Sunflower Health Plan Concert Genetic Oncology: Mol Analysis Solid Tmrs Hem Malig (PDF) Form

Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 CONCERT GENETICS ONCOLOGY: MOLECULAR ANALYSIS OF SOLID TUMORS AND HEMATOLOGIC MALIGNANCIES See Important Reminder at the end of this policy for important regulatory and legal information. OVERVIEW The molecular analysis of solid tumors and hematologic malignancies aims to identify somatic oncogenic mutations in cancer. These mutations, often called “driver” mutations, are becoming increasingly useful for targeted therapy selection, and may give insight into prognosis and treatment response in a subset of cancers. In addition, molecular analysis of solid tumors and hematologic malignancies, in particular, can also aid in making a diagnosis of a specific type of malignancy. For solid tumors, molecular analysis can be performed via direct testing of the tumor (which is addressed in this policy) or via circulating tumor DNA or circulating tumor cells (CTCs) (see Other Related Policies). For hematologic malignancies, molecular analysis can be performed on blood samples or bone marrow biopsy samples. For individuals with advanced cancer, somatic comprehensive genomic profiling offers the potential to evaluate a large number of genetic markers in the cancer simultaneously in order to provide potential treatment options beyond the current standard of care. While the primary goal of the molecular analysis of solid tumors and hematologic malignancies is to identify biomarkers that diagnose or to give prognostic and treatment selection information, this testing also has the potential to uncover clinically relevant germline variations that are associated with a hereditary cancer susceptibility syndrome, and other conditions, if confirmed to be present in the germline. Current tumor testing strategies include tumor-only testing, tumor- normal paired testing with germline variant subtraction, and tumor-normal paired testing with explicit analysis of a group of genes associated with germline cancer predisposition. This is an evolving area and clear guidelines around the optimal approach for identification and reporting of the presumed germline pathogenic variants (PGPVs) are emerging. 1 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 POLICY REFERENCE TABLE Below is a list of higher volume tests and the associated laboratories for each coverage criteria section. This list is not all inclusive. Coding Implications This clinical policy references Current Procedural Terminology (CPT®). CPT® is a registered trademark of the American Medical Association. All CPT codes and descriptions are copyrighted 2022, American Medical Association. All rights reserved. CPT codes and CPT descriptions are from the current manuals and those included herein are not intended to be all-inclusive and are included for informational purposes only. Codes referenced in this clinical policy are for informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage. Providers should reference the most up-to-date sources of professional coding guidance prior to the submission of claims for reimbursement of covered services. Coverage Criteria Sections Example Tests (Labs) Common CPT Codes Common ICD Codes Ref Molecular Profiling Panel Testing of Solid Tumors and Hematologic Malignancies Tumor-Type Agnostic Solid Tumor Molecular Profiling Panel Tests FoundationOne CDx (Foundation Medicine) MSK-IMPACT (Memorial Sloan Kettering Medical Center) Oncotype MAP PanCancer Tissue Test (OncotypeDX) OmniSeq (Integrated Oncology) OnkoSight Advanced Solid Tumor NGS Panel (BioReference Labs) Tempus xT (Tempus) Precise Tumor (Myriad) C00-D49, Z85 1, 2, 4, 5, 7, 25, 26, 31 0037U 0048U 0244U 81445, 81449, 81455, 81456 Guardant360 TissueNext (Guardant) 0334U PGDx elio tissue complete (Personal Genome Diagnostics, Inc) 0250U 2 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 Tumor-Type Agnostic Tumor-Type Agnostic Solid Tumor Solid Tumor Molecular Profiling Molecular Profiling Panel Tests with IHC Panel Tests with IHC and Cytogenetic and Cytogenetic Analyses Analyses Comprehensive Comprehensive Molecular Profiling Molecular Profiling Panels for Panels for Hematologic Hematologic Malignancies and Malignancies and Myeloid Malignancy Myeloid Malignancy Panels Panels MI Cancer Seek - NGS Analysis (Caris MI Cancer Seek - NGS Analysis (Caris Life Sciences Life Sciences 0211U 0211U C00-D49, C00-D49, Z85 Z85 MI Profile (Caris Life Sciences) MI Profile (Caris Life Sciences) 81455 81455 1, 2, 5, 1, 2, 5, 7, 25, 7, 25, 26, 31 26, 31 OmniSeq INSIGHT, Solid Tumor NGS OmniSeq INSIGHT, Solid Tumor NGS Panel (DNA and RNA) (LabCorp Panel (DNA and RNA) (LabCorp Oncology) Oncology) Tempus xT with PD-L1 IHC, MMR IHC Tempus xT with PD-L1 IHC, MMR IHC (Tempus) (Tempus) Solid Tumor Expanded Panel (Quest) Solid Tumor Expanded Panel (Quest) 0379U 0379U FoundationOne Heme (Foundation FoundationOne Heme (Foundation Medicine) Medicine) 81455 81455 C91, C92, C91, C92, D46.9 D46.9 6, 10, 6, 10, 12, 15 12, 15 Tempus xT Hematologic Malignancy Tempus xT Hematologic Malignancy (Tempus) (Tempus) NeoTYPE Myeloid Disorders Profile NeoTYPE Myeloid Disorders Profile (NeoGenomics Laboratories) (NeoGenomics Laboratories) OncoHeme Next-Generation Sequencing OncoHeme Next-Generation Sequencing for Myeloid Neoplasms, Varies (Mayo for Myeloid Neoplasms, Varies (Mayo Clinic Laboratories) Clinic Laboratories) Onkosight Myeloid Disorder Panel Onkosight Myeloid Disorder Panel (BioReference Laboratories) (BioReference Laboratories) 81450, 81451 81450, 81451 Colorectal Cancer Colorectal Cancer Focused Molecular Focused Molecular Profiling Panels Profiling Panels Lung Cancer Focused Lung Cancer Focused Molecular Profiling Molecular Profiling Panels Panels Cutaneous Melanoma Cutaneous Melanoma Focused Molecular Focused Molecular Profiling Panels Profiling Panels PraxisTM Extended RAS Panel PraxisTM Extended RAS Panel (Illumina) (Illumina) 0111U 0111U C18-C20 C18-C20 2 2 Colon Cancer Mutation Panel (Ohio State Colon Cancer Mutation Panel (Ohio State University Molecular Pathology Lab) University Molecular Pathology Lab) 81445 81445 Oncomine Dx Target Test (NeoGenomics Oncomine Dx Target Test (NeoGenomics Laboratories) Laboratories) 0022U 0022U C34 C34 1 1 OnkoSight Advanced Comprehensive OnkoSight Advanced Comprehensive Lung (BioReference Laboratories) Lung (BioReference Laboratories) 81445 81445 Melanoma Panel (Knight Diagnostics) Melanoma Panel (Knight Diagnostics) 81210, 81404 C43, D03 81210, 81404 C43, D03 9 9 OnkoSight Melanoma Panel OnkoSight Melanoma Panel (BioReference Laboratories) (BioReference Laboratories) 81445 81445 Acute Myeloid Acute Myeloid Leukemia (AML) Leukemia (AML) MyAML Gene Panel Assay (LabPMM, MyAML Gene Panel Assay (LabPMM, Invivoscribe Technologies) Invivoscribe Technologies) 0050U 0050U C92, D47 C92, D47 10 10 3 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 Focused Molecular Focused Molecular Profiling Panels Profiling Panels NeoTYPE AML Prognostic Profile NeoTYPE AML Prognostic Profile (NeoGenomics) (NeoGenomics) 81450 81450 LeukoVantage, Acute Myeloid Leukemia LeukoVantage, Acute Myeloid Leukemia (AML) (Quest Diagnostics) (AML) (Quest Diagnostics) Myeloproliferative Myeloproliferative Neoplasms (MPNs) Neoplasms (MPNs) Panel Tests Panel Tests Myeloproliferative Neoplasm, JAK2 Myeloproliferative Neoplasm, JAK2 V617F with Reflex to CALR and MPL, V617F with Reflex to CALR and MPL, Varies (Mayo Medical Laboratories) Varies (Mayo Medical Laboratories) MPN, JAK2/MPL/CALR by NGS MPN, JAK2/MPL/CALR by NGS (BioReference Laboratories) (BioReference Laboratories) D47 D47 12 12 81206, 81207, 81206, 81207, 81208, 81219, 81208, 81219, 81270, 81338, 81270, 81338, 81339 81339 Single Gene Testing of Solid Tumors and Hematologic Malignancies Single Gene Testing of Solid Tumors and Hematologic Malignancies Tumor Specific Tumor Specific BCR/ABL Kinase BCR/ABL Kinase Domain Analysis Domain Analysis Tumor Specific Tumor Specific BCR/ABL BCR/ABL Quantitation and Quantitation and Breakpoint Analysis Breakpoint Analysis ABL1 Kinase Domain Mutation Analysis ABL1 Kinase Domain Mutation Analysis (NeoGenomics) (NeoGenomics) Onkosight NGS ABL1 Sequencing Onkosight NGS ABL1 Sequencing (BioReference Laboratories) (BioReference Laboratories) BCR-ABL1 Gene Rearrangement, BCR-ABL1 Gene Rearrangement, Quantitative, PCR (Quest Diagnostics) Quantitative, PCR (Quest Diagnostics) BCR-ABL1 Transcript Detection for BCR-ABL1 Transcript Detection for Chronic Myelogenous Leukemia (CML) Chronic Myelogenous Leukemia (CML) and Acute Lymphocytic Leukemia and Acute Lymphocytic Leukemia (ALL), Quantitative (LabCorp) (ALL), Quantitative (LabCorp) 81170 81170 C91, C92 C91, C92 15, 16 15, 16 81206, 81207 C83, C85, 81206, 81207 C83, C85, C91, C92, C91, C92, D45, D47 D45, D47 10, 12, 10, 12, 15, 16, 15, 16, 18 18 BCR/ABL1 (T(9;22)) RNA Quantitative BCR/ABL1 (T(9;22)) RNA Quantitative with Interpretation (University of Iowa) with Interpretation (University of Iowa) 0016U 0016U MRDx BCR-ABL Test (MolecularMD) MRDx BCR-ABL Test (MolecularMD) 0040U 0040U Tumor Specific BRAF Tumor Specific BRAF Variant Analysis Variant Analysis BRAF Mutation Analysis (NeoGenomics) 81210 BRAF Mutation Analysis (NeoGenomics) 81210 Tumor Specific Tumor Specific BRCA1/2 Variant BRCA1/2 Variant Analysis Analysis BRCA1 Mutation Analysis BRCA1 Mutation Analysis BRCA2 Mutation Analysis BRCA2 Mutation Analysis BRCA1/2 Mutation Analysis BRCA1/2 Mutation Analysis 81162, 81163, 81162, 81163, 81164, 81165, 81164, 81165, 81166, 81167, 81166, 81167, 81216 81216 C18-C21, C18-C21, C34, C43, C34, C43, C71, C73, C71, C73, C91.4 C91.4 C56, C61 C56, C61 1, 2, 9, 1, 2, 9, 13, 19 13, 19 5, 22, 5, 22, 25 25 Tumor Specific CALR Tumor Specific CALR Variant Analysis Variant Analysis Calreticulin (CALR) Mutation Analysis Calreticulin (CALR) Mutation Analysis (Quest Diagnostics) (Quest Diagnostics) 81219 81219 C94 D47.1 C94 D47.1 12 12 Tumor Specific Tumor Specific CEBPA Variant CEBPA Variant Analysis Analysis CEBPA Mutation Analysis (LabCorp) CEBPA Mutation Analysis (LabCorp) 81218 81218 C92 C92 10 10 4 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 Tumor Specific Tumor Specific EGFR Variant EGFR Variant Analysis Analysis Tumor Specific ESR1 Tumor Specific ESR1 Variant Analysis Variant Analysis EGFR Mutation Analysis (NeoGenomics EGFR Mutation Analysis (NeoGenomics Laboratories) Laboratories) 81235 81235 C34 C34 ESR1 Variant Analysis ESR1 Variant Analysis 81479 81479 C50 C50 1 1 4 4 Tumor Specific FLT3 Tumor Specific FLT3 Variant Analysis Variant Analysis FLT3 ITD and TKD Mutation Detection FLT3 ITD and TKD Mutation Detection (ARUP Laboratories) (ARUP Laboratories) 81245, 81246 C92 81245, 81246 C92 10 10 LeukoStrat CDx FLT3 Mutation Assay LeukoStrat CDx FLT3 Mutation Assay (Versiti) (Versiti) FLT3 ITD MRD by NGS (LABPMM, FLT3 ITD MRD by NGS (LABPMM, Invivoscribe Technologies) Invivoscribe Technologies) 0023U 0023U 0046U 0046U Tumor Specific IDH1 Tumor Specific IDH1 and IDH2 Variant and IDH2 Variant Analysis Analysis Tumor Specific IGHV Tumor Specific IGHV Somatic Somatic Hypermutation Hypermutation Analysis Analysis IDH1/IDH2 Mutation Analysis IDH1/IDH2 Mutation Analysis (NeoGenomics) (NeoGenomics) 81120, 81121 C71, C92, 81120, 81121 C71, C92, 10, 20 10, 20 D49.6 D49.6 IgVH Mutation Analysis (NeoGenomics) 81261, 81262, IgVH Mutation Analysis (NeoGenomics) 81261, 81262, 81263 81263 C83, C91, C83, C91, D47.Z1 D47.Z1 18, 28, 18, 28, 36 36 Tumor Specific JAK2 Tumor Specific JAK2 Variant Analysis Variant Analysis JAK2 Exons 12 to 15 Sequencing (Mayo JAK2 Exons 12 to 15 Sequencing (Mayo Clinic) Clinic) 0027U 0027U JAK2 Mutation (University of Iowa) JAK2 Mutation (University of Iowa) 0017U 0017U JAK2 V617F Mutation Analysis (Quest JAK2 V617F Mutation Analysis (Quest Diagnostics) Diagnostics) 81270 81270 6, 12, 6, 12, 16 16 C91, C92, C91, C92, C94, D45, C94, D45, D47.1, D47.1, D47.3, D47.3, D75.81 D75.81 Tumor Specific KIT Tumor Specific KIT Variant Analysis Variant Analysis KIT Mutation Analysis (ProPath) KIT Mutation Analysis (ProPath) KIT (D816V) Digital PCR (Labcorp) KIT (D816V) Digital PCR (Labcorp) 81272, 81273 C43, C49.A, 81272, 81273 C43, C49.A, C92, D47.1, C92, D47.1, D47.02 D47.02 8, 9, 8, 9, 10, 11 10, 11 Tumor Specific KRAS Tumor Specific KRAS Variant Analysis Variant Analysis KRAS Mutation Analysis KRAS Mutation Analysis (NeoGenomics) (NeoGenomics) Tumor Specific Tumor Specific MGMT Methylation MGMT Methylation Analysis Analysis MGMT Promoter Methylation Assay MGMT Promoter Methylation Assay (UCSF Molecular Diagnostics (UCSF Molecular Diagnostics Laboratory) Laboratory) 81275, 81276 C18-21, C34 1, 2, 24 81275, 81276 C18-21, C34 1, 2, 24 81287 81287 C71 C71 20 20 Tumor Specific Tumor Specific MLH1 Methylation MLH1 Methylation Analysis Analysis Tumor Specific MPL Tumor Specific MPL Variant Analysis Variant Analysis MLH1 Promoter Methylation Analysis MLH1 Promoter Methylation Analysis (NeoGenomics) (NeoGenomics) 81288 81288 C18-C21, C18-C21, C54.1 C54.1 3, 23 3, 23 MPL Mutation Analysis (MedFusion) MPL Mutation Analysis (MedFusion) 81338, 81339 D45, D47.1, 81338, 81339 D45, D47.1, 12 12 D47.3, D47.3, D75.81 D75.81 5 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 Tumor Specific Tumor Specific Microsatellite Microsatellite Instability (MSI) Instability (MSI) Analysis Analysis Tumor Specific Tumor Specific NPM1 Variant NPM1 Variant Analysis Analysis Microsatellite Instability (MSI) by PCR Microsatellite Instability (MSI) by PCR (NeoGenomics) (NeoGenomics) 81301 81301 Microsatellite Instability (MSI) (Quest Microsatellite Instability (MSI) (Quest Diagnostics) Diagnostics) C15-C23, C15-C23, C50, C53, C50, C53, C54.1, C62, C54.1, C62, C80 C80 NPM1 MRD by NGS (LabPMM, NPM1 MRD by NGS (LabPMM, Invivoscribe Technologies) Invivoscribe Technologies) 0049U 0049U C92 C92 Onkosight NGS NPM1 Sequencing Onkosight NGS NPM1 Sequencing (BioReference Laboratories) (BioReference Laboratories) 81310 81310 2, 4, 2, 4, 14, 26, 14, 26, 27, 29, 27, 29, 30, 31, 30, 31, 32, 34 32, 34 10 10 Tumor Specific NRAS Tumor Specific NRAS Variant Analysis Variant Analysis NRAS Mutation Analysis NRAS Mutation Analysis (NeoGenomics) (NeoGenomics) Tumor Specific Tumor Specific PIK3CA Variant PIK3CA Variant Analysis Analysis PIK3CA Mutation Analysis (Quest PIK3CA Mutation Analysis (Quest Diagnostics) Diagnostics) PIK3CA Mutation Analysis, PIK3CA Mutation Analysis, therascreen - QIAGEN (LabCorp) therascreen - QIAGEN (LabCorp) 81311 81311 C18-C21 C18-C21 2, 24 2, 24 81309 81309 C50, C55 C50, C55 4, 14 4, 14 0155U, 0177U 0155U, 0177U Tumor Specific RET Tumor Specific RET Variant Analysis Variant Analysis RET Targeted Mutation Analysis RET Targeted Mutation Analysis RET Sequencing Analysis RET Sequencing Analysis 81404, 81405, 81404, 81405, 81406 81406 C34, C73 C34, C73 1, 6 1, 6 Tumor Specific TP53 Tumor Specific TP53 Variant Analysis Variant Analysis TP53 MutationAnalysis (NeoGenomics) 81352 TP53 MutationAnalysis (NeoGenomics) 81352 C92, R71, C92, R71, R79 R79 10, 18, 10, 18, 28 28 Measurable (Minimal) Residual Disease (MRD) Analysis Measurable (Minimal) Residual Disease (MRD) Analysis Measurable (Minimal) Residual Disease (MRD) Analysis MyMRD® NGS Panel, Laboratory for MyMRD® NGS Panel, Laboratory for Personalized Medicine Personalized Medicine 0171U 0171U C91, R71, R79 19, 28, 33 ClonoSEQ (Adaptive Biotechnologies) ClonoSEQ (Adaptive Biotechnologies) 0364U 0364U Tumor Mutational Burden (TMB) Tumor Mutational Burden (TMB) Tumor Mutational Burden (TMB) Tumor Mutational Burden (MedFusion) 81479 Tumor Mutational Burden (Nebraska Medical Center - Molecular Diagnostic Laboratory) Red Blood Cell Genotyping in Multiple Myeloma Red Blood Cell Genotyping in Multiple Myeloma - C00-D49, Z85 4, 5, 7, 4, 5, 7, 14, 25, 29, 30, 31, 32 31, 32 Red Blood Cell Red Blood Cell Genotyping in Genotyping in PreciseType HEA (Immucor) PreciseType HEA (Immucor) 0001U 0001U C90.0, R71, C90.0, R71, R79 R79 37 37 6 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 Multiple Myeloma Multiple Myeloma Navigator ABO Sequencing (Grifols Navigator ABO Sequencing (Grifols Immunohematology Center) Immunohematology Center) Navigator ABO Blood Group NGS Navigator ABO Blood Group NGS (Grifols Immunohematology Center) (Grifols Immunohematology Center) 0180U 0180U 0221U 0221U Cancer Exome and Genome Sequencing Cancer Exome and Genome Sequencing Cancer Cancer Exome/Genome Exome/Genome Sequencing Sequencing Oncomap ExTra (Exact Sciences Oncomap ExTra (Exact Sciences Laboratories) Laboratories) 0329U 0329U C00-D49, C00-D49, Z85 Z85 35 35 Cancer Whole Exome Sequencing with Cancer Whole Exome Sequencing with Transcriptome (Columbia University - Transcriptome (Columbia University - Personalized Genomic Medicine) Personalized Genomic Medicine) 81415, 81416, 81415, 81416, 81425, 81426 81425, 81426 Tempus xE (Tempus) Tempus xE (Tempus) EXaCT-1 Whole Exome Testing (Weill EXaCT-1 Whole Exome Testing (Weill Cornell Medicine) Cornell Medicine) 0036U 0036U Genetic Testing to Confirm the Identity of Laboratory Specimens Genetic Testing to Confirm the Identity of Laboratory Specimens Genetic Testing to Genetic Testing to Confirm the Identity Confirm the Identity of Laboratory of Laboratory Specimens Specimens 81265, 81266, know error® DNA Specimen Provenance 81265, 81266, know error® DNA Specimen Provenance 81479 Assay (DSPA) (Strand Diagnostics, LLC) Assay (DSPA) (Strand Diagnostics, LLC) 81479 ToxProtect (Genotox Laboratories LTD) 0007U ToxProtect (Genotox Laboratories LTD) 0007U C00.0-D49 C00.0-D49 35 35 ToxLok™ (InSource Diagnostics) ToxLok™ (InSource Diagnostics) 0079U 0079U OTHER RELATED POLICIES This policy document provides coverage criteria for Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies. Please refer to: ● Oncology: Cytogenetic Testing for coverage criteria related to tumor testing with IHC, FISH, etc (e.g., ALK, BCR/ABL FISH analysis, ERBB2 [HER2] IHC analysis, NTRK fusion analysis, ROS1 analysis) ● Genetic Testing: Hereditary Cancer Susceptibility Syndromes for coverage criteria related to genetic testing for hereditary cancer predisposition syndromes. ● Oncology: Cancer Screening for coverage criteria related to the use of non-invasive fecal, urine, or blood tests for screening for cancer. 7 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 ● Oncology: Circulating Tumor DNA and Circulating Tumor Cells (Liquid Biopsy) for criteria related to circulating tumor DNA (ctDNA) or circulating tumor cell testing performed on peripheral blood for cancer diagnosis, management and surveillance. ● Oncology: Algorithmic Testing for coverage criteria related to gene expression profiling and tumor biomarker tests with algorithmic analyses. ● Genetic Testing: Whole Genome and Whole Exome Sequencing for the Diagnosis of Genetic Disorders for coverage criteria related to whole genome and whole exome sequencing in rare genetic syndromes. ● Genetic Testing: General Approach to Genetic Testing for coverage criteria related to tumor and hematologic malignancy testing that is not specifically discussed in this or another non-general policy. back to top CRITERIA It is the policy of health plans affiliated with Centene Corporation® that the specific genetic testing noted below is medically necessary when meeting the related criteria: Molecular Profiling Panel Testing of Solid Tumors and Hematologic Malignancies Tumor-Type Agnostic Solid Tumor Molecular Profiling Panel Tests I. Tumor-type agnostic solid tumor molecular profiling panel tests (81445, 81449, 81455, 81456, 0037U, 0048U, 0244U, 0250U, 0334U) are considered medically necessary when: A. The member/enrollee has recurrent, relapsed, refractory, metastatic, or advanced stages III or IV cancer, AND B. The member/enrollee is seeking further cancer treatment (e.g., therapeutic chemotherapy). II. Repeat testing via a tumor-type agnostic solid tumor molecular profiling panel (81445, 81449, 81455, 81456, 0037U, 0048U, 0211U, 0244U, 0250U, 0334U) is considered medically necessary when: 8 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 A. The member/enrollee has progression of any of the following: 1. Metastatic colon cancer, OR 2. Advanced or metastatic non-small cell lung cancer (NSCLC), OR 3. Advanced or metastatic gastric adenocarcinoma, OR 4. Metastatic prostate cancer, OR 5. Ovarian cancer that is platinum-sensitive. III. Tumor-type agnostic solid tumor molecular profiling panel tests (81445, 81449, 81455, 81456, 0037U, 0048U, 0244U, 0250U, 0334U) are considered investigational for all other indications. back to top Tumor-Type Agnostic Solid Tumor Molecular Profiling Panel Tests with IHC and Cytogenetic Analyses I. Tumor-type agnostic solid tumor molecular profiling panel tests with IHC and cytogenetic analyses (0211U, 81455, 0379U) are considered medically necessary when: A. The member/enrollee has recurrent, relapsed, refractory, metastatic, or advanced stages III or IV cancer, AND B. The member/enrollee is seeking further cancer treatment (for example, therapeutic chemotherapy). II. Repeat testing via a tumor-type agnostic solid tumor molecular profiling panel with IHC and cytogenetic analyses (0211U, 81455, 0379U) is considered medically necessary when: A. The member/enrollee has progression of any of the following: 1. Metastatic colon cancer, OR 2. Advanced or metastatic non-small cell lung cancer (NSCLC), OR 3. Advanced or metastatic gastric adenocarcinoma, OR 4. Metastatic prostate cancer, OR 9 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 5. Ovarian cancer that is platinum-sensitive. III. Tumor-type agnostic molecular profiling panel tests with IHC and cytogenetic analyses (0211U, 81455, 0379U) are considered investigational for all other indications. Note: Additional codes representing additional IHC and/or cytogenetics analyses may be billed alongside the PLA or GSP codes. back to top Comprehensive Molecular Profiling Panels For Hematologic Malignancies and Myeloid Malignancy Panels I. Comprehensive molecular profiling panels for hematologic malignancies and myeloid malignancy panels in bone marrow or peripheral blood (81450, 81451, 81455) are considered medically necessary when: A. The member/enrollee has blood work (CBC) and bone marrow evaluation which are consistent with acute myeloid leukemia (AML), OR B. The member/enrollee has a newly diagnosed myelodysplastic syndrome with persistent cytopenia(s) (at least 4-6 months), AND 1. Other causes of cytopenia(s) have been ruled out, including: a) Nutritional anemias (for example: iron deficiency anemia, folate deficiency anemia, vitamin B12 deficiency anemia), AND b) Thyroid disease, AND c) Drug-induced cytopenia, AND d) Viral infection (for example: HIV), OR C. The member/enrollee is suspected to have a myeloproliferative neoplasm, AND 1. Comprehensive panel can be ordered as part of initial genetic evaluation, or after JAK2, CALR, and MPL analysis were previously performed and the results were negative, OR D. The member/enrollee has a diagnosis of chronic myelogenous leukemia, AND 1. There has been progression to accelerated phase or blast phase, OR 10 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 2. BCR-ABL1 kinase domain mutation analysis has been performed and the results were negative. II. Comprehensive molecular profiling panels for hematologic malignancies and myeloid malignancy panels in bone marrow or peripheral blood (81450, 81451, 81455) are considered investigational for all other indications. Note: If a multigene panel is performed, appropriate panel codes should be used. This COA is not intended to address liquid biopsies. back to top Colorectal Cancer Focused Molecular Profiling Panels I. Colorectal cancer focused molecular profiling panels (0111U, 81445) in solid tumors are considered medically necessary when: A. The member/enrollee has suspected or proven metastatic, synchronous or metachronous colorectal cancer, AND B. The member/enrollee is seeking further cancer treatment (e.g., therapeutic chemotherapy), AND C. One of the following: 1. The member/enrollee has not had previous somatic testing via a multigene cancer panel for the same primary diagnosis of colorectal cancer, OR 2. The member/enrollee HAS had previous somatic testing via a multigene cancer panel for a primary colorectal cancer diagnosis, and has a new primary colorectal cancer diagnosis for which this testing is being ordered. II. Colorectal cancer-focused molecular profiling panels (0111U, 81445) are considered investigational for all other indications. Note: If a panel is performed, appropriate panel codes should be used. back to top 11 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 Lung Cancer Focused Molecular Profiling Panels I. Lung cancer focused molecular profiling panels (0022U, 81445) are considered medically necessary when: A. The member/enrollee has a diagnosis of any of the following: 1. Advanced (stage IIIb or higher) or metastatic lung adenocarcinoma, OR 2. Advanced (stage IIIb or higher) or metastatic large cell lung carcinoma, OR 3. Advanced (stage IIIb or higher) or metastatic squamous cell lung carcinoma, OR 4. Advanced (stage IIIb or higher) or metastatic non-small cell lung cancer (NSCLC) not otherwise specified (NOS), AND B. The member/enrollee is seeking further cancer treatment (e.g., therapeutic chemotherapy). II. III. Repeat lung cancer-focused molecular profiling panels (0022U, 81445) is medically necessary when the member/enrollee has progression on targeted therapy for non-small cell lung cancer. Lung cancer-focused molecular profiling panels (0022U, 81445) are considered investigational for all other indications. Note: If a panel is performed, appropriate panel codes should be used. back to top Cutaneous Melanoma Focused Molecular Profiling Panels I. Cutaneous melanoma focused molecular profiling panels (81210, 81404, 81445) are considered medically necessary when: A. The member/enrollee has a new diagnosis of stage IV melanoma or has recurrent melanoma, AND B. The member/enrollee is seeking further cancer treatment (e.g. therapeutic chemotherapy), AND 12 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 C. One of the following: 1. The member/enrollee has not had previous somatic testing via a multigene cancer panel for the same primary melanoma diagnosis, OR 2. The member/enrollee HAS had previous somatic testing via a multigene cancer panel for a primary melanoma diagnosis, and has a new primary melanoma diagnosis for which this testing is being ordered. II. Cutaneous melanoma focused molecular profiling panels (81210, 81404, 81445) are considered investigational for all other indications. Note: If a panel is performed, appropriate panel codes should be used. back to top Acute Myeloid Leukemia (AML) Focused Molecular Profiling Panels I. Acute myeloid leukemia focused molecular profiling panels (0050U, 81450) for the diagnosis or evaluation of acute myeloid leukemia (AML) are considered medically necessary when: A. The member/enrollee has a suspected or confirmed diagnosis of acute myeloid leukemia (AML). II. Acute myeloid leukemia focused molecular profiling panels (0050U, 81450) for the diagnosis or evaluation of acute myeloid leukemia (AML) is considered investigational for all other indications. Note: If a multigene panel is performed, appropriate panel codes should be used. back to top Myeloproliferative Neoplasms (MPNs) Panel Tests I. Myeloproliferative neoplasm (MPN) molecular profiling panel tests (81206, 81207, 81208, 81219, 81270, 81338, 81339) are considered medically necessary when: A. The member/enrollee is suspected to have a myeloproliferative neoplasm (i.e., polycythemia vera, essential thrombocythemia, primary myelofibrosis, and chronic myeloid leukemia), AND 13 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 B. The panel does not include genes other than JAK2, CALR, MPL, and BCR/ABL1. II. Myeloproliferative neoplasm (MPN) molecular profiling panel tests (81206, 81207, 81208, 81219, 81270, 81338, 81339) are considered investigational for all other indications. back to top SINGLE-GENE TESTING OF SOLID TUMORS AND HEMATOLOGIC MALIGNANCIES Tumor Specific BCR/ABL Kinase Domain Analysis I. Tumor specific BCR/ABL kinase domain analysis (81170) in hematologic malignancies is considered medically necessary when: A. The member/enrollee has a diagnosis of chronic myeloid leukemia (CML) or Ph- like acute lymphocytic leukemia (ALL), AND B. Any of the following: 1. Initial response to TKI therapy is inadequate, OR 2. Loss of response to TKI therapy, OR 3. Disease progression to the accelerated or blast phase, OR 4. Relapsed/refractory disease. back to top Tumor Specific BCR/ABL Quantitation and Breakpoint Analysis I. Tumor specific BCR/ABL1 quantitation and breakpoint analysis (0016U, 0040U, 81206, 81207) in hematologic malignancies is considered medically necessary when: A. The member/enrollee is suspected to have a myeloproliferative neoplasm (i.e., polycythemia vera, essential thrombocythemia, primary myelofibrosis, and chronic myeloid leukemia), OR 14 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 B. The member/enrollee is undergoing workup for or to monitor disease progression of: 1. Acute lymphoblastic leukemia (ALL), OR 2. Acute myeloid leukemia (AML), OR 3. Chronic myelogenous leukemia (CML), OR 4. B-cell lymphoma. back to top Tumor Specific BRAF Variant Analysis I. Tumor specific BRAF variant analysis (81210) in solid tumors and hematologic malignancies is considered medically necessary when: A. The member/enrollee has a diagnosis of: 1. Suspected or proven metastatic, synchronous or metachronous colorectal cancer, OR 2. Advanced or metastatic non-small-cell lung cancer (NSCLC), OR 3. Stage III or stage IV cutaneous melanoma, OR 4. Indeterminate thyroid nodules requiring biopsy, OR 5. Anaplastic thyroid carcinoma or locally recurrent, advanced and/or metastatic papillary, follicular or Hurthle cell thyroid carcinoma, OR 6. Low-grade glioma or pilocytic astrocytoma, OR B. The member/enrollee is being evaluated for: 1. Hairy cell leukemia (for individuals without cHCL [classical hairy cell leukemia] immunophenotype). back to top 15 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 Tumor Specific BRCA1/2 Variant Analysis I. Tumor specific BRCA1/2 variant analysis (81162, 81163, 81164, 81165, 81166, 81167, 81216) in solid tumors is considered medically necessary when: A. The member/enrollee has a diagnosis of: 1. Ovarian, fallopian tube and/or primary peritoneal cancer, OR 2. Metastatic prostate cancer. back to top Tumor Specific CALR Variant Analysis I. Tumor specific CALR variant analysis (81219) is considered medically necessary when: A. The member/enrollee is suspected to have a myeloproliferative neoplasm. back to top Tumor Specific CEBPA Variant Tests I. Tumor specific CEBPA variant analysis (81218) in hematologic malignancies is considered medically necessary when: A. The member/enrollee has cytogenetically normal acute myeloid leukemia (AML). back to top Tumor Specific EGFR Variant Analysis I. Tumor specific EGFR variant analysis (81235) in solid tumors is considered medically necessary when: A. The member/enrollee has a diagnosis of any of the following: 1. Advanced or metastatic lung adenocarcinoma, OR 2. Advanced or metastatic large cell lung carcinoma, OR 16 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 3. Advanced or metastatic squamous cell lung carcinoma, OR 4. Advanced or metastatic non-small cell lung cancer (NSCLC) not otherwise specified (NOS). back to top Tumor Specific ESR1 Variant Analysis I. Tumor specific ESR1 variant analysis (81479) in solid tumors is considered medically necessary when: A. The member/enrollee is a postmenopausal female or adult male with the following: 1. ER-positive and HER2-negative breast cancer, AND 2. Disease progression after one or two prior lines of endocrine therapy, including one line containing a CDK4/6 inhibitor. back to top Tumor Specific FLT3 Variant Analysis I. Tumor specific FLT3 variant analysis (81245, 81246, 0023U, 0046U) in hematologic malignancies is considered medically necessary when: A. The member/enrollee has suspected or confirmed acute myeloid leukemia (AML), OR B. The member/enrollee has a diagnosis of acute lymphocytic leukemia (ALL), OR C. The member/enrollee has a diagnosis of myelodysplastic syndrome (MDS). back to top Tumor Specific IDH1 and IDH2 Variant Analysis I. Tumor specific IDH1 and IDH2 variant analysis (81120, 81121) in solid tumors or hematologic malignancies is considered medically necessary when: 17 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 A. The member/enrollee has a diagnosis of a glioma, OR B. The member/enrollee has a diagnosis of acute myeloid leukemia. back to top Tumor Specific IGHV Somatic Hypermutation Analysis I. Tumor specific IGHV somatic hypermutation analysis (81261, 81262, 81263) in hematologic malignancies is considered medically necessary when: A. The member/enrollee has a diagnosis of: 1. Chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), OR 2. Primary cutaneous B-cell lymphoma, OR 3. Mantle cell lymphoma, OR 4. Post-transplant lymphoproliferative disorder. back to top Tumor Specific JAK2 Variant Analysis I. Tumor specific JAK2 variant analysis (81270, 0017U, 0027U) in solid tumors or hematologic malignancies is considered medically necessary when: A. The member/enrollee is suspected to have a myeloproliferative neoplasm (example: polycythemia vera, essential thrombocythemia, primary myelofibrosis, and chronic myeloid leukemia), OR B. The member/enrollee has acute lymphoblastic leukemia, OR C. The member/enrollee is suspected to have a myelodysplastic syndrome. back to top 18 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 Tumor Specific KIT Variant Analysis I. Tumor specific KIT variant analysis (81272, 81273) in solid tumors or hematologic malignancies is considered medically necessary when: A. The member/enrollee is suspected to have, or is being evaluated for systemic mastocytosis, OR B. The member/enrollee has a diagnosis of acute myeloid leukemia, OR C. The member/enrollee has stage IV cutaneous melanoma, OR D. The member/enrollee has a suspected or confirmed gastrointestinal stromal tumor (GIST). back to top Tumor Specific KRAS Variant Analysis I. Tumor specific KRAS variant analysis (81275, 81276) in solid tumors is considered medically necessary when: A. The member/enrollee has suspected or proven metastatic, synchronous or unresectable metachronous colorectal cancer, OR B. The member/enrollee is undergoing workup for metastasis of non-small cell lung cancer. II. Somatic KRAS variant analysis (81275, 81276) in solid tumors, as a stand alone test, in an individual with non-small cell lung cancer (NSCLC) is considered investigational. back to top Tumor Specific MGMT Methylation Analysis I. Tumor specific MGMT promoter methylation analysis (81287) in solid tumors is considered medically necessary when: A. The member/enrollee has a high grade glioma (stage III or IV), including one of the following: 19 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 1. Anaplastic oligodendroglioma, OR 2. Anaplastic astrocytoma, OR 3. Anaplastic glioma, OR 4. Glioblastoma. back to top Tumor Specific MLH1 Methylation Analysis I. Tumor specific MLH1 promoter methylation analysis (81288) in solid tumors is considered medically necessary when: A. The member/enrollee has a diagnosis of colorectal cancer or endometrial (uterine) cancer, AND B. Previous tumor testing showed loss of MLH1 on immunohistochemistry analysis. back to top Tumor Specific MPL Variant Analysis I. Tumor specific MPL variant analysis (81338, 81339) in hematologic malignancies is considered medically necessary when: A. The member/enrollee displays clinical symptoms of a myeloproliferative neoplasm (i.e., polycythemia vera, essential thrombocythemia, primary myelofibrosis, and chronic myeloid leukemia), such as chronically elevated red blood cell counts. back to top Tumor Specific Microsatellite Instability (MSI) Analysis I. Tumor specific microsatellite instability (MSI) analysis (81301) in solid tumors is considered medically necessary when: A. The member/enrollee has a diagnosis of: 20 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 1. Colorectal cancer, OR 2. Endometrial cancer, OR 3. Gastric cancer, OR 4. Locally advanced, recurrent or metastatic esophageal and esophagogastric junction cancer, OR 5. Recurrent, progressive or metastatic cervical cancer, OR 6. Testicular cancer (nonseminoma) and has had progression after high dose chemotherapy or third-line therapy, OR 7. Unresectable or metastatic gallbladder cancer, OR 8. Unresectable or metastatic intrahepatic or extrahepatic cholangiocarcinoma, OR 9. Unresectable or metastatic breast cancer, OR 10. Small bowel adenocarcinoma, OR 11. Metastatic occult primary. back to top Tumor Specific NPM1 Variant Analysis I. Tumor specific NPM1 variant analysis (81310, 0049U) in hematological malignancies is considered medically necessary when: A. The member/enrollee has cytogenetically normal acute myeloid leukemia (AML). back to top Tumor Specific NRAS Variant Analysis I. Tumor specific NRAS variant analysis (81311) in solid tumors is considered medically necessary when: 21 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 A. The member/enrollee has suspected or proven metastatic, synchronous or metachronous colorectal cancer. back to top Tumor Specific PIK3CA Variant Analysis I. Tumor specific PIK3CA variant analysis (81309, 0155U, 0177U) in solid tumors is considered medically necessary when: A. The member/enrollee has recurrent or stage IV, HR positive, HER2 negative invasive breast cancer, OR B. The member/enrollee has a diagnosis of uterine rhabdomyosarcoma. back to top Tumor Specific RET Variant Analysis I. Tumor specific RET variant analysis (81404, 81405, 81406) in solid tumors is considered medically necessary when: A. The member/enrollee has a diagnosis of medullary thyroid cancer, OR B. Anaplastic thyroid carcinoma or locally recurrent, advanced and/or metastatic papillary, follicular or Hurthle cell thyroid carcinoma, OR C. Advanced or metastatic adenocarcinoma, large cell, or non small-cell cancer of the lung. back to top Tumor Specific TP53 Variant Analysis I. Tumor specific TP53 variant analysis (81352) in bone marrow or peripheral blood is considered medically necessary when: A. The member/enrollee has a diagnosis of acute myeloid leukemia, chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), OR 22 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 B. The member/enrollee is undergoing diagnostic workup for mantle cell lymphoma (MCL). back to top MEASURABLE (MINIMAL) RESIDUAL DISEASE (MRD) ANALYSIS I. Measurable (minimal) residual disease (MRD) analysis (0171U, 0364U) in bone marrow or peripheral blood is medically necessary when: A. The member/enrollee has a diagnosis of: 1. Acute Lymphocytic Leukemia (ALL), OR 2. Multiple Myeloma, OR 3. Chronic Lymphocytic Leukemia (CLL). back to top TUMOR MUTATIONAL BURDEN (TMB) I. Tumor mutational burden (TMB) testing (81479) is considered medically necessary when: A. The member/enrollee has a diagnosis of any of the following: 1. Recurrent or metastatic breast cancer, OR 2. Recurrent, progressive or metastatic cervical cancer, OR 3. Unresectable or metastatic gallbladder cancer, OR 4. Unresectable or metastatic extrahepatic cholangiocarcinoma, OR 5. Suspected metastatic malignant occult primary tumor, OR 6. Recurrent ovarian/fallopian tube/primary peritoneal cancer, OR 7. Metastatic or advanced pancreatic adenocarcinoma, OR 23 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 8. Metastatic castration-resistant prostate cancer, OR 9. Progression of testicular cancer (nonseminoma) after high dose or third line therapy, OR 10. Endometrial carcinoma or uterine sarcoma. back to top RED BLOOD CELL GENOTYPING IN MULTIPLE MYELOMA I. Red blood cell genotyping (0001U, 0180U, 0221U) in individuals with multiple myeloma is considered medically necessary when: A. The member/enrollee has a diagnosis of multiple myeloma, AND B. The member/enrollee is currently being treated or will be treated with Daratumumab (DARA). back to top CANCER EXOME AND GENOME SEQUENCING I. Cancer exome and genome sequencing in solid tumors and hematologic malignancies (0036U, 0329U, 81415, 81416, 81425, 81426) is considered investigational. back to top GENETIC TESTING TO CONFIRM THE IDENTITY OF LABORATORY SPECIMENS I. Genetic testing to confirm the identity of laboratory specimens (e.g., known error, ToxProtect) (0007U, 0079U, 81265, 81266, 81479), when billed separately, is considered investigational because it is generally considered to be an existing component of the genetic testing process for quality assurance. back to top 24 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 Medically Necessary Tumor Testing By Cancer Type: Cancer Type Any solid tumor Recommended Molecular Analysis (see coverage criteria sections above) Comprehensive molecular profiling panel for solid tumors ALL AML Ewing Sarcoma (bone cancer) Ewing Sarcoma (bone cancer) Breast Cancer CNS Cancer Glioma-low grade CNS Cancer Medulloblastoma Cervical Cancer CLL/SLL CML BCR-ABL1, TCF3-PBX1, ETV6- RUNX1, IL3-IGH, KMT2A, ABL2, CRLF2, CSF1R, EPOR, FLT3, IL7R, JAK1, JAK2, JAK3, PDGFRB, SH2B3, MRD FISH, karyotype rearrangements: CBFB-MYH11, GAT2- MECOM, BCR-ABL, KMT2A-MLLT3, DEK-NUP214, RUNX1, RUNX1T1, ASXL1, KIT, NPM1, RUNX1, TP53, CEBPA, FLT3, IDH1, IDH2, Comprehensive molecular profiling panel Translocations: ETV1, ETV4, EWSR1, FEV, FLI1, ERG, FUS, MSI or MMR (MLH1, MSH2, MSH6, PMS2 by IHC) BRCA1, BRCA2, PD-L1, PIK3CA, NTRK1/2/3, MSI, MLH1, MSH2, MSH6, PMS2, TMB 1p/19q, TERT promoter, H3F3A, HIST1H3B, BRAF, IDH1, IDH2, ATRX, MGMT Promoter Methylation APC, CTNNB1, GAB1, YAP1, TP53 MLH1, MSH2, MSH6, PMS2, MSI, PD- L1, NTRK1/2/3, TMB, CCND1, 11:14 translocation, 11q:v translocation, CD19, CD200, CD5, FCER2, IGK, IGL, MME, MS4A1, CD247, CD3D, CD3E, CD3G, LEF1, ATM, CD38, IGH, ITGA4, ZAP70, TP53 BCR-ABL1, ABL1 Kinase Domain Timing of Analysis Recurrent, relapsed, refractory, metastatic, or advanced stages III or IV cancer At diagnosis, or relapsed/refractory disease Workup Initial workup Progression after treatment Recurrent or metastatic Pre-adjuvant therapy Post-operative staging Recurrent, progressive or metastatic disease Initial diagnosis Chronic phase adult CML 25 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 Cancer Type Colorectal Cancer Colorectal Cancer Recommended Molecular Analysis (see coverage criteria sections above) BRAF, KRAS, NRAS, HER2 amplifications (by NGS or IHC) MSI or MMR (MLH1, MSH2, MSH6, PMS2 by IHC) if not previously done NTRK1/2/3, Comprehensive molecular profiling panel MSI or MMR (MLH1, MSH2, MSH6, PMS2 by IHC) Cutaneous Melanoma BRAF, KIT Esophageal and EGJ Cancers HER2, PD-L1, NTRK1/2/3 MSI or MMR (MLH1, MSH2, MSH6, PMS2 by IHC) Gallbladder Cancer MSI or MMR (MLH1, MSH2, MSH6 PMS2 by IHC) BRAF, ERBB2, FGFR2, IDH1, NTRK1/2/3, TMB HER2, PD-L1, MSI if not previously done, NTRK1/2/3, Comprehensive molecular profiling panel MSI or MMR (MLH1, MSH2, MSH6, PMS2 by IHC) Gastric Cancer Gastric Cancer Timing of Analysis Invasive, metastatic, synchronous (any T, any N, M1) Newly diagnosed Workup for metastatic or recurrent disease Locally advanced, recurrent or metastatic adenocarcinoma Unresectable or metastatic disease Locally advanced, recurrent or metastatic disease Workup Hairy Cell Leukemia CCND1, CD19, CD200, CD22, CD5, Initial diagnosis IL2RA, IL3RA, ITGAE, ITGAX, MME, MS4A21, BRAF, IGH Hepatobiliary Cancers MSI (PCR) or MMR (MLH1, MSH2, MSH6, PMS2 by IHC) TMB, BRAF, HER2, FGFR2, IDH1, NTRK1/2/3, RET TP53, CD19, CD5, FCER2, IGK, IGL, MME, MS4A1, BCL2, BCL6, CCND1, CD3E, CR2, MKI67, SOX11, IGH, CCND2 rearrangement, CCND3 rearrangement, CCND1 MRD ASXL1, BCOR, CALR, CBL, DDX41, DNMT3A, ETV6, EZH2, FLT3, GATA2, Mantle Cell Lymphoma Multiple Myeloma Myelodysplastic Syndrome Unresectable or metastatic extrahepatic cholangiocarcinoma Initial diagnosis Follow up/surveillance Initial evaluation 26 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 Cancer Type Myeloproliferative Neoplasms (polycythemia vera PV, essential thrombocythemia ET, myelofibrosis MF) Non-small Cell Lung Cancer B-Cell Lymphomas Occult Primary Ovarian Cancer Pancreatic Adenocarcinoma Prostate Cancer Prostate Cancer Testicular Cancer Recommended Molecular Analysis (see coverage criteria sections above) IDH1, IDH2, JAK2, MPL, NF1, NPM1, NRAS, PHF6, PPM1D, RUNX1, SETBP1, SF3B1, SRSF2, STAG2, STAT3, TET2, TP53, U2AF1, WT1, ZRSR2 Comprehensive hematologic malignancy panel testing BCR-ABL, cytogenetics, FISH, Comprehensive molecular profiling panel For PV, ET, MF: JAK2, For ET, MF: MPL, CALR, ASXL1, EZH2, RAS EGFR, KRAS, MET, NTRK1/2/3, RET, ALK, ROS1, BRAF, PD-L1 (IHC), Comprehensive molecular profiling panel IGH, IGK, IGL MSI or MMR (MLH1, MSH2, MSH6, PMS2 by IHC), TMB, Comprehensive molecular profiling panel BRCA1/2, homologous recombination deficiency, TMB, NTRK1/2/3 MSI or MMR (MLH1, MSH2, MSH6, PMS2 by IHC), Comprehensive molecular profiling panel ALK, BRAF, BRCA1, BRCA2, ERBB2, FGFR2, KRAS, MLH1, MSH2, MSH6, NRG1, NTRK1, NTRK2, NTRK3, PALB2, PMS2, RET, ROS1 MSI and/or MMR (MLH1, MSH2, MSH6, PMS2) ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, RAD54L, MSI or MMR (MLH1, MSH2, MSH6, PMS2 by IHC), TMB MSI, MMR (MLH1, MSH2, MSH6, PMS2 by IHC), TMB Timing of Analysis Diagnosis and prognostication Pre-adjuvant therapy, metastatic disease Initial diagnosis Initial evaluation of suspected malignancy Recurrent disease (if not previously done) Locally advanced or metastatic disease Metastatic disease Progressive metastatic disease Recurrent disease 27 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 Cancer Type Thyroid Carcinoma (anaplastic carcinoma) Thyroid Carcinoma (anaplastic, follicular, Hürthle cell, medullary, papillary carcinomas) Uterine Neoplasms (endometrial carcinoma) Uterine Neoplasms (uterine sarcoma) Recommended Molecular Analysis (see coverage criteria sections above) BRAF, ALK, RET, TMB, NTRK1/2/3 MSI or MMR (MLH1, MSH2, MSH6, PMS2) BRAF, ALK, RET, TMB, NTRK1/2/3 MSI or MMR (MLH1, MSH2, MSH6, PMS2) MMR (MLH1, MSH2, MSH6, PMS2 by IHC) TMB, NTRK1/2/3, POLE, TP53 expression Comprehensive genomic profiling panel NTRK1/2/3, TMB, MSI Timing of Analysis Initial workup Recurrence or metastatic disease Diagnosis Metastatic or recurrent disease back to top NOTES AND DEFINITIONS 1. Tumor mutation burden testing is a measurement of mutations carried by tumor cells and is a predictive biomarker that is being studied to evaluate its association with response to immunotherapy. 2. Advanced cancer is cancer that is unlikely to be cured or controlled with treatment. The cancer may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body. Treatment may be given to help shrink the tumor, slow the growth of cancer cells, or relieve symptoms. 3. Myeloproliferative Neoplasms are rare overlapping blood diseases in which the bone marrow makes too many red blood cells, white blood cells, or platelets. There are seven subcategories of myeloproliferative neoplasms: ■ Chronic myeloid leukemia (CML) ■ Polycythemia vera (PV) ■ Primary myelofibrosis (PMF) ■ Essential thrombocytopenia (ET) ■ Chronic neutrophilic leukemia 28 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 ■ Chronic eosinophilic leukemia ■ Chronic eosinophilic leukemia-not otherwise specified ■ MPN, unclassifiable (MPN-U) back to top CLINICAL CONSIDERATIONS Clinical decision making should not be made based on variants of uncertain significance. NCCN and ASCO recommend that all individuals diagnosed with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer have germline and somatic tumor testing (if not previously performed) for BRCA1 and BRCA2 mutations. The genetic testing of tumors and hematologic malignancies (somatic mutation profiling) may reveal incidental germline findings or suspicion of a clinically significant germline mutation. Providers should communicate the potential for these incidental findings with their patients prior to somatic mutation profiling. ACMG (2020) recognized that tumor testing is an emerging area and that the identification of presumed germline pathogenic variants (PGPVs) have profound health and reproductive implications for the individual with cancer as well as their family members. Thus, individuals undergoing tumor testing should be informed prior to testing that a germline variant may be uncovered. PGPVs should be carefully evaluated, confirmed, and reported when tumor testing is performed. Currently, there is a lack of evidence for best practices to report PGPVs to patients who want them. back to top BACKGROUND AND RATIONALE Tumor-Type Agnostic Solid Tumor Molecular Profiling Panel Tests National Comprehensive Cancer Network (NCCN) The NCCN guidelines on Breast Cancer (2.2023) recommend comprehensive somatic testing to aid in clinical management of patients with recurrent/stage IV breast cancer. (p. BINV-18) 29 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 The NCCN guideline on Occult Primary (3.2023) recommends MSI and MMR testing as part of the initial work up for patients with cancer of unknown primary. The guideline further recommends consideration of NGS to identify actionable genomic aberrations after a histological determination of the tumor has been made. (p. OCC-1). The NCCN guideline on Non-Small Cell Lung Cancer (2.2023) recommends molecular testing for advanced or metastatic disease, including EGFR, ALK, KRAS, ROS1, BRAF, NTRK1/2/3, METex14 skipping, RET, PD-L1. They also recommend broader molecular profiling with the goal of identifying rare driver mutations for which effective drugs may already be available. (p. NSCL-18). The guidelines also state that repeat somatic genetic testing can be helpful to aid in deciding next therapeutic steps when a patient’s tumor shows evidence of progression on first- line therapy. (p. NSCL-H 6 of 7) The NCCN guideline for Colon Cancer (3.2022) recommends all patients with metastatic colorectal cancer have tumor genotyping for KRAS, NRAS, BRAF individually or as part of an NGS panel. Testing can be performed on the primary tumor and/or metastases (p. COL-B 4 of 8). The NCCN guideline for Gastric Cancer (2.2022) recommends that patients with inoperable locally advanced, recurrent or metastatic adenocarcinoma of the stomach considering trastuzumab therapy have IHC for HER2 and NGS when limited diagnostic tissue is available or patient can't undergo a traditional biopsy. The guidelines also recommend that repeat tumor testing can be considered when there is clinical or radiologic evidence for disease progression of advanced gastric cancer (p. GAST-B 3 of 6). The NCCN guideline for Ovarian Cancer Including Fallopian Tumor Cancer and Primary Peritoneal Cancer (1.2023) recommends that patients with recurrent disease, tumor molecular analysis have at a minimum, tests to identify potential benefit from targeted therapeutics that have tumor specific or tumor-agnostic benefit. (p OV-6) More comprehensive testing may be particularly important in less common histologies with limited approved therapeutic options. (p. OV-B 1 of 3) These guidelines also recommend that molecular testing be performed on the most recent tumor tissue available. (p. OV-8) The NCCN guideline for Pancreatic Adenocarcinoma (2.2022) recommends tumor/somatic molecular profiling for patients with local advanced/metastatic disease who are candidates for anti-cancer therapy to identify uncommon mutations. They also recommend considering specifically testing for potentially actionable somatic findings including but not limited to fusions (ALK, NRG1, NTRK, ROS1, FGFR2, RET), mutations BRAF, BRCA1/2, KRAS, PALB2, amplifications (HER2), MSI, and or mismatch repair deficiency. (p. PANC-1A) The NCCN guideline for Prostate Cancer (1.2023) recommends for somatic tumor testing and that tumor molecular and biomarker analysis may be used for treatment decision-making, 30 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 including understanding eligibility for biomarker-directed treatments, genetic counseling, early use of platinum chemotherapy, and eligibility for clinical trials. The guidelines also recommend that repeat tumor profiles can be considered at the time of progression of disease. They also recommend tumor testing for alterations in homologous recombination DNA report genes such as BRCA1/2, ATM, PALB2, FANCA, RAD512D, CHEK2, CDK12, is for patients with metastatic prostate cancer. (p. PROS-C 3 of 3) Comprehensive Molecular Profiling Panels for Hematologic Malignancies and Myeloid Malignancy Panels National Comprehensive Cancer Network (NCCN) The NCCN guidelines for acute myeloid leukemia (3.2022) recommends for patients over the age of 18 testing that includes a complete blood count, platelets, differential, comprehensive metabolic panel, uric acid, lactate dehydrogenase, vitamin B12 and folic acid, prothrombin time, partial thromboplastin time, fibrinogen, and bone marrow core biopsy and aspirate analyses. (p.EVAL-1). Multiplex gene panels and comprehensive next-generation sequencing (NGS) analysis are recommended for the ongoing management of AML and various phases of treatment (p. EVAL-1A). The NCCN guidelines for myelodysplastic syndromes (1.2023) recommend that patients who have persistent cytopenia (at least 4 to 6 months) and lack other underlying conditions that could cause cytopenia should be evaluated for myelodysplastic syndromes. (p. MS-3) NCCN describes cytopenia that is suspicious for myelodysplasia as the presence of peripheral blood dysplasia, blasts, or MDS-associated cytogenetic abnormalities. They say cytopenias are defined as values lower than standard lab hematologic levels, being cognizant of age, sex, ethnic, and altitude norms (p. MDS-1, p. MDS-2). NCCN recommends ruling out other causes of anemia, such as nutritional deficiency of folate and vitamin B12, as well as measuring thyroid stimulating hormone levels, and HIV testing if clinically indicated (p. MDS-1). The NCCN guidelines for myeloproliferative neoplasms (3.2022) recommend for patients suspected of having an MPN to have molecular testing for JAK2 V617F, CALR and MPL mutations for patient with symptoms of essential thrombocythemia or myelofibrosis, and JAK2 exon 12 mutations for patients with polycythemia vera. This testing can be done in a stepwise manner, or as an NGS multigene panel (p. MPN-1). The NCCN guidelines for chronic myeloid leukemia (1.2023) indicate that a patient with advanced phase CML in either accelerated or blast phase should consider mutational analysis with a myeloid mutation panel (CML-1). Patients on TKI therapy who have progressed to accelerated or blast phase should consider a myeloid mutation panel to identify BCR-ABL-1- 31 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 independent resistance mutations in patients with no BCR-ABL 1 kinase domain mutations (p. CML-E). Tumor-Type Agnostic Solid Tumor Molecular Profiling Panel Tests with IHC and Cytogenetic Analyses National Comprehensive Cancer Network (NCCN) The NCCN guideline on Occult Primary (2.2023) recommends MSI and MMR testing as part of the initial work up for patients with cancer of unknown primary. (p. OCC-1) The guideline further recommends consideration of NGS to identify actionable genomic aberrations in individuals with localized adenocarcinoma or carcinoma not otherwise specified. (p. OCC-2) The NCCN guideline on Non-Small Cell Lung Cancer (2.2023) recommends molecular testing for advanced or metastatic disease, including EGFR, ALK, KRAS, ROS1, BRAF, NTRK1/2/3, METex14 skipping, RET, PD-L1. They also recommend broader molecular profiling with the goal of identifying rare driver mutations for which effective drugs may already be available. (p. NSCL-18) The NCCN guideline for Colon Cancer (3.2022) recommends all patients with metastatic colorectal cancer have tumor genotyping for KRAS, NRAS, BRAF individually or as part of an NGS panel. (p. COL-B 4 of 8) The NCCN guideline for Gastric Cancer (2.2022) recommends that patients with inoperable locally advanced, recurrent or metastatic adenocarcinoma of the stomach considering trastuzumab therapy have IHC for HER2 and NGS when limited diagnostic tissue is available or patient can't undergo a traditional biopsy. (p. GAST-B 3 of 6) The NCCN guideline for Ovarian Cancer including Fallopian Tube Cancer and Primary Peritoneal Cancer (1.2023) recommends that patients with recurrent disease, tumor molecular analysis have at a minimum, tests to identify potential benefit from targeted therapeutics that have tumor specific or tumor-agnostic benefit. (p OV-6) More comprehensive testing may be particularly important in less common histologies with limited approved therapeutic options. (p. OV-B 1 of 3) The NCCN guideline for Pancreatic Adenocarcinoma (2.2022) recommends tumor/somatic molecular profiling for patients with local advanced/metastatic disease who are candidates for anti-cancer therapy to identify uncommon mutations. They also recommend considering specifically testing for potentially actionable somatic findings including but not limited to fusions (ALK, NRG1, NTRK, ROS1, FGFR2, RET), mutations BRAF, BRCA1/2, KRAS, PALB2, amplifications (HER2), MSI, and or mismatch repair deficiency. (p. PANC-1A) 32 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 The NCCN guideline for Prostate Cancer (1.2023) recommends for somatic tumor testing and that tumor molecular and biomarker analysis may be used for treatment decision-making, including understanding eligibility for biomarker-directed treatments, genetic counseling, early use of platinum chemotherapy, and eligibility for clinical trials. They also recommend tumor testing for alterations in homologous recombination DNA report genes such as BRCA1/2, ATM, PALB2, FANCA, RAD512D, CHEK2, CDK12, is for patients with metastatic prostate cancer. (p. PROS-C 3 of 3) Colorectal Cancer Focused Molecular Profiling Panels National Comprehensive Cancer Network (NCCN) The NCCN guideline for Colon Cancer (3.2022) recommends all patients with metastatic colorectal cancer have tumor genotyping for KRAS, NRAS, BRAF individually or as part of an NGS panel. (p. COL-B 4 of 8). Lung Cancer Focused Molecular Profiling Panels National Comprehensive Cancer Network (NCCN) The NCCN guideline for Non-Small Cell Lung Cancer (2.2023) recommends at this time that when feasible, testing be performed via a broad, panel-based approach, most typically performed by NGS. For patients who, in broad panel testing do not have identifiable driver oncogenes (especially in never smokers), consider RNA-based NGS if not already performed, to maximize detection of fusion events. (p. NSCL-H 2 OF 7) Cutaneous Melanoma Focused Molecular Profiling Panels National Comprehensive Cancer Network (NCCN) The NCCN guidelines for cutaneous melanoma (1.2023) recommend BRAF and KIT testing, but broader genomic profiling (such as larger NGS panels, BRAF non-V600 mutations) is recommended if feasible, especially if the test results might guide future treatment decisions or eligibility for participation in a clinical trial (p. ME-C 4 of 8). Acute Myeloid Leukemia (AML) Focused Molecular Profiling Panel 33 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 National Comprehensive Cancer Network (NCCN) The NCCN guidelines for acute myeloid leukemia (3.2022) recommends for patients over the age of 18 testing that includes a complete blood count, platelets, differential, comprehensive metabolic panel, uric acid, lactate dehydrogenase, vitamin B12 and folic acid, prothrombin time, partial thromboplastin time, fibrinogen, and bone marrow core biopsy and aspirate analyses. (p.EVAL-1). Multiplex gene panels and comprehensive next-generation sequencing (NGS) analysis are recommended for the ongoing management of AML and various phases of treatment (p. EVAL-1A). Myeloproliferative Neoplasms (MPNs) Panel Tests National Comprehensive Cancer Network (NCCN) The NCCN guidelines on myeloproliferative neoplasms (3.2022) recommend that FISH or RT- PCR to detect BCR-ABL1 transcripts is recommended to exclude the diagnosis of CML. Additionally, they recommend that molecular testing for JAK2 mutations is recommended in initial work-up for all patients with suspected MPN. They further recommend that if testing for JAK2 mutations is negative, additional testing of MPL and CALR mutations should be performed. Alternatively, molecular testing using a multi-gene NGS panel that includes JAK2, MPL and CALR can be used as part of the initial work-up in all patients. The guidelines also state that NGS may also be useful to establish the clonality in certain circumstances and may identify second, third and fourth mutations that may hold prognostic relevance. (p. MPN-1) Tumor Specific BCR/ABL Kinase Domain Analysis National Comprehensive Cancer Network (NCCN) The NCCN guidelines on chronic myeloid leukemia (1.2023) outline recommended methods for diagnosis and treatment management of chronic myelogenous leukemia, including BCR/ABL1 tests for diagnosis, monitoring, and ABL kinase domain single nucleotide variants. BCR/ABL1 kinase domain mutation analysis is recommended, among other times, when patients fail to meet milestones related to disease response, the disease has progressed to the accelerated or blast phase, or there are clinical signs of loss of complete cytogenetic response. (p. CML-E) The NCCN guidelines for acute lymphoblastic leukemia (1.2022) recommend somatic genetic testing for all patients with ALL, as Ph-like ALL has a phenotype associated with recurrent gene fusions/mutations which may guide TKI treatment decision-making. (p. ALL-1 and ALL-1A) 34 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 Similar recommendations are made in the NCCN guidelines for pediatric acute lymphoblastic leukemia (1.2022). (p. PEDALL-1 and PEDALL-1A) Tumor Specific BCR/ABL Quantitation and Breakpoint Analysis National Comprehensive Cancer Network (NCCN) The NCCN guidelines on pediatric acute lymphocytic leukemia (1.2022) recommend that the presence of recurrent genetic abnormalities, specifically BCR-ABL1 and ETV6-RUNX1, should be evaluated using karyotyping, FISH, or RT-PCR. They further recommend that if testing for those recurrent genetic abnormalities is negative, additional testing for recurrent genetic abnormalities is encouraged in some patients and may aid in risk stratification. (p. PEDALL-1 and PEDALL-1A) The NCCN guidelines on acute lymphocytic leukemia (1.2022) recommend that the presence of recurrent genetic abnormalities, specifically BCR-ABL1, should be evaluated using karyotyping, FISH, or RT-PCR. They further recommend that if testing for BCR-ABL1 is negative, additional testing for recurrent genetic abnormalities associated with Ph-like ALL is essential. (p. ALL-1 and ALL-1A) The NCCN guidelines on B-cell lymphomas (2.2023) include molecular testing for BCR-ABL as one of the essential steps in diagnostic testing for lymphoblastic lymphoma. (p. BLAST-1). The NCCN guidelines for myeloproliferative neoplasms (3.2022) recommend evaluation for BCR-ABL1 to exclude a diagnosis of CML. (p. MPN-1) The NCCN guidelines of acute myeloid leukemia (3.2022) recommend BCR-ABL1 testing to assist in risk stratification of AML. (p. AML-A 1 of 4) The NCCN guidelines for chronic myeloid leukemia (1.2023) recommend quantitative RT-PCR testing for BCR/ABL1 for patients undergoing work-up for CML. (p. CML-1) Tumor Specific BRAF Variant Analysis National Comprehensive Cancer Network (NCCN) The NCCN guidelines on Thyroid Carcinoma (3.2022) recommend molecular diagnostic testing for evaluating FNA results that are suspicious for follicular cell neoplasms or AUS/FLUS. Additionally they comment that molecular testing has shown to be beneficial when making targeted therapy decisions. The guideline also comments that individuals with anaplastic thyroid 35 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 cancer and/or metastatic disease should undergo molecular testing including BRAF, NTRK, ALK, RET and tumor mutational burden if not previously done. (p. ANAP-1, p. PAP-9, p. FOLL-8, p. HURT-8) The NCCN guideline on Hairy Cell Leukemia (1.2023) recommends molecular testing for BRAF V600E as a useful part of diagnostic work-up for individuals that do not have cHCL[classical hairy cell leukemia]immunophenotype. (p. HCL-1) The NCCN guideline on Cutaneous Melanoma (1.2023) recommends BRAF mutation testing in patients with stage III cutaneous melanoma at high risk for recurrence. Additionally, the panel strongly encourages testing for BRAF and KIT gene mutations in all patients with stage IV melanoma as this could impact treatment options. (ME-C 4 of 8) The NCCN guideline on Central Nervous System Cancers (2.2022) states that BRAF fusion and/or mutation testing is clinically indicated in patients with low-grade glioma or pilocytic astrocytoma. (p. GLIO-1). The NCCN guidelines for Non-Small Cell Lung Cancer (2.2023) recommend molecular testing including BRAF analysis for advanced or metastatic adenocarcinoma, large cell, NSCLC not otherwise specified, or squamous cell carcinoma. (p. NSCL-18) The NCCN guidelines for Colon Cancer (3.2022) recommends BRAF mutation testing (among other genetic testing) for suspected or proven metastatic synchronous adenocarcinoma. (p. COL- 4) Tumor Specific BRCA1/2 Variant Analysis National Comprehensive Cancer Network (NCCN) The NCCN guideline on Ovarian Cancer, Including Fallopian Tube Cancer and Primary Peritoneal Cancer (1.2023) recommends that all patients with ovarian cancer, fallopian tube cancer or primary peritoneal cancer should have genetic risk evaluation and germline and somatic testing of BRCA1 and BRCA2 if not previously done. (p. OV-1) In addition to BRCA1/2 testing, other methods for evaluating HR deficiency status (e.g. genomic instability, loss of heterozygosity) can be considered. Additional somatic tumor testing can be considered at the physician’s discretion to identify genetic alterations for which FDA-approved tumor specific or tumor-agnostic targeted therapy options exist. (p. OV-B 1 of 3) The NCCN guideline on Prostate Cancer (1.2023) recommend evaluating tumor for alterations in homologous recombination DNA repair genes such as BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, CHEK2 and CDK12 in patients with metastatic prostate cancer and tumor testing for MSI-H and/or dMMR can be considered. (p. PROS-C, 3 of 3) 36 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 American Society of Clinical Oncology (ASCO) ASCO (2020) published the following recommendations for somatic and germline genetic testing for women diagnosed with ovarian cancer: ● All women diagnosed with epithelial ovarian cancer should have germline genetic testing for BRCA1/2 and other ovarian cancer susceptibility genes. In women who do not carry a germline pathogenic or likely pathogenic BRCA1/2 variant, somatic tumor testing for BRCA1/2 pathogenic or likely pathogenic variants should be performed. Women with identified germline or somatic pathogenic or likely pathogenic variants in BRCA1/2 genes should be offered treatments that are US Food and Drug Administration (FDA) approved in the upfront and the recurrent setting. (Recommendation 1.2, p. 6) ● Women diagnosed with clear cell, endometrioid, or mucinous ovarian cancer should be offered somatic tumor testing for mismatch repair deficiency (dMMR). Women with identified dMMR should be offered FDA-approved treatment based on these results. (Recommendation 1.2, p. 6) ● Genetic evaluations should be conducted in conjunction with health care providers familiar with the diagnosis and management of hereditary cancer. (Recommendation 1.4, p. 6) ● First- or second-degree blood relatives of a patient with ovarian cancer with a known germline pathogenic cancer susceptibility gene variant should be offered individualized genetic risk evaluation, counseling, and genetic testing. (Recommendation 1.5, p. 6) ● Clinical decision making should not be made based on a variant of uncertain significance. (p. 2) ● Women with epithelial ovarian cancer should have testing at the time of diagnosis. (p. 2) Tumor Specific CALR Variant Analysis National Comprehensive Cancer Network (NCCN) The NCCN guidelines on myeloproliferative neoplasms (3.2022) recommend that FISH or RT- PCR to detect BCR-ABL1 transcripts is recommended to exclude the diagnosis of CML (p. MS- 6). Additionally, they recommend that molecular testing for JAK2 mutations is recommended in initial work-up for all patients with suspected MPN. They further recommend that if testing for JAK2 mutations is negative, additional testing of MPL and CALR mutations should be performed. Alternatively, molecular testing using a multi-gene NGS panel that includes JAK2, MPL and CALR can be used as part of the initial work-up in all patients. The guidelines also state that NGS may also be useful to establish the clonality in certain circumstances and may identify second, third and fourth mutations that may hold prognostic relevance. (p. MS-7) 37 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 Tumor Specific CEBPA Variant Analysis National Comprehensive Cancer Network (NCCN) The NCCN guidelines on acute myeloid leukemia (3.2022) state that a variety of gene mutations are associated with specific prognoses and may guide medical decision making while other mutations may have therapeutic implications. Presently this includes c-KIT, FLT-ITD, FLT-TKD, NPM1, CEBPA, IDH1/IDH2, RUNX1, ASXL1, and TP53. Additionally, they recommend that ASXL1, BCR-ABL1 and PML-RAR alpha be tested in all patients and further recommend that multiplex gene panels and NGS analysis be used for a comprehensive prognostic assessment. (p. MS-3) Tumor Specific EGFR Variant Analysis National Comprehensive Cancer Network (NCCN) The NCCN guidelines on Non-Small Cell Lung Cancer (2.2023) state that molecular testing for EGFR mutations should be performed when adjuvant TKI therapy is a consideration for NSCLC stage IB–IIIA. While the testing process may be technically easier on a resection specimen, initial diagnostic biopsy specimens are also acceptable for testing for this indication. (p. NSCL- H, 3 of 7) Tumor Specific ESR1 Variant Analysis The NCCN guidelines on Breast Cancer (2.2023) recommend that post-menopausal females or adult males with ER-positive, HER2-negative, ESR1-mutation breast cancer that have progressed following one or two lines of endocrine therapy, including one line containing a CDK4/6 inhibitor, be considered for treatment with Elacestrant. (p. BINV-Q 6 of 14) Tumor Specific FLT3 Variant Analysis National Comprehensive Cancer Network (NCCN) The NCCN guidelines on acute myeloid leukemia (3.2022) state that a variety of gene mutations are associated with specific prognoses and may guide medical decision making while other mutations may have therapeutic implications. Presently this includes c-KIT, FLT-ITD, FLT-TKD, NPM1, CEBPA, IDH1/IDH2, RUNX1, ASXL1, and TP53. Additionally, they recommend that 38 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 ASXL1, BCR-ABL1 and PML-RAR alpha be tested in all patients and further recommend that multiplex gene panels and NGS analysis be used for a comprehensive prognostic assessment. (p. MS-3) Tumor Specific IDH1 and IDH2 Variant Analysis National Comprehensive Cancer Network (NCCN) The NCCN guidelines on acute myeloid leukemia (3.2022) state that a variety of gene mutations are associated with specific prognoses and may guide medical decision making while other mutations may have therapeutic implications, including IDH1/IDH2.. (p. EVAL-1) The NCCN guideline on Central Nervous System Cancers (2.2022) states that IDH mutation testing (IDH1 and IDH2) is required for the work-up for all gliomas. (p. BRAIN-F 2 of 10) Tumor Specific IGHV Somatic Hypermutation Analysis The NCCN chronic lymphocytic leukemia/small lymphocytic lymphoma guidelines (2.2023) state that molecular testing for the immunoglobulin heavy chain variable region gene (IGHV) is useful for prognostic and/or therapy determination. (p. CSLL-1) The NCCN B-cell lymphomas guidelines (2.2023) recommend IGHV sequencing for individuals with mantle cell lymphoma, (p. MANT-1) These guidelines also state that molecular analysis of immunoglobulin gene rearrangements can be useful under some circumstances for patients with post-transplant lymphoproliferative disorders. (p. PTLD-1) The NCCN primary cutaneous B-cell lymphomas guidelines (1.2023) state that flow cytometry or IGH gene rearrangement studies can be of use for patients with primary cutaneous B-cell lymphoma, if adequate biopsy material is available. (p. CUTB-1) Tumor Specific JAK2 Variant Analysis National Comprehensive Cancer Network (NCCN) The NCCN guidelines on Myeloproliferative Neoplasms (3.2022) recommend that FISH or RT- PCR to detect BCR-ABL1 transcripts to exclude the diagnosis of CML (p. MS-6). Additionally, they recommend molecular testing for JAK2 mutations in the initial work-up for all patients with 39 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 suspected MPN. They further recommend that if testing for JAK2 mutations is negative, additional testing of MPL and CALR mutations should be performed. Alternatively, molecular testing using a multi-gene NGS panel that includes JAK2, MPL and CALR can be used as part of the initial work-up in all patients. The guidelines also state that NGS may also be useful to establish the clonality in certain circumstances and may identify second, third and fourth mutations that may hold prognostic relevance. (p. MS-7) The NCCN guidelines on Pediatric Acute Lymphoblastic Leukemia (1.2022) recommend that those with the Ph-like phenotype is associated with recurrent gene fusions and mutations that activate tyrosine kinase pathways and includes gene fusions involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, or PDGFRB and mutations involving FLT3, IL7R, SH2B3, JAK1, JAK3, and JAK2 (in combination with CRLF2 gene fusions). Testing for these abnormalities at diagnosis may aid in risk stratification. (p. ALL-1A) The NCCN guidelines for Myelodysplastic Syndromes (1.2023) list JAK2 as a potentially mutated gene in MDS. (p. MDS-C 2 of 3) Tumor Specific KIT Variant Analysis National Comprehensive Cancer Network (NCCN) The NCCN guideline on Cutaneous Melanoma (1.2023) recommends BRAF mutation testing in patients with stage III cutaneous melanoma at high risk for recurrence. Additionally, the panel strongly encourages testing for BRAF and KIT gene mutations in all patients with stage IV melanoma as this could impact treatment options. They further recommend that if feasible, broader genomic profiling with NGS panels be performed in individuals with stage IV or recurrent melanoma especially if the test results could guide future treatment options. (p. ME-C, 4 of 8) Current NCCN guidelines for Gastrointestinal Stromal Tumors (2.2022) recommend KIT mutation analysis to aid in diagnosis of and treatment selection for a gastrointestinal stromal tumor. (p. GIST-B) The NCCN guideline on Acute Myeloid Leukemia (3.2022) recommends all patients should be tested for mutations in these genes, and multiplex gene panels and comprehensive next- generation sequencing (NGS) analysis are recommended for the ongoing management of AML and various phases of treatment. Presently, c-KIT, FLT3-ITD, FLT3-TKD, NPM1, CEBPA (biallelic), IDH1/IDH2, RUNX1, ASXL1, TP53, BCR-ABL, and PML-RAR alpha are included in this group. (p. MS-3) 40 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 The NCCN guidelines for systemic mastocytosis (2.2022) recommends that all patients presenting with signs or symptoms of mastocytosis undergo molecular testing for KIT mutations. (p. SM-1) Tumor Specific KRAS Variant Analysis National Comprehensive Cancer Network (NCCN) The NCCN guideline on Colon Cancer (3.2022) all patients with metastatic colorectal cancer should have tumor genotyped for RAS (KRAS and NRAS) and BRAF mutations individually or as part of an NGS panel. Patients with any known KRAS mutation (exon 2, 3, 4) or NRASmutation (exon 2, 3, 4) should not be treated with either cetuximab or panitumumab. BRAF V600E mutation makes response to panitumumab or cetuximab highly unlikely unless given with a BRAF inhibitor. (p.COL-B 4 of 8) The NCCN guideline on Non-Small Cell Lung Cancer(2.2023) strongly advises broader molecular profiling with the goal of identifying rare driver mutations for which effective drugs may already be available, or to appropriately counsel patients regarding the availability of clinical trials. The following genes are recommended - EGFR mutation, ALK, KRAS, ROS1, BRAF, NTRK1/2/3, METex14 skipping, RET, ERBB2 (HER2). (p. NSCL- 18) American Society of Clinical Oncology (ASCO), College of American Pathologists (CAP), and Association for Molecular Pathology (AMP) ASCO, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology (2017) published the following recommendations for the use of molecular biomarkers for the evaluation of colorectal cancer: ● Patients with CRC considered for anti-EGFR therapy must receive RAS mutational testing. Mutational analysis should include KRAS and NRAS codons 12 and 13 of exon 2, 59 and 61 of exon 3, and 117 and 146 of exon 4. (p. 193) ● BRAF p.V600 (BRAF c.1799 [p.V600]) mutational analysis should be performed in CRC tissue in patients with CRC for prognostic stratification (p. 201) ● BRAF p.V600 mutational analysis should be performed in dMMR tumors with loss of MLH1 to evaluate for Lynch syndrome risk. Presence of a BRAF mutation strongly favors a sporadic pathogenesis. The absence of BRAF mutation does not exclude risk of Lynch syndrome. (p. 201) ● Clinicians should order MMR status testing in patients with CRCs for the identification of patients at high risk for Lynch syndrome and/or prognostic stratification. (p. 192) 41 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 ● There is insufficient evidence to recommend BRAF c.1799 p.V600 mutational status as a predictive molecular biomarker for response to anti-EGFR inhibitors. (p. 192) Tumor Specific MGMT Methylation Analysis National Comprehensive Cancer Network (NCCN) The NCCN guideline on Central Nervous System Cancers (2.2022) recommends molecular testing of glioblastoma, because if a driver mutation (such as BRAF V600E-activating mutations, or NTRK fusions) is detected, it may be reasonable to treat with a targeted therapy on a compassionate use basis and/or the patient may have more treatment options in the context of a clinical trial. Molecular testing also has a valuable role in improving diagnostic accuracy and prognostic stratification that may inform treatment selection. The panel also recommends IDH mutation testing in patients with glioma. (p. BRAIN-F, 2 of 10) Tumor Specific MLH1 Methylation Analysis National Comprehensive Cancer Network (NCCN) The NCCN guideline on Genetic/Familial High-Risk Assessment: Colorectal (2.2022) states that patients with colorectal or endometrial (uterine) cancer with tumors that show abnormal MLH1 IHC should have testing for MLH1 promoter methylation. Hypermethylation of the MLH1 promoter in these tumors has been associated with sporadic cancer, and not Lynch syndrome (p. LS-A 1 of 8). American Society of Clinical Oncology (ASCO) ASCO (2015) endorsed the following guidelines related to MSI, BRAF, and MLH1 testing in the assessment of CRC: ● Tumor testing for DNA mismatch repair (MMR) deficiency with immunohistochemistry for MMR proteins and/or MSI should be assessed in all CRC patients. As an alternate strategy, tumor testing should be carried out in individuals with CRC younger than 70 years, or those older than 70 years who fulfill any of the revised Bethesda guidelines. (p. 210) ● If loss of MLH1/PMS2 protein expression is observed in the tumor, analysis of BRAF V600E mutation or analysis of methylation of the MLH1 promoter should be carried out first to rule out a sporadic case. If the tumor is MMR deficient and somatic BRAF 42 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 mutation is not detected or MLH1 promoter methylation is not identified, testing for germline mutations is indicated. (p. 210) Tumor Specific MPL Variant Analysis National Comprehensive Cancer Network (NCCN) The NCCN guideline on myeloproliferative neoplasms (3.2022) recommends molecular testing (blood or bone marrow) for JAK2 V617F mutation; if negative, test for CALR and MPL mutations (for patients with essential thrombocythemia and myelofibrosis) and JAK2 exon 12 mutations (for patients, with polycythemia vera) or molecular testing using multigene NGS panel that includes JAK2, CALR, and MPL. (p. MPN-1) Tumor Specific Microsatellite Instability (MSI) Analysis National Comprehensive Cancer Network (NCCN) The NCCN guidelines for Colon Cancer (3.2022) recommend determination of tumor MMR and MSI in all individuals with colorectal cancer. (p. COL-B 4 of 8) The NCCN guidelines for Uterine Neoplasms (1.2023) recommend MSI (among other studies) for patients with endometrial carcinoma. (p. ENDO-A 2 of 4) The NCCN guideline on Gastric Cancer (2.2022) recommends MSI testing for all newly diagnosed gastric cancers. (p. GAST-1) The NCCN guideline on Esophageal and Esophagogastric Junction Cancer (5.2022) recommends MSI by PCR or NGS for patients with locally advanced, recurrent, or metastatic esophageal and EGJ cancers. (p. ESOPH-B 4 of 6) The NCCN guidelines for Cervical Cancer (1.2023) recommend MSI testing for patients with progressive, recurrent, or metastatic disease. (p. CERV-A 1 of 3) The NCCN guideline for Testicular Cancer (1.2023) recommends MSI testing in individuals with nonseminoma testicular cancer who have had progression after high-dose chemotherapy or third line therapy. (p. TEST-15) The NCCN guidelines for Hepatobiliary Cancers (5.2022) recommends MSI testing for unresectable or metastatic gallbladder cancer (p. GALL-5) or unresectable or metastatic intrahepatic cholangiocarcinoma (p. INTRA-1) or extrahepatic cholangiocarcinoma. (p. EXTRA- 1) 43 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 The NCCN guidelines for Breast Cancer (2.2023) can be considered for patients with unresectable or metastatic breast cancer when considering pembrolizumab as treatment. (p. BINV-R 1 of 3) The NCCN guidelines for Small Bowel Adenocarcinoma (1.2023) recommend universal MSI testing for all patients with newly diagnosed small bowel adenocarcinoma. (p. SBA-B) The NCCN guidelines for an Occult Primary (3.2023) recommend MSI testing as part of work- up for patients with a suspected metastatic malignancy of unknown or uncertain etiology. (p. OCC-1) Tumor Specific NPM1 Variant Analysis National Comprehensive Cancer Network (NCCN) The NCCN guidelines on acute myeloid leukemia (3.2022) state that a variety of gene mutations are associated with specific prognoses and may guide medical decision making while other mutations may have therapeutic implications. Presently this includes c-KIT, FLT-ITD, FLT-TKD, NPM1, CEBPA, IDH1/IDH2, RUNX1, ASXL1, and TP53. Additionally, they recommend that ASXL1, BCR-ABL1 and PML-RAR alpha be tested in all patients and further recommend that multiplex gene panels and NGS analysis be used for a comprehensive prognostic assessment. (p. MS-3) Tumor Specific NRAS Variant Analysis American Society of Clinical Oncology (ASCO), College of American Pathologists (CAP), and Association for Molecular Pathology (AMP) ASCO, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology (2017) published the following recommendations for the use of molecular biomarkers for the evaluation of colorectal cancer: ● Patients with CRC considered for anti-EGFR therapy must receive RAS mutational testing. Mutational analysis should include KRAS and NRAS codons 12 and 13 of exon 2, 59 and 61 of exon 3, and 117 and 146 of exon 4. (p.193) ● BRAF p.V600 (BRAF c.1799 [p.V600]) mutational analysis should be performed in CRC tissue in patients with CRC for prognostic stratification. (p. 201) ● BRAF p.V600 mutational analysis should be performed in dMMR tumors with loss of MLH1 to evaluate for Lynch syndrome risk. Presence of a BRAF mutation strongly 44 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 favors a sporadic pathogenesis. The absence of BRAF mutation does not exclude risk of Lynch syndrome. (p. 201) Clinicians should order MMR status testing in patients with CRCs for the identification of patients at high risk for Lynch syndrome and/or prognostic stratification. (p. 192) ● ● There is insufficient evidence to recommend BRAF c.1799 p.V600 mutational status as a predictive molecular biomarker for response to anti-EGFR inhibitors. (p. 192) National Comprehensive Cancer Network (NCCN) The NCCN guideline on Colon Cancer (3.2022) recommends that all patients with metastatic colorectal cancer should have tumor genotyped for RAS (KRAS and NRAS) and BRAF mutations individually or as part of an NGS panel. (p. COL-B 4 of 8) Tumor Specific PIK3CA Variant Analysis National Comprehensive Cancer Network (NCCN) The NCCN guidelines on breast cancer (2.2023) recommends that recurrent or stage IV HR- positive/HER2-negative breast cancers be assessed for PIK3CA mutations with tumor or liquid biopsy to identify candidates for Alpelisib + fulvestrant. They also recommend that recurrent or stage IV MSH-H/dMMR breast cancers that have progressed following prior treatment be considered for treatment with Pembrolizumab. (p. BINV-R 1 of 3) The NCCN guidelines on uterine neoplasms (1.2022) recommend for Rhabdomyosarcoma, DICER1 mutations are present in up to 95% of embryonal RMS. PIK3CA and TP53 mutations in pleomorphic tumors. And FOXO1 fusion in alveolar tumors. (p. UTSARC-A 7 of 8) Tumor Specific RET Variant Analysis National Comprehensive Cancer Network (NCCN) The NCCN guidelines on thyroid carcinoma (3.2022) recommend molecular diagnostic testing for evaluating FNA results that are suspicious for follicular cell neoplasms or AUS/FLUS and somatic RET testing in all individuals with newly diagnosed medullary thyroid carcinoma. Additionally they comment that molecular testing has shown to be beneficial when making targeted therapy decisions. (p. THYR-B) The guideline also comments that individuals with anaplastic thyroid cancer and/or metastatic disease should undergo molecular testing including BRAF, NTRK, ALK, RET and tumor mutational burden if not previously done. (p. ANAP-3) 45 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 The NCCN guideline on non-small cell lung cancer (2.2023) recommends analysis for RET gene rearrangements, noting that NGS-based methodology has a high specificity and that RNA-based NGS is preferable to DNA-based NGS for fusion detection. (p. NSCL-H, 5 of 7) Tumor Specific TP53 Variant Analysis National Comprehensive Cancer Network (NCCN) The NCCN guidelines on acute myeloid leukemia (3.2022) state that a variety of gene mutations are associated with specific prognoses and may guide medical decision making while other mutations may have therapeutic implications. Presently this includes c-KIT, FLT-ITD, FLT-TKD, NPM1, CEBPA, IDH1/IDH2, RUNX1, ASXL1, and TP53. Additionally, they recommend that ASXL1, BCR-ABL1 and PML-RAR alpha be tested in all patients and further recommend that multiplex gene panels and NGS analysis be used for a comprehensive prognostic assessment. (p. MS-3) The NCCN guidelines on B-cell lymphoma (2.2023) recommend TP53 mutation analysis for patients with a diagnosis of mantle cell lymphoma in order to direct treatment selection, as patients with a TP53 mutation have been associated with poor prognosis when treated with conventional therapy. (p. MANT-1) The NCCN guidelines for chronic lymphocytic leukemia/small lymphocytic lymphoma (2.2023) recommend TP53 sequencing analysis and IGHV mutation analysis to inform prognosis and therapeutic options for patients diagnosed with CLL/SLL or upon progression or recurrence (p. CSLL-1). Minimal residual disease testing at the end of treatment for CLL is recommended. (p. CSLL-2, 2 of 2) Measurable (Minimal) Residual Disease (MRD) Analysis National Comprehensive Cancer Network (NCCN) The NCCN guidelines for acute lymphoblastic leukemia (1.2022) recommend baseline flow cytometric and/or molecular characterization of leukemic clone to facilitate subsequent minimal/measurable residual disease (MRD) analysis (p. ALL-1). After treatment induction, MRD is recommended to determine consolidation therapy (p. ALL-3). For surveillance on bone marrow aspirate, MRD assessment is recommended (p. ALL-6). The NCCN guidelines for multiple myeloma (3.2023) recommend consideration of MRD testing by NGS in the initial diagnostic workup (p. MYEL-1) or follow up/surveillance, prognostication 46 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 (p. MYEL-4). The NCCN guidelines for chronic lymphocytic leukemia/small lymphocytic lymphoma (3.2022) recommend minimal residual disease testing at the end of treatment for CLL/SLL. MRD evaluation should be performed using an assay with a sensitivity of 10-4 according to the standardized ERIC method or standardized NGS method (p. CSLL-E 1 of 2). Tumor Mutational Burden (TMB) National Comprehensive Cancer Network (NCCN) The NCCN guidelines for Breast Cancer (2.2023) recommend consideration of tumor mutation burden testing for patients for whom pembrolizumab is being considered for treatment. (p. BINV-R 1 of 3) The NCCN guidelines for Cervical Cancer (1.2023) recommend consideration of tumor mutation burden testing for patients for whom pembrolizumab is being considered for treatment. (p. CERV-F 1 of 3) The NCCN guidelines for Hepatobiliary Cancers (5.2022) recommend tumor mutational burden testing for unresectable or metastatic gallbladder cancer. (p. GALL-5) These guidelines also recommend tumor mutational burden testing for unresectable or metastatic intrahepatic cholangiocarcinoma (p. INTRA-1) and unresectable or metastatic extrahepatic cholangiocarcinoma. (p. EXTRA-1) The NCCN guidelines for Occult Primary Cancers (3.2023) recommends consideration of tumor mutational burden testing for patients with suspected metastatic malignancy of uncertain pathology. (p. OCC-1) The NCCN guidelines for Ovarian Cancer, Including Fallopian Tube Cancer and Primary Peritoneal Cancer (1.2023) recommend tumor analysis, including tumor mutational burden, for recurrent ovarian/Fallopian tube/primary peritoneal cancer. (p. OV-B 1 of 3) The NCCN guidelines for Pancreatic Adenocarcinoma (2.2022) recommend testing tumor mutational burden for patients with locally advanced and metastatic pancreatic cancer as pembrolizumab may be considered for treatment. (p. PANC-F 6 of 9) The NCCN guideline for Prostate Cancer (1.2023) states that tumor mutational burden testing may be considered for patients with metastatic castration-resistant prostate cancer. (p. PROS-C 3 of 3) 47 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 The NCCN guidelines for Testicular Cancer (1.2023) recommend tumor mutational burden testing for patients with nonseminoma testicular cancer who have experienced disease progression after high-dose chemotherapy or third-line therapy. (p. TEST-15) The NCCN guidelines for Uterine Neoplasms (1.2022) recommend consideration of tumor mutational burden testing for patients with endometrial cancer (p. ENDO-A 2 of 4). The guidelines also recommend tumor mutational burden testing be done for patients with uterine sarcoma. (p. UTSARC-A 1 of 8) Red Blood Cell Genotyping in Multiple Myeloma Association for the Advancement of Blood and Biotherapies The AABB (Association for the Advancement of Blood and Biotherapies; formerly known as the American Association of Blood Banks) published Association Bulletin #16-02 on January 15 2016 (updated July 2022) recommending that all patients should undergo baseline phenotype and genotype prior to initiation of anti-CD38 monoclonal antibody treatment (daratumumab) to mitigate the potential of anti-CD38 interference with serologic testing. The bulletin also notes that this genotyping can be performed after the initiation of treatment. (p. 2 and 3) Cancer Exome and Genome Sequencing None of the National Comprehensive Cancer Network (NCCN) guidelines currently recommend or address performing cancer exome and/or genome sequencing as part of evaluation for cancers or tumors. Genetic Testing to Confirm the Identity of Laboratory Specimens None of the National Comprehensive Cancer Network (NCCN) guidelines currently recommend or address performing separate genetic testing to confirm the identity of laboratory specimens. Reviews, Revisions, and Approvals Policy developed back to top Revision Date 03/23 Approval Date 03/23 48 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 REFERENCES 1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 2.2023. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf 2. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 3.2022. http://www.nccn.org/professionals/physician_gls/PDF/colon.pdf 3. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal. Version 2.2022. https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf 4. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 2.2023. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf 5. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer, Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf 6. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Myelodysplastic Syndromes. Version 1.2023 https://www.nccn.org/professionals/physician_gls/pdf/mds.pdf 7. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma. Version 2.2022. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf 8. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Gastrointestinal Stromal Tumors (GISTs). Version 2.2022. https://www.nccn.org/professionals/physician_gls/pdf/gist.pdf 9. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Cutaneous Melanoma. Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf 10. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia. Version 3.2022. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf 11. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Systemic Mastocytosis. Version 2.2022 https://www.nccn.org/professionals/physician_gls/pdf/mastocytosis.pdf 12. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Myeloproliferative Neoplasms. Version 3.2022 https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf 49 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 13. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. Version 3.2022. https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf 14. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Uterine Neoplasms. Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf 15. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Chronic Myeloid Leukemia. Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf 16. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Pediatric Acute Lymphoblastic Leukemia. Version 1.2022. https://www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf 17. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Acute Lymphoblastic Leukemia. Version 1.2022. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf 18. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in B-Cell Lymphomas. Version 2.2023. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf 19. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Hairy Cell Leukemia. Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/hairy_cell.pdf 20. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Central Nervous System Cancers. Version 2.2022. https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf 21. Li MM, Chao E, Esplin ED, et al. Points to consider for reporting of germline variation in patients undergoing tumor testing: a statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2020;22(7):1142-1148. doi:10.1038/s41436-020-0783-8 22. Konstantinopoulos PA, Norquist B, Lacchetti C, et al. Germline and Somatic Tumor Testing in Epithelial Ovarian Cancer: ASCO Guideline. J Clin Oncol. 2020;38(11):1222- 1245. doi:10.1200/JCO.19.02960 23. Stoffel EM, Mangu PB, Gruber SB, et al. Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. J Clin Oncol. 2015;33(2):209-217. doi:10.1200/JCO.2014.58.1322 24. Sepulveda AR, Hamilton SR, Allegra CJ, et al. Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology. J Mol Diagn. 2017;19(2):187-225. doi:10.1016/j.jmoldx.2016.11.001 50 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 25. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf 26. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer. Version 2.2022. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf 27. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Esophageal and Esophagogastric Junction Cancer. Version 5.2022. https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf 28. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia. Version 2.2023. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf 29. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer. Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf 30. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Hepatobiliary Cancers. Version 5.2022. https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf 31. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Occult Primary (Cancer of Unknown Primary [CUP]). Version 3.2023. https://www.nccn.org/professionals/physician_gls/pdf/occult.pdf 32. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Testicular Cancer. Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/testicular.pdf 33. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. Version 3.2023. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf 34. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Small Bowel Adenocarcinoma. Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/small_bowel.pdf 35. National Comprehensive Cancer Network. Biomarker Compendium. https://www.nccn.org/professionals/biomarkers/content/ 9/15/2022. 36. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Primary Cutaneous B-Cell Lymphomas. Version 1.2023. https://www.nccn.org/professionals/physician_gls/pdf/primary_cutaneous.pdf 37. Association for the Advancement of Blood and Biotherapies Association Bulletin #16- 02: Mitigating the Anti-CD38 Interference with Serologic Testing. (2016, January 15). https://www.aabb.org/docs/default-source/default-document- library/resources/association-bulletins/ab16-02.pdf 51 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 back to top Important Reminder This clinical policy has been developed by appropriately experienced and licensed health care professionals based on a review and consideration of currently available generally accepted standards of medical practice; peer-reviewed medical literature; government agency/program approval status; evidence-based guidelines and positions of leading national health professional organizations; views of physicians practicing in relevant clinical areas affected by this clinical policy; and other available clinical information. The Health Plan makes no representations and accepts no liability with respect to the content of any external information used or relied upon in developing this clinical policy. This clinical policy is consistent with standards of medical practice current at the time that this clinical policy was approved. “Health Plan” means a health plan that has adopted this clinical policy and that is operated or administered, in whole or in part, by Centene Management Company, LLC, or any of such health plan’s affiliates, as applicable. The purpose of this clinical policy is to provide a guide to medical necessity, which is a component of the guidelines used to assist in making coverage decisions and administering benefits. It does not constitute a contract or guarantee regarding payment or results. Coverage decisions and the administration of benefits are subject to all terms, conditions, exclusions and limitations of the coverage documents (e.g., evidence of coverage, certificate of coverage, policy, contract of insurance, etc.), as well as to state and federal requirements and applicable Health Plan-level administrative policies and procedures. This clinical policy is effective as of the date determined by the Health Plan. The date of posting may not be the effective date of this clinical policy. This clinical policy may be subject to applicable legal and regulatory requirements relating to provider notification. If there is a discrepancy between the effective date of this clinical policy and any applicable legal or regulatory requirement, the requirements of law and regulation shall govern. The Health Plan retains the right to change, amend or withdraw this clinical policy, and additional clinical policies may be developed and adopted as needed, at any time. This clinical policy does not constitute medical advice, medical treatment or medical care. It is not intended to dictate to providers how to practice medicine. Providers are expected to exercise professional medical judgment in providing the most appropriate care, and are solely responsible for the medical advice and treatment of members/enrollees. This clinical policy is not intended to recommend treatment for members/enrollees. Members/enrollees should consult with their treating physician in connection with diagnosis and treatment decisions. 52 Concert Genetics Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies V2.2023 Date of Last Revision: 3/1/2023 Providers referred to in this clinical policy are independent contractors who exercise independent judgment and over whom the Health Plan has no control or right of control. Providers are not agents or employees of the Health Plan. This clinical policy is the property of the Health Plan. 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Note: For Medicare members/enrollees, to ensure consistency with the Medicare National Coverage Determinations (NCD) and Local Coverage Determinations (LCD), all applicable NCDs, LCDs, and Medicare Coverage Articles should be reviewed prior to applying the criteria set forth in this clinical policy. Refer to the CMS website at http://www.cms.gov for additional information. ©2023 Centene Corporation. All rights reserved. All materials are exclusively owned by Centene Corporation and are protected by United States copyright law and international copyright law. No part of this publication may be reproduced, copied, modified, distributed, displayed, stored in a retrieval system, transmitted in any form or by any means, or otherwise published without the prior written permission of Centene Corporation. You may not alter or remove any trademark, copyright or other notice contained herein. Centene® and Centene Corporation® are registered trademarks exclusively owned by Centene Corporation. 53