PD‑L1 therapies in NSCLC and other tumors

Definition — EGFR alterations examples

ExamplesEGFR alterations include exon 19 deletions, exon 21 L858R substitutions, T790M resistance mutation, and exon 20 insertions

Assay relevanceMultiple FDA‑cleared tissue and plasma assays (e.g., cobas EGFR v2) detect these variants for targeted EGFR therapies

Clinical usePresence of activating EGFR mutations guides use of EGFR TKIs in NSCLC

Definition — TMB ≥10 mutations per megabase

DefinitionTMB ≥10 mutations per megabase defined as threshold used by FoundationOne CDx tissue test for eligibility for certain immunotherapies

Assay exampleFoundationOne CDx reports TMB (mut/Mb) and is cited in FDA companion diagnostic listings

Clinical implicationPatients with TMB ≥10 mut/Mb may be considered for tumor‑agnostic immunotherapy indications per FDA labeling

Definition — MET protein expression example

Definition/exampleMET protein expression defined as ≥50% of tumor cells exhibiting strong membrane and/or cytoplasmic staining (3+) — used with telisotuzumab vedotin (Emrelis)

AssayVentana MET (SP44) RxDx Assay referenced in FDA listings

Clinical useThreshold identifies MET‑high tumors for MET‑targeted therapy selection in NSCLC

Definition — PLA codes cited for diagnostic tests

DefinitionPLA codes cited for diagnostic tests (examples in policy: 0155U, 0177U, 0037U, 0239U, 0211U)

Coding useInclude PLA/CPT codes on prior authorization submissions and claims for FDA‑approved companion diagnostics where specified

Examples in documenttherascreen PIK3CA (0155U/0177U), FoundationOne Liquid CDx (0239U), FoundationOne CDx (0037U), MI Cancer Seek (0211U)

Scope — somatic vs germline

Scope statementThis policy addresses somatic (tumor) testing for selecting targeted treatments and does not address germline testing for inherited cancer risk

ImplicationGermline BRCA and other hereditary testing are covered in separate germline testing policies

ReasoningSomatic testing focuses on tumor‑acquired variants to guide FDA‑approved targeted therapies

Definition — cfDNA/plasma companion diagnostic (alternative to tissue)

DefinitionctDNA (liquid biopsy) used as alternative to tissue when performed with FDA‑approved companion diagnostic plasma tests (e.g., FoundationOne Liquid CDx, Guardant360 CDx)

ConditionsUse permitted when tissue is insufficient or biopsy not feasible and when agent/test used consistent with FDA label

DocumentationPolicy requires documentation that tissue is insufficient and follow‑up tissue testing planned if plasma is negative

Provider Resources, Guidance, and Documentation Details

Note

Policy Update History

2026-02-26material_revisionLatest

Added ALK and BRAF tissue testing indications and added NTRK gene fusion testing (NTRK testing medically necessary in recurrent/unresectable or stage IV breast cancer); expanded multiple gene-specific sections (ALK, BRAF, NTRK and others).

2023-05-25coding_update

Updated coding section with nomenclature changes including additions (0242U, 81456, multiple panel and gene-specific codes) and removals of specific CPT codes; updated coding descriptions and nomenclature for panels (e.g., 81445/81455).

2022-10-28coding_update

Updated Coding Section to add 0338U (effective 2022-10-01) and revised policy sections including removal and addition of certain gene fusion testing statements.

2022-03-10policy_posting

Policy added to the BCBSKS website (initial posting of the coverage policy).

2024-08-30coding_revision

Foundation One Liquid CDx plasma PMA supplement entries and associated PLA code updates reflected in coding (P190032/S016 noted); coding and regulatory table updated.

2023-05-25policy_structure_update

Added Section H: NTRK Gene Fusion Testing and expanded policy title and gene-specific sections to clarify indications and companion diagnostic linkages.

Policy Summary

Payerblue cross blue shield - kansas

PolicyGenetic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Advanced Cancer

Policy CodePolicy N/A

Change TypeMultiple additions and coding updatesctDNA expandednew gene-specific indications

Effective DateMar 10, 2022

Last ReviewFeb 26, 2026

Next Review DateFeb 26, 2026

Key ActionVerify member benefits and any prior authorization requirements with BCBSKS and document that the test and intended FDA-approved therapy will be used consistent with the drug's label.

SourceLink

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Genetic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment in Advanced Cancer

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Coverage Criteria and Medical Necessity

General coverage criteria for biomarker testing

Covered when ALL of the following are met

Supported by policy scope and objective statements

FDA-linked companion diagnostic coverage

Covered when the listed FDA-cleared/approved companion diagnostic corresponds to the indicated drug and biomarker in the specified cancer type

Linkage requirement: Companion diagnostic must be the FDA-listed test (diagnostic name/manufacturer) associated with the specific drug NDA/BLA for the cancer indication.

See Table 1 (FDA companion diagnostics list current to 11/01/2025)

Biomarker specifics are enumerated per FDA-listed CDx entry

Regulatory companion diagnostic linkages (informational)

FDA‑cleared/approved companion diagnostics and their indicated biomarkers (administrative linkage rather than clinical eligibility criteria):

mCRPC plasma CDx: FoundationOne Liquid CDx (plasma) cleared for detection of BRCA1/BRCA2 (and ATM per specific supplements) to inform PARP inhibitor use in mCRPC.

P190032; PLA 0239U

P170019/S015; PLA 0037U

Multiple PMA/510(k) entries and PLA codes

Regulatory-authorized companion diagnostics and biomarker definitions

Covered companion diagnostics and biomarker definitions as listed (no explicit coverage algorithm in these chunks):

Mapping of authorized diagnostics to drug indications

ALK Testing (Medically Necessary)

ALK testing is covered when ALL of the following are met

See Ventana ALK D5F3 CDx entries and Policy Guidelines

BRAF Testing

BRAF testing is covered when ANY of the following are met

Pediatric low‑grade glioma: Testing for BRAF V600 variants or BRAF fusion rearrangements in relapsed or refractory pediatric low‑grade glioma to select tovorafenib.

BRCA1 and BRCA2 Testing

BRCA1/2 testing criteria

BRACAnalysis CDx listed as companion diagnostic

Somatic BRCA1/2 variant analysis on tumor tissue to select FDA‑approved targeted therapies in advanced epithelial ovarian/fallopian tube/primary peritoneal cancer, mCRPC, and prostate cancer.

Claudin 18 (CLDN18) Testing

CLDN18 testing criteria

See VENTANA CLDN18 RxDx assay entry

EGFR Testing

EGFR testing criteria

cobas EGFR Mutation Test v2 and FoundationOne CDx entries

EGFR exon 20 insertions: Tumor tissue analysis for EGFR exon 20 insertion variants to select therapies (e.g., mobocertinib) when used consistent with FDA label.

ESR1 Testing

ESR1 testing criteria

Guardant360 CDx and related plasma CDx entries noted for ESR1

EZH2 Testing

EZH2 testing criteria

FGFR2 Testing

FGFR2 testing criteria

FoundationOne CDx listed for FGFR2 fusions

FGFR3 Testing

FGFR3 testing criteria

FLT3 Testing

FLT3 testing criteria

LeukoStrat CDx FLT3 Mutation Assay listed (PLA 0023U)

FOLR1 Testing

FOLR1 testing criteria

HER2 Testing

HER2 testing criteria

HER2 testing of tumor tissue to select FDA‑approved HER2‑targeted therapies in metastatic solid tumors when results meet companion diagnostic criteria and agent use is consistent with FDA label.

Multiple HER2 CDx assays referenced (PathVysion, PATHWAY 4B5, Ventana HER2 Dual ISH)

HRR Gene Testing

Homologous Recombination Repair (HRR) gene testing criteria

FoundationOne CDx lists HRR genes for mCRPC

HRD Testing

Homologous Recombination Deficiency (HRD) testing criteria

Myriad myChoice CDx and FoundationFocus CDxBRCA referenced

Homologous Recombination Repair (HRR) Gene Testing (somatic, tissue)

Covered when ALL of the following are met

FoundationOne CDx tissue HRR listing (P170019/S015)

Homologous Recombination Deficiency (HRD) Testing (tissue)

Covered when ALL of the following are met

Myriad myChoice CDx and FoundationFocus/FoundationOne CDxBRCA referenced

HLA Testing (tissue)

IDH1/IDH2 Testing

Oncomine Dx Target Test entries (0022U) and related PMAs

KIT Testing

MET Exon 14 Skipping Alteration (tissue or plasma)

FoundationOne CDx MET exon 14 entries; plasma CDx alternatives noted

Mismatch Repair / Microsatellite Instability (MMR/MSI) Testing

Idylla CDx MSI Test and MMR IHC pharmDx entries

NTRK Gene Fusion Testing (tissue or plasma)

FoundationOne CDx / Liquid CDx entries for NTRK fusions

PDGFRA Testing

PDGFRA for avapritinib: Tumor tissue PDGFRA testing (e.g., D842V) to select avapritinib in unresectable or metastatic GIST is medically necessary when used consistent with FDA label.

therascreen PDGFRA RGQ PCR Kit referenced

PDGFRB Testing

PIK3CA Testing

therascreen PIK3CA RGQ PCR Kit (PLA 0155U/0177U) referenced

PD-L1 Testing

PD‑L1 IHC 22C3 pharmDx and other assays referenced

RAS (KRAS/NRAS) Testing

cobas KRAS, FoundationOne CDx entries referenced

RET Testing

FoundationOne CDx RET entries referenced

ROS1 Testing

TP53 (17p deletion) Testing

Vysis CLL FISH Probe Kit referenced

Tumor Mutational Burden (TMB) Testing

FoundationOne CDx TMB entry

Circulating Tumor DNA (ctDNA) / Liquid Biopsy Testing

See DD.1–DD.12 and EE.1 for specifics; plasma CDx examples include FoundationOne Liquid CDx, Guardant360 CDx, cobas EGFR v2

Medically necessary ctDNA/plasma testing

Covered uses of circulating tumor DNA (ctDNA) / plasma testing when ALL listed conditions for each indication are met as specified in individual items below.

DD.3; EE.1

DD.4; cobas EGFR v2 plasma CDx referenced

DD.5

DD.6; Guardant360 CDx and other plasma CDx referenced

DD.7; FoundationOne Liquid CDx entries

DD.8

DD.9; FoundationOne Liquid CDx referenced

DD.10; therascreen PIK3CA kit referenced

DD.11

DD.12; Agilent/Resolution ctDNA assays referenced

DD.14

EE.1

Experimental / Investigational

Not covered / investigational uses

DD.13

DD.15; FF.1

Testing to select FDA‑approved targeted therapies

Covered when ALL of the following are met

Based on evidence summary and PCO framework

ASCO Provisional Clinical Opinion–based coverage

Additional recommended scenarios

ASCO Provisional Clinical Opinion guidance

Medical necessity criteria for genomic and fusion testing

Covered when criteria below are met per Provisional Clinical Opinions and policy additions

PCO framework and policy additions

PCO 3.1–3.2

Repeat testing at progression: Repeat genomic testing (tissue or liquid) may be considered at progression or suspected acquired resistance when results would guide next‑line therapy.

ASCO suggestion; see Policy Guidelines

Medical necessity for somatic biomarker testing to select FDA‑approved targeted therapies

Covered when ALL of the following are met (examples by gene/biomarker):

Applies across gene/biomarker sections

Each gene section includes tumor‑type specific indications

See ctDNA section and EE.1

Testing and coverage criteria

Covered when aligned with FDA approvals, guideline recommendations, and clinical utility:

Tissue preferred but liquid biopsy acceptable in defined circumstances

ASCO guidance cited

Policy coding clarifications

Coding, PLA and Regulatory Identifiers

Example PLA Codes from FDA companion diagnostics tableHCPCS

0023U

PLA code listed for LeukoStrat CDx FLT3 Mutation Assay (Invivoscribe Technologies, Inc.)

PLA Codes mentioned (example)CPT

0023U

PLA code associated with LeukoStrat CDx FLT3 Mutation Assay

PLA Codes mentionedCPT

0022U

PLA code associated with Oncomine Dx Target Test (listed for Anaplastic Thyroid Cancer and other tissue indications)

PLA Codes mentionedCPT

0239U	PLA code associated with Foundation One Liquid CDx (referenced for multiple plasma indications including PIK3CA/BRCA testing)
0326U	PLA code associated with Guardant360 CDx (referenced for ESR1 ctDNA testing)

PLA Codes mentionedCPT

0211U

PLA code associated with MI Cancer Seek (Caris Life Sciences) for PIK3CA and MSI-H related entries

PLA CodesHCPCS

0155U	PLA code associated with therascreen PIK3CA RGQ PCR Kit (QIAGEN) for tissue PIK3CA testing
0177U	PLA code associated with therascreen PIK3CA RGQ PCR Kit for plasma PIK3CA testing

Other PLA/CodesHCPCS

0037U	PLA/code associated with Foundation One CDx (listed for multiple tissue indications, e.g., colorectal, ovarian, NSCLC)
0211U	PLA/code associated with MI Cancer Seek (Caris) (appears in multiple tissue entries)
0523U	PLA/code associated with ONCO/Reveal Dx Lung & Colon Cancer Assay (Pillar Biosciences)
0471U	PLA/code associated with Idylla CDx MSI Test (Biocartis US, Inc.)

PMA / 510(k) identifiersmixed

P980024	PMA approval for PathVysion HER-2 DNA Probe Kit (Abbott) — 12/11/1998
P990081	PMA for PATHWAY anti-HER2/neu (4B5) antibody (Ventana) — 11/28/2000
P190001	PMA for therascreen PIK3CA kit — 05/24/2019
P190004	PMA supplement/clearance associated with therascreen PIK3CA — 05/24/2019

Examples of PLA/CPT codes listedCPT

0471U

PLA/CPT code referenced for Idylla CDx MSI Test (Colorectal Cancer)

Examples of PLA/CPT codes listedCPT

0473U

PLA/CPT code referenced for xT CDx (Tempus Labs) tissue/matching blood/saliva assay

Examples of PLA/CPT codes listedCPT

0037U

PLA/CPT code referenced for Foundation One CDx (listed for Low-Grade Glioma and other entries)

Examples of PLA/CPT codes listedCPT

0239U

PLA/CPT code referenced for Foundation One Liquid CDx (mCRPC plasma and other plasma indications)

PLA / Proprietary Laboratory Analyses codesCPT

0239U	PLA code referenced for Foundation One Liquid CDx (multiple plasma assays)
0037U	PLA code referenced for Foundation One CDx (tissue) and BRACAnalysis CDx (whole blood)
0326U	PLA code referenced for Guardant360 CDx (plasma)

Referenced PLA/Test Codesmixed

0037U	PLA code associated with Foundation One CDx referenced across multiple NSCLC and solid tumor entries
0022U	PLA code associated with Oncomine Dx Target Test referenced for multiple tissue indications
0523U	PLA code referenced for TruSight/ONCO panels in NSCLC/solid tumor contexts

PMA / 510(k) / Supplement Identifiersmixed

P170019	PMA identifier for Foundation One CDx (initial approval and supplements referenced)
P160045	PMA identifier for Oncomine Dx Target Test (and supplements)
P120022	PMA identifier for therascreen EGFR RGQ PCR Kit
P150013	PMA identifier for PD-L1 IHC 22C3 pharmDx
P140025	PMA identifier for Ventana ALK (D5F3) CDx Assay
P110027	PMA identifier referenced for therascreen KRAS RGQ PCR Kit

Listed PLA / Test Codesmixed

0239U	Foundation One Liquid CDx (plasma) - NTRK fusions and other plasma indications
0037U	Foundation One CDx (tissue) - listed for multiple solid tumor biomarkers (e.g., NTRK, MSI-H, TMB)
0211U	MI Cancer Seek (Caris) - PLA code referenced for MSI-H and other solid tumor entries
0543U	TruSight Oncology Comprehensive (Illumina) - PLA code listed for NTRK fusions and broad panels
0172U	Myriad myChoice CDx - PLA code associated with HRD (Myriad)

Regulatory/PLA codes citedmixed

0211U	PLA code referenced for MI Cancer Seek / Caris Life Sciences (MSI-H)
0543U	PLA code referenced for TruSight Oncology Comprehensive (NTRK fusions)
0037U	PLA code referenced for Foundation One CDx (various tissue indications)
0154U	PLA code referenced for FGFR testing (listed in regulatory entries)

Listed CPT/PLA and molecular pathology codesmixed

0037U	Targeted genomic sequence analysis, solid organ neoplasm, DNA analysis of 324 genes (FoundationOne CDx PLA)
0048U	Oncology DNA targeted sequencing of 468 genes (MSK-IMPACT PLA)
0155U	PIK3CA gene analysis (therascreen PIK3CA RGQ PCR Kit PLA)
0177U	PIK3CA gene analysis of 11 variants utilizing plasma (therascreen PIK3CA RGQ PCR Kit PLA)
0239U	Targeted genomic sequence analysis panel, cell-free DNA, analysis of 311+ genes (FoundationOne Liquid CDx PLA)
0242U	Targeted genomic sequence analysis panel, cell-free circulating DNA analysis of 55-74 genes (Guardant360 CDx PLA)
0338U	Circulating tumor cell selection/identification HER2 CTC (example PLA)
81162	BRCA1/BRCA2 full sequence and duplication/deletion analysis
81163	BRCA1/BRCA2 full sequence analysis
81164	BRCA1/BRCA2 duplication/deletion analysis

1–10 of 24

1/3

Previously listed NTRK translocation CPT codes (removed per revisions)CPT

81191	NTRK1 translocation analysis
81192	NTRK2 translocation analysis
81193	NTRK3 translocation analysis
81194	NTRK1/2/3 translocation analysis

Example FDA‑approved companion diagnostic plasma tests (named examples)mixed

Guardant360 CDx	Example plasma companion diagnostic (Guardant360 CDx) referenced for EGFR, ESR1, and other plasma indications
FoundationOne Liquid CDx	Example plasma companion diagnostic (FoundationOne Liquid CDx) referenced for BRCA1/2, BRAF, NTRK fusions, EGFR, and other plasma indications

Updated Coding: Removed codesCPTNot Covered

0211U

Removed (previously listed PLA/CPT code)

Myriad MyChoice GIS threshold

AssayMyriad myChoice CDx (genomic instability score - GIS)

Positive criterionHRD-positive defined by pathogenic BRCA1/2 variant and/or GIS above Myriad-defined threshold

PurposeUsed to identify patients with ovarian (epithelial), fallopian tube, or primary peritoneal cancer eligible for HRD-directed therapy

High MSI definition

DefinitionHigh MSI (MSI‑H) defined as instability in ≥2 of 5 PCR microsatellite markers or >30% of tested biomarkers showing instability (panel-dependent)

Testing methodsMSI PCR panels (5-marker) or MMR IHC for MLH1, MSH2, PMS2, MSH6

Clinical implicationMSI‑H/dMMR identifies patients likely to respond to PD‑1/PD‑L1 immunotherapy

Myriad HRD positive criteria

HRD-positive (policy definition)Presence of a deleterious or suspected deleterious BRCA1 or BRCA2 mutation and/or genomic instability as assessed by an FDA‑approved assay (e.g., Myriad myChoice)

Assay exampleMyriad myChoice CDx assesses BRCA1/2 variants and computes a genomic instability score (GIS)

Clinical useDetermines eligibility for PARP inhibitor/HRD‑directed therapies in ovarian and related cancers

PD-L1 Combined Positive Score (CPS) examples

Example: Esophageal SCCPD‑L1 CPS ≥ 10 (PD‑L1 IHC 22C3 pharmDx) for pembrolizumab in ESCC

Example: Gastric/GEJPD‑L1 CPS ≥ 1 used in some gastric/GEJ adenocarcinoma indications

Scoring noteCPS combines PD‑L1 staining on tumor and immune cells per assay instructions

CLDN18 expression threshold (CLDN18.2)

ThresholdCLDN18 (claudin‑18.2) positive defined as ≥75% viable tumor cells staining (TC ≥75%)

Assay exampleVENTANA CLDN18 (43‑14A) RxDx Assay (Ventana) used for zolbetuximab selection

IndicationGastric or gastroesophageal junction (GEJ) adenocarcinoma

PD-L1 Tumor Proportion Score (TPS) thresholds

TPS ≥50% examplePD‑L1 Tumor Proportion Score (TPS) ≥50% — used in approvals requiring high tumor cell PD‑L1 expression (e.g., some PD‑1/PD‑L1 therapies)

TPS ≥1% examplePD‑L1 TPS ≥1% — used in other approvals with lower PD‑L1 expression thresholds

Assays referencedPD‑L1 IHC 22C3 pharmDx (TPS thresholds) and Ventana PD‑L1 assays with assay‑specific cutoffs

MET protein expression threshold

MET protein expression thresholdMET protein expression defined as ≥50% of tumor cells exhibiting strong membrane and/or cytoplasmic staining (3+)

Assay exampleVentana MET (SP44) RxDx Assay used in telisotuzumab vedotin (Emrelis) context

Clinical useThreshold used to identify patients for MET‑targeted therapy selection in NSCLC

Tumor mutational burden (TMB) threshold

TMB thresholdTumor mutational burden (TMB) ≥10 mutations per megabase

Assay exampleFoundationOne CDx (tissue) reports TMB and is used for certain immunotherapy indications

Clinical implicationTMB ≥10 mut/Mb used as companion diagnostic criterion for some immune checkpoint inhibitors

PD-L1 tumor cell staining (TC) examples

TC ≥50% examplePD‑L1 tumor cell staining (TC) ≥50% — used with some assays (e.g., SP263/SP142) to indicate high PD‑L1 tumor cell expression

TC ≥1% examplePD‑L1 tumor cell staining (TC) ≥1% — lower threshold used in other indications/assays (e.g., 22C3 for some agents)

Assay variabilityPD‑L1 thresholds are assay‑ and indication‑specific; reference the FDA‑cleared assay labeling

Panel gene counts (81445 vs 81455)

Panel size examplesCPT 81445: genomic sequence analysis panel, 5–50 genes; CPT 81455: genomic panel, 51+ genes

Use guidancePanel selection should align with intended biomarker detection and FDA companion diagnostic requirements

Coding noteMultiple PLA/CPT panel PLA codes (e.g., 0037U) correspond to specific multi‑gene assays such as FoundationOne CDx

Criteria for plasma testing when tissue insufficient

When allowedPlasma testing is allowed when the individual does not have sufficient tissue for standard molecular testing using FFPE tissue

Documentation requiredDocument insufficient tissue for standard molecular testing and that follow‑up tissue‑based analysis is planned if plasma testing identifies no driver variant

Intended usePlasma ctDNA tests used as alternative must be FDA‑approved companion diagnostic plasma tests and used consistent with the therapy's FDA label

Provider Responsibilities, Documentation, and Prior Authorization

Prior Authorization

Verify benefits / prior authorization

Contact BCBSKS Customer Service to confirm member coverage and any plan-specific prior authorization requirements.

Billing Rule

PLA code example — LeukoStrat CDx (FLT3)

When ordering an FDA companion diagnostic such as the LeukoStrat CDx FLT3 Mutation Assay, include the specific PLA code listed for that test (0023U) on submissions and billing where applicable.

LeukoStrat CDx FLT3 Mutation Assay — PLA code 0023U.

Documentation Required

Document companion diagnostic availability and CLIA status

Reference the FDA companion diagnostic listed in Table 1 when one exists.
If using an LDT, document that the laboratory is CLIA‑licensed for high‑complexity testing.

Billing Rule

Include listed PLA codes for tests (e.g., therascreen PIK3CA)

therascreen PIK3CA RGQ PCR Kit — PLA codes 0155U and 0177U.

Billing Rule

Use FDA‑listed CPT/PLA codes on submissions

Include the FDA‑listed CPT/PLA code(s) associated with the companion diagnostic on prior authorization submissions and claims to support coverage determination.

Where Table 1 lists PLA/CPT codes for an FDA‑approved companion diagnostic, include those codes on PA requests and claims.

Billing Rule

Billing/code linkage examples for FDA companion diagnostics

FoundationOne Liquid CDx — PLA 0239U
FoundationOne CDx — PLA 0037U
Guardant360 CDx — PLA 0326U

Billing Rule

Reference test PLA/CPT identifiers on orders and claims

Reference the specific PLA/CPT identifiers listed for tissue companion diagnostics (e.g., 0037U, 0022U) when ordering, documenting, and billing those tests.

FoundationOne CDx and other tissue CDx — PLA 0037U
Oncomine Dx Target Test — PLA 0022U

Note

Prior authorization not specified in policy section (informational)

Informational: the policy section listing FDA‑approved companion diagnostics and PLA codes does not itself state payer prior authorization rules; verify plan-specific requirements separately.

Prior Authorization

Prior authorization may be required to establish label‑consistent use

PA may be requested to confirm label‑consistent intended use and that the individual has no FDA‑labeled contraindications.
Document specimen type (tissue, plasma, blood/bone marrow) and the specific FDA‑approved test when required.

Prior Authorization

PA may be required for ctDNA companion diagnostics

When using plasma ctDNA as a tissue alternative, reference the FDA‑approved plasma CDx and document conformity with the test and drug labels.

Prior Authorization

Documentation expectations for PA of plasma ctDNA tests

Document tissue infeasibility (insufficient tissue, no biopsy‑amenable lesion, contraindication) when plasma is substituted at progression or diagnosis.
Plan for follow‑up tissue analysis if plasma testing is negative, per policy guidance.

Note

Verify plan‑specific prior authorization requirements

Contextual note: the policy does not list a universal prior authorization mandate for all tests; verify member‑ and plan‑specific prior authorization requirements with BCBSKS.

Prior Authorization

Verify medical necessity and prior authorization for coded procedures

Inclusion of a code in the policy does not guarantee member coverage—confirm benefits at time of service.

Prior Authorization

PA expectation for companion diagnostic testing

Requests should reference the specific FDA‑approved companion diagnostic listed for the biomarker–drug pairing.

Prior Authorization

PA guidance for repeat and concurrent testing

Repeat testing may be considered at progression to identify acquired resistance variants when next‑line therapy decisions would be affected.

Prior Authorization

Benefit verification required

Verify member benefits with BCBSKS Customer Service because coverage may be preempted by state/federal mandates or specific member contract exclusions.

Confirm whether state law or contract provisions alter coverage before proceeding.

Note

Regulatory status — FDA list not comprehensive for LDTs

Documentation Required

Document CDx availability and CLIA status on orders/PA

Include the specific FDA‑cleared diagnostic name (e.g., Foundation One Liquid CDx, Foundation One CDx) and the biomarker(s) detected when submitting PA or claims.
If using an LDT, include CLIA high‑complexity laboratory certification documentation.

Note

PLA codes listed (informational)

Informational: numerous PLA codes are listed throughout the policy for reference; use the specific code(s) tied to the test being ordered when completing authorization or billing paperwork.

Documentation Required

Use regulatory listings to support PA/claims documentation

Use FDA regulatory listings (PMA/510(k)/PLA identifiers) cited in the policy to support documentation for prior authorization and claims when ordering an FDA‑approved companion diagnostic.

Reference PMA/510(k) or PLA identifiers as evidence that a tissue or plasma test is an FDA‑authorized companion diagnostic for a given drug–biomarker pairing.

Note

No step‑therapy rules specified

Informational: no step‑therapy requirements are specified in the policy excerpt; clinical sequencing requirements (other than the PIK3CA/alpelisib context) are not detailed here.

Documentation Required

Document prior endocrine therapy for alpelisib selection

Document prior endocrine therapy and progression when requesting testing for alpelisib selection.

Note

ASCO guidance — repeat genomic testing for acquired resistance

ASCO suggests repeat genomic testing for suspected acquired resistance when the results would guide next‑line therapy; include this rationale in prior authorization requests for repeat testing.

Use ASCO guidance to support PA for repeat testing when progression suggests acquired resistance that would change therapy.

Documentation Required

Document clinical context and intended FDA‑approved therapy

Include tumor type, clinical stage, and the intended FDA‑approved therapy in PA/claims documentation.

Denial Risk

Ensure testing is intended for label‑consistent use

Confirm and document that the requested test result will guide use of an FDA‑approved targeted therapy per its label and that no FDA‑labeled contraindications exist.

Denial Risk

Denial risk — missing follow‑up tissue plan or investigational ctDNA uses

If ordering plasma testing because tissue is insufficient, document plans for follow‑up tissue testing if plasma is negative.
Avoid using plasma ctDNA for indications the policy designates investigational (e.g., RET via plasma).

Denial Risk

Coverage contingent on member contract

Coverage of listed procedure codes is contingent on the member's contract; inclusion of a code in this policy does not guarantee coverage—verify contract benefits prior to ordering.

Confirm member contract terms at time of service to determine coverage and reimbursement.

Note

Check for state‑specific coverage mandates

Plans may need to modify local coverage to conform to applicable state law regarding biomarker testing; verify any state‑specific mandates that could affect coverage before ordering.

Denial Risk

Investigational risk for off‑label somatic tests without FDA‑approved therapies

If the requested test is for a gene without an FDA‑approved therapy, note that the policy considers such testing investigational.

Eligibility Requirements

Experimental, Investigational, and Not Covered Uses

Background and Definitions

Definition — Liquid biopsy / ctDNA

DefinitionLiquid biopsy / circulating tumor DNA (ctDNA): tumor‑derived fragments of cell‑free DNA detectable in blood used for genomic characterization of tumors

PurposeUsed to detect somatic variants when tissue biopsy is not feasible or to monitor for resistance variants

Assay typesIncludes FDA‑approved plasma companion diagnostic assays (e.g., FoundationOne Liquid CDx, Guardant360 CDx)

Definition — Homologous recombination deficiency (HRD)

DefinitionHomologous recombination deficiency (HRD): loss of homologous recombination repair capacity leading to genomic instability

AssessmentAssessed by pathogenic BRCA1/2 variants and/or a genomic instability score (GIS) from assays such as Myriad myChoice

Clinical relevanceHRD is associated with ovarian and prostate cancers and can inform PARP inhibitor therapy selection

Definition — HRD-positive

DefinitionHRD‑positive: presence of a deleterious or suspected deleterious BRCA1/2 mutation and/or a genomic instability score above the assay‑defined threshold (e.g., Myriad myChoice)

Assay exampleMyriad myChoice CDx determines HRD‑positive status via BRCA1/2 variant detection and GIS

ImplicationDefines eligibility for HRD‑directed targeted therapies in ovarian cancer and related indications

Definition — dMMR / MSI-H

DefinitiondMMR / MSI‑H: mismatch repair deficiency (dMMR) or high microsatellite instability (MSI‑H) indicating defects in DNA repair genes

MarkersMMR IHC assesses MLH1, PMS2, MSH2, MSH6; MSI PCR uses 5 markers (MLH1, MSH2, MSH6, PMS1, PMS2)

MSI‑H thresholdMSI‑H defined as instability in ≥2 of 5 PCR markers or >30% unstable biomarkers depending on panel

Definition — ctDNA

DefinitionctDNA: circulating tumor DNA — tumor‑derived fragments of cell‑free DNA detectable in plasma used for tumor genomic profiling

SourceDerived from apoptotic/necrotic tumor cells from primary tumor, metastases, or circulating tumor cells

UseUsed as alternative to tissue biopsy for somatic variant detection and longitudinal monitoring

Definition — LDT must meet CLIA high-complexity standards

RequirementLaboratory‑developed tests (LDTs) must be developed/validated in‑house and performed in CLIA‑certified high‑complexity laboratories

Regulatory noteFDA has not required regulatory review of LDTs to date; LDTs are not comprehensively listed in the FDA companion diagnostic table

DocumentationProviders should document CLIA high‑complexity lab status when ordering LDTs

Definition — Companion diagnostic (FDA CDx)

DefinitionCompanion diagnostic (CDx): an FDA‑cleared or ‑approved diagnostic test linked to a specific targeted therapy (drug) and biomarker

ExamplesFoundationOne CDx, FoundationOne Liquid CDx, BRACAnalysis CDx, cobas EGFR Mutation Test v2

UsageWhen selecting an FDA‑approved targeted therapy, use the FDA‑listed companion diagnostic identified for that drug/biomarker pairing

Definition — PLA code

DefinitionPLA code: Proprietary Laboratory Analytic code used to identify specific FDA‑authorized laboratory tests (PLA/HCPCS codes like 0155U, 0177U)

PurposeInclude PLA codes on submissions/claims when billing for FDA‑cleared companion diagnostic assays

Exampletherascreen PIK3CA RGQ PCR Kit PLA codes 0155U (tissue) and 0177U (plasma)

Definition — MSI-H / dMMR and related proteins

DefinitionMSI‑H / dMMR: microsatellite instability‑high and deficient mismatch repair proteins (MLH1, PMS2, MSH2, MSH6) used to identify patients for immunotherapy

IHC vs PCRIHC assesses loss of MMR proteins; PCR assesses microsatellite marker instability — both identify MSI‑H/dMMR status

Clinical relevanceMSI‑H/dMMR status indicates potential responsiveness to PD‑1/PD‑L1 inhibitors

Definition — cfDNA/plasma companion diagnostic (e.g., Foundation One Liquid CDx)

DefinitioncfDNA/plasma companion diagnostic: plasma‑based (liquid biopsy) assays (e.g., FoundationOne Liquid CDx, Guardant360 CDx) cleared to detect tumor alterations in ctDNA

ExamplesFoundationOne Liquid CDx (PLA 0239U) for BRCA1/2 in mCRPC; FoundationOne Liquid CDx for NTRK fusions

Use caseMay be used as alternative to tissue when FDA‑approved companion diagnostic exists and tissue is not feasible

Definition — Companion diagnostic (CDx) (additional)

DefinitionCompanion diagnostic (CDx): FDA‑cleared/approved diagnostic assay (tissue, plasma, or whole blood) used to identify biomarker alterations for selection of associated targeted therapies

DocumentationPolicy lists PMA/510(k)/PLA identifiers for CDx assays — providers should reference the specific CDx when documenting testing rationale

Regulatory linkageCoverage tied to use consistent with the FDA‑approved CDx and drug label

Definition — PD-L1 TPS

DefinitionPD‑L1 TPS (Tumor Proportion Score): percentage of tumor cells with PD‑L1 membrane staining; thresholds include ≥1% and ≥50% depending on assay and indication

AssaysPD‑L1 IHC 22C3 pharmDx (TPS ≥1% or ≥50% per indication); Ventana PD‑L1 assays have assay‑specific cutoffs

Clinical implicationTPS thresholds used in FDA approvals to select patients for PD‑1/PD‑L1 therapies in NSCLC and other tumors

Definition — EGFR alterations examples

ExamplesEGFR alterations include exon 19 deletions, exon 21 L858R substitutions, T790M resistance mutation, and exon 20 insertions

Assay relevanceMultiple FDA‑cleared tissue and plasma assays (e.g., cobas EGFR v2) detect these variants for targeted EGFR therapies

Clinical usePresence of activating EGFR mutations guides use of EGFR TKIs in NSCLC

Definition — TMB ≥10 mutations per megabase

DefinitionTMB ≥10 mutations per megabase defined as threshold used by FoundationOne CDx tissue test for eligibility for certain immunotherapies

Assay exampleFoundationOne CDx reports TMB (mut/Mb) and is cited in FDA companion diagnostic listings

Clinical implicationPatients with TMB ≥10 mut/Mb may be considered for tumor‑agnostic immunotherapy indications per FDA labeling

Definition — MET protein expression example

Definition/exampleMET protein expression defined as ≥50% of tumor cells exhibiting strong membrane and/or cytoplasmic staining (3+) — used with telisotuzumab vedotin (Emrelis)

AssayVentana MET (SP44) RxDx Assay referenced in FDA listings

Clinical useThreshold identifies MET‑high tumors for MET‑targeted therapy selection in NSCLC

Definition — PLA codes cited for diagnostic tests

DefinitionPLA codes cited for diagnostic tests (examples in policy: 0155U, 0177U, 0037U, 0239U, 0211U)

Coding useInclude PLA/CPT codes on prior authorization submissions and claims for FDA‑approved companion diagnostics where specified

Examples in documenttherascreen PIK3CA (0155U/0177U), FoundationOne Liquid CDx (0239U), FoundationOne CDx (0037U), MI Cancer Seek (0211U)

Scope — somatic vs germline

Scope statementThis policy addresses somatic (tumor) testing for selecting targeted treatments and does not address germline testing for inherited cancer risk

ImplicationGermline BRCA and other hereditary testing are covered in separate germline testing policies

ReasoningSomatic testing focuses on tumor‑acquired variants to guide FDA‑approved targeted therapies

Definition — cfDNA/plasma companion diagnostic (alternative to tissue)

DefinitionctDNA (liquid biopsy) used as alternative to tissue when performed with FDA‑approved companion diagnostic plasma tests (e.g., FoundationOne Liquid CDx, Guardant360 CDx)

ConditionsUse permitted when tissue is insufficient or biopsy not feasible and when agent/test used consistent with FDA label

DocumentationPolicy requires documentation that tissue is insufficient and follow‑up tissue testing planned if plasma is negative

Policy Update History

2026-02-26material_revisionLatest

2023-05-25coding_update

2022-10-28coding_update

Updated Coding Section to add 0338U (effective 2022-10-01) and revised policy sections including removal and addition of certain gene fusion testing statements.

2022-03-10policy_posting

Policy added to the BCBSKS website (initial posting of the coverage policy).

2024-08-30coding_revision

Foundation One Liquid CDx plasma PMA supplement entries and associated PLA code updates reflected in coding (P190032/S016 noted); coding and regulatory table updated.

2023-05-25policy_structure_update

Added Section H: NTRK Gene Fusion Testing and expanded policy title and gene-specific sections to clarify indications and companion diagnostic linkages.