Concert Genetic Oncology: Cytogenetic Testing Form

Concert Genetic Oncology: Cytogenetic Testing
V1.2025
Date of Last Revision: 11/2024
CENTENE
Corporation
Revision log
Coding Implications

# CONCERT GENETIC ONCOLOGY: CYTOGENETIC TESTING

See Important Reminder at the end of this policy for important regulatory and legal
information.

## OVERVIEW

Cytogenetic analysis of solid tumors and hematologic malignancies aims to both classify the type
of tumor or cancer present and 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 (skin or buccal cells/saliva is occasionally used in patients who have received a
hematopoietic stem cell transplant).

## POLICY REFERENCE TABLE

### 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
2023, 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.

The tests, associated laboratories, CPT codes, and ICD codes contained within this document
serve only as examples to help users navigate claims and corresponding criteria; as such, they are
not comprehensive and are not a guarantee of coverage or non-coverage. Please see the Concert
Platform for a comprehensive list of registered tests.

| Criteria Sections | Example Tests (Labs) | Common CPT Codes | Common ICD Codes | Ref |
|-------------------|---------------------|-----------------|-----------------|-----|
| Tumor Specific ALK Gene Rearrangement (Qualitative FISH and PCR) Tests | ALK FISH, Non-Small cell Lung Cancer (Labcorp) | 88271, 88274 | C34, C73 | 1, 4, 21, 22, 23, 26 |
| Bladder Cancer Diagnostic and Recurrence FISH Tests | UroVysion Bladder Kit (Quest Diagnostics) | 88120, 88121 | C67, R31.9, Z85, Z85.5 | 30, 31 |
| Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) FISH Panel Analysis | FISH for Chronic Lymphocytic Leukemia (Cleveland Clinic Laboratories) | 88271, 88274, 88275, 88291 | C91, C94, C95, Z85.6 | 10 |
|  | FISH, B-Cell Chronic Lymphocytic Leukemia Panel (Quest Diagnostics) |  |  |  |
| Tumor Specific ERBB2 (HER2) Deletion/Duplication (FISH and CISH) | ERBB2 (HER2/neu) Gene Amplification by FISH with Reflex, Tissue (ARUP Laboratories) | 88360, 88377 | C08, C15, C16, C18, C19, C20, C50 | 2, 3, 5, 6, 11, 12, 14, 17, 20, 21, 25, 27 |
| Multiple Myeloma FISH Panel Analysis | Oncology FISH Analysis - Multiple Myeloma FISH Panel (Baylor Genetics, LLC) | 88237, 88271, 88275, 88291 | C90 | 13 |
|  | Multiple Myeloma (MM) Profile, FISH (Labcorp) |  |  |  |
| NTRK Fusion Analysis Panel | NTRK NGS Fusion Panel (NeoGenomics Laboratories) | 81191, 81192, 81193, 81194 | C15, C16, C18, C34, C49.9, C50, | 1, 2, 3, 4, 5, 6, 8, 9, |

|  |  |  | C51, C53, C54, C73, C80.1, C91 | 11, 12, 15, 16, 17, 18, 19, 20, 21, 23, 24, 25, 27, 32, 33 |
| Tumor Specific PD-L1 Protein Analysis | PD-L1, IHC with Interpretation (Quest Diagnostics) | 88341, 88342, 88360, 88361 | C11, C15, C16, C34, C50, C51, C53, C67 | 1, 3, 5, 6, 11, 12, 14, 15, 27, 28, 29 |
| Tumor Specific FOLR1 Protein Analysis | FOLR1 Immunohistochemistry Analysis (Labcorp) | 88360 | C56 | 20 |
| Tumor Specific PML/RARA Gene Rearrangement (Qualitative FISH and PCR) | FISH, APL, PML/RARA, Translocation 15, 17 (Quest Diagnostics) | 81315, 81316, 88271, 88274, 88275, 88291 | C91-C95 | 7 |
|  | PML/RARA (t(15;17) (NeoGenomics Laboratories) |  |  |  |
| Tumor Specific RET Gene Rearrangement Tests (FISH) | RET FISH (NeoGenomics Laboratories) | 88271, 88275, 88291, 88374, 88377 | C34, C53, C73 | 1, 2, 3, 4, 5, 6, 11, 21, 27 |
|  | Oncology FISH Analysis - RET Rearrangement (Baylor Genetics) |  |  |  |
| ]

## 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:



















### Tumor Specific RET Gene Rearrangement Tests (FISH)

I. Tumor specific RET gene rearrangement testing via fluorescent in situ hybridization
   (FISH) (88374, 88377, 88271, 88275, 88291) in solid tumors is considered medically
   necessary when:
   A. The member/enrollee has a diagnosis of:
      1. Recurrent or persistent locoregional or metastatic medullary thyroid
         cancer, AND
         a) Germline testing for RET mutations is negative or has not been
            done, OR
      2. Anaplastic thyroid carcinoma, OR
      3. Locally recurrent, advanced and/or metastatic papillary thyroid carcinoma,
         OR
      4. Locally recurrent, advanced and/or metastatic follicular thyroid
         carcinoma, OR
      5. Locally recurrent, advanced and/or metastatic oncocytic carcinoma
         (formerly called Hurtle cell carcinoma), OR
      6. Advanced or metastatic adenocarcinoma of the lung, OR
      7. Advanced or metastatic large cell cancer of the lung, OR
      8. Advanced or metastatic non-small cell cancer of the lung, not otherwise
         specified, OR
      9. Locally advanced or metastatic squamous cell carcinoma of the cervix,
         OR
      10. Locally advanced or metastatic adenocarcinoma of the cervix, OR

Concert Genetic Oncology: Cytogenetic Testing V1.2025 Date of Last Revision: 11/2024 CENTENE Corporation

11. Locally advanced or metastatic adenosquamous carcinoma of the cervix, OR
12. Recurrent unresectable or stage IV breast cancer, OR
13. Suspected or confirmed metastatic colon cancer, OR
14. Resectable, borderline resectable, locally advanced or metastatic pancreatic adenocarcinoma, OR
15. Locally advanced, recurrent or metastatic esophageal or esophagogastric junction cancer, OR
16. Locally advanced, recurrent or metastatic gastric cancer, OR
17. Recurrent or metastatic vaginal cancer.

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Tumor Specific ROS1 Gene Rearrangement I. Tumor specific ROS1 gene rearrangement analysis via fluorescent in situ hybridization (FISH) (88271, 88274) in solid tumors is considered medically necessary when: A. The member/enrollee has a diagnosis of:

1. Advanced or metastatic lung adenocarcinoma, OR
2. Advanced or metastatic large cell lung carcinoma, OR
3. Advanced or metastatic squamous cell lung carcinoma, OR
4. Advanced or metastatic non-small cell lung cancer (NSCLC) not otherwise specified (NOS), OR
5. Locally advanced or metastatic ampullary adenocarcinoma, OR
6. Resectable or borderline resectable, or locally advanced or metastatic pancreatic adenocarcinoma, OR
7. Pediatric (diagnosed age 18 years or younger) diffuse high-grade glioma.

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DEFINITIONS

1. Advanced cancer: 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.

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BACKGROUND AND RATIONALE Tumor Specific ALK Gene Rearrangement (Qualitative FISH and PCR) Tests National Comprehensive Cancer Network (NCCN)

The NCCN Thyroid Carcinoma guidelines (3.2024) recommend that individuals with anaplastic thyroid cancer should undergo molecular testing including BRAF, NTRK, ALK, RET, MSI, dMMR, and tumor mutational burden if not previously done (p. ANAP-1). ALK testing is also recommended for locally recurrent, advanced, and/or metastatic papillary thyroid carcinoma (p. PAP-10) and locally recurrent, advanced, and/or metastatic follicular thyroid carcinoma. (p. FOLL-9)

NCCN Non-Small Cell Lung Cancer guidelines (7.2024) recommend ALK rearrangement testing in patients with Stage IB-IIIA, IIIB [T3,N2] disease perioperatively for consideration of systemic therapy (p. NSCL-E, 1 of 5) as well as for patients with advanced or metastatic adenocarcinoma, large cell, squamous cell, or NSCLC not otherwise specified (NOS). (p. NSCL-19)

NCCN guidelines for Ampullary Adenocarcinoma (2.2024) recommend somatic molecular profiling for patients with locally advanced/metastatic disease if systemic therapy is being considered. Potentially actionable somatic findings include fusions involving the ALK gene. (p. AMP-3)

NCCN guidelines for Histiocytic Neoplasms (2.2024) recommends molecular testing of a tissue biopsy during the diagnostic workup for Langerhans cell histiocytosis and Erdheim-Chester disease, and suggests RNA based molecular panel including fusion testing for ALK; however if ALK rearrangement is suspected clinically, or if fusion panel testing is not available, ALK immunohistochemistry and FISH studies may be performed. (p. LCH-2, ECD-2)

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NCCN guidelines for Pancreatic Adenocarcinoma (3.2024) recommend somatic molecular profiling for patients with locally advanced/metastatic disease as well as those with resectable or borderline resectable disease if systemic therapy is being considered. Potentially actionable somatic findings include fusions involving the ALK gene. (p. PANC-1A)

NCCN guidelines for Pediatric Central Nervous System Cancers (1.2024) recommend broad molecular testing to classify pediatric diffuse high-grade gliomas. This includes detection of fusions involving the ALK gene. (p. PGLIO-B, 2 of 4)

Bladder Cancer Diagnostic and Recurrence FISH Tests Centers for Medicare and Medicaid Services

The CMS local coverage determination (LCD) entitled “Lab: Bladder/Urothelial Tumor Markers” includes the following utilization guidelines for bladder marker testing.

Regarding the UroVysion Bladder Cancer Kit: “It is used to detect chromosomal abnormalities in voided urine to assist not only in bladder cancer surveillance but also in the initial identification of bladder cancer.”

“Follow-up after initial diagnosis/most recent occurrence and treatment

• Maximum of 4 bladder tumor marker studies per year for years 1-2
• Maximum of 3 bladder tumor marker studies per year for year 3
• Maximum of 2 bladder tumor marker studies for year 4 and
• Maximum of 1 bladder tumor marker studies follow-up annually for up to 15 years.”

“For high risk patients with persistent hematuria and a negative FISH assay following a comprehensive diagnostic (no tumor identified) workup, ONE repeat FISH testing in conjunction with cystoscopy is considered reasonable and necessary within 1 year of the original attempted diagnosis.”

The CMS LCD Reference Article “Billing and Coding: Lab: Bladder/Urothelial Tumor Markers” states the following: “This A/B MAC will only cover bladder tumor marker fluorescence in situ hybridization (FISH) testing services when performed using validated assays. To date, UroVysion Bladder Cancer Kit is the only Federal Drug Administration (FDA) approved assay that is designed to detect aneuploidy for chromosomes 3, 7, 17 and loss of the 9p21 locus via FISH.

Bladder cancer tumor markers performed by any technology, immunoassay, molecular or FISH testing, are not covered for screening of all patients with hematuria.”

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Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) FISH Panel Analysis National Comprehensive Cancer Network (NCCN)

NCCN Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma guidelines (3.2024) recommend FISH testing for +12; del(11q); del(13q); del(17p) during the diagnostic workup for CLL/SLL as this information is useful for prognosis and treatment planning. (p. CSLL-1)

Tumor Specific ERBB2 (HER2) Deletion/Duplication (FISH and CISH) National Comprehensive Cancer Network (NCCN)

NCCN Esophageal and Esophagogastric Junction Cancers guidelines (4.2024) recommend HER2/ERBB2 testing using FISH or IHC for patients with inoperable locally advanced, recurrent or metastatic adenocarcinoma if trastuzumab is being considered for treatment. (p. ESOPH-B, 3 of 6)

NCCN Head and Neck Cancers guidelines (4.2024) recommend HER2/ERBB2 testing prior to treatment for individuals diagnosed with recurrent, unresectable, or metastatic salivary gland tumors. (p. SALI-4)

NCCN Colon Cancer guidelines (4.2024) recommend HER2/ERBB2 testing during the workup for suspected or proven metastatic colorectal cancer. (p. COL-2) These guidelines also recommend HER2 analysis for metastatic appendiceal adenocarcinoma. (p. COL-I 2 of 3)

NCCN Gastric Cancer guidelines (2.2024) recommend HER2/ERBB2 testing for patients with inoperable locally advanced, recurrent or metastatic adenocarcinoma of the stomach if trastuzumab is being considered. (p. GAST-B, 3 of 6)

NCCN Breast Cancer guidelines (4.2024) recommend HER2/ERBB2 testing be performed on all patients with newly diagnosed primary or metastatic breast cancer. (p. BINV-A 1 of 2)

NCCN Cervical Cancer guidelines (3.2024) recommend HER2 testing for recurrent, advanced or metastatic cervical carcinoma. (p. CERV-A 1 of 7)

NCCN Uterine Neoplasms guidelines (2.2024) recommend HER2 IHC with reflex to FISH for all serous and carcinosarcoma endometrial tumors and recommends consideration of HER2 testing for all tumors that have abnormal p53 by IHC. (p. ENDO-A, 1 of 4)

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NCCN guidelines for Pancreatic Adenocarcinoma (3.2024) indicate that testing for potentially actionable somatic findings including HER2 amplifications is recommended for patients with locally advanced or metastatic disease (p. PANC-5), recurrence after resection (p. PANC-9), and with resectable or borderline resectable disease being considered for neoadjuvant systemic therapy. (p. PANC-F, 1 of 12)

NCCN guidelines for Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer (3.2024) recommend HER2 testing by IHC for recurrent disease after primary treatment. (p. OV- 6)

NCCN guidelines for Vaginal Cancer (1.2025) recommend consideration of HER2 testing by IHC or FISH for recurrent or metastatic vaginal cancer. (p. VAG-5, VAG-6, VAG-A 2 of 2)

NCCN guidelines for Bladder Cancer (4.2024) recommend consideration of IHC for HER2 overexpression for stage IIIB or higher muscle invasive bladder cancer. (p. BL-8-10)

NCCN guidelines for Small Bowel Adenocarcinoma (4.2024) recommend testing for HER2 amplifications for patients with metastatic disease. (p. SBA-5)

Multiple Myeloma FISH Panel Analysis National Comprehensive Cancer Network (NCCN)

NCCN Multiple Myeloma guidelines (4.2024) recommend FISH testing during the initial workup of multiple myeloma for prognostic purposes. The recommended FISH testing includes: del(13), del (17p13), t(4;14), t(11;14), t(14;16), t(14;20), 1q21 gain/1q21 amplification, 1p deletion. (p. MYEL-1)

NTRK Fusion Analysis Panel National Comprehensive Cancer Network (NCCN)

The NCCN Thyroid Carcinoma guidelines (3.2024) recommend that individuals with anaplastic thyroid cancer or locally recurrent, advanced, and/or metastatic papillary, follicular, and oncocytic carcinoma (formerly called Hurthle cell carcinoma) undergo molecular testing including NTRK as part of disease workup. (p. ANAP-1, p. PAP-10, p. FOLL-9, p. ONC-9)

The NCCN Colon Cancer Guidelines (4.2024) recommend broad molecular profiling to identify rare and actionable mutations and fusions, including NTRK, for patients with suspected or proven metastatic adenocarcinoma. (p. COL-2) For individuals who are NTRK gene fusion-

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positive, NCCN lists the following biomarker-directed therapies: entrectinib, larotrectinib, and repotrectinib. (p. COL-D 2 of 11)

The NCCN Non-Small Cell Lung Cancer guidelines (7.2024) recommends NTRK molecular analysis for patients with advanced or metastatic adenocarcinoma, large cell carcinoma, and NSCLC not otherwise specified (NOS) and recommends consideration of NTRK testing for advanced or metastatic squamous cell carcinoma of the lung. (p. NSCL-19) For individuals who are NTRK gene fusion-positive, NCCN lists the following biomarker-directed therapies: entrectinib, larotrectinib, and repotrectinib. (p. NSCL-33)

The NCCN Occult Primary guidelines (1.2025) states that patients with metastatic or unresectable NTRK gene fusion positive adenocarcinomas without a known acquired resistance mutation, who have no satisfactory treatment options or who have progressed on treatment can be treated with entrectinib and/or larotrectinib or repotrectinib. (p. OCC-B, 2 of 11)

The NCCN Cervical Cancer guidelines (3.2024) recommends NTRK fusion analysis for patients with cervical sarcoma. (p. CERV-A 1 of 7)

The NCCN Vulvar Cancer guidelines (4.2024) recommends consideration of NTRK fusion analysis for recurrent, progressive, or metastatic squamous cell carcinoma of the vulva. (p. VULVA-A 2 of 4)

The NCCN Uterine Neoplasms guidelines (2.2024) recommends consideration of NTRK fusion analysis for recurrent or metastatic endometrial carcinoma (p. ENDO-A 2 of 4) or metastatic uterine sarcoma. (p. UTSARC-A 1 of 8)

The NCCN Breast Cancer guidelines (4.2024) recommend NTRK fusion testing for recurrent unresectable or stage IV disease if eligible for larotrectinib, entrectinib or repotrectinib treatment (no known resistance mutation and no satisfactory alternatives or have progressed on treatment). (p. BINV-Q 6 of 14)

The NCCN Gastric Cancer guidelines (2.2024) recommends consideration of comprehensive genomic profiling including NTRK fusion analysis for unresectable locally advanced, recurrent, or metastatic gastric cancer. (p. GAST-B 5 of 6)

The NCCN Esophageal and Esophagogastric Junction Cancer guidelines (4.2024) recommends consideration of comprehensive genomic profiling including NTRK fusion analysis for unresectable, locally advanced, recurrent, or metastatic esophageal cancer. (p. ESOPH-B 5 of 6) For individuals who are NTRK gene fusion-positive, NCCN lists the following biomarker- directed therapies: entrectinib, larotrectinib, and repotrectinib. (p. ESOPH-F 6 of 22)

The NCCN Acute Lymphoblastic Leukemia guidelines (2.2024) and Pediatric Acute Lymphoblastic Leukemia guidelines (6.2024) recommend NTRK fusion analysis for acute

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lymphoblastic leukemia (ALL) for the purposes of risk stratification. (p. ALL-3; p. PEDALL-A 1 of 2)

The NCCN Soft Tissue Sarcoma guidelines (2.2024) recommend larotrectinib, entrectinib or repotrectinib for patients with advanced or metastatic disease and NTRK gene fusion-positive tumors. (p. SARC-G 1 of 13)

The NCCN Neuroendocrine and Adrenal Tumors guidelines (2.2024) recommends consideration of NTRK fusion testing for patients with unresectable or metastatic extrapulmonary poorly differentiated neuroendocrine carcinoma/large or small cell carcinoma/mixed neuroendocrine- non-neuroendocrine neoplasm. (p. PDNEC-1) For individuals who are NTRK gene fusion- positive, NCCN lists the following biomarker-directed therapies: entrectinib, larotrectinib, and repotrectinib. (p. NE-H 5 of 9)

The NCCN Head and Neck Cancers guidelines (4.2024) recommend use of NGS profiling and other appropriate biomarker testing to evaluate NTRK prior to treatment for metastatic salivary gland tumors. (p. SALI-4)

The NCCN Hepatocellular Carcinoma guidelines (2.2024) indicate that larotrectinib, entrectinib, and repotrectinib are options for treatment in patients with NTRK gene fusion positive tumors. (p. HCC-I, 1 of 2)

The NCCN Ovarian Cancer/Fallopian Tube Cancer/ Primary Peritoneal Cancer guidelines (3.2024) recommend tumor molecular testing including NTRK testing for recurrent disease if prior testing for these markers was not done. (p. OV-6) For individuals who are NTRK gene fusion-positive, NCCN lists the following biomarker-directed therapies: entrectinib, larotrectinib, and repotrectinib. (p. OV-C 8 of 12)

The NCCN Small Bowel Adenocarcinoma guidelines (4.2024) recommends larotrectinib and entrectinib as options for subsequent-line treatment of metastatic small bowel adenocarcinoma that is NTRK gene fusion positive. (p. SBA-D 1 of 7)

The NCCN Pediatric Central Nervous System Cancers guidelines (1.2024) state that broad molecular testing is required for comprehensive classification of pediatric diffuse high-grade gliomas, including NGS with fusion detection for ROS1, MET, NTRK1/2/3, ALK, FGFR1/2/3. (p. PGLIO-B, 2 of 4)

The NCCN guidelines for Pancreatic Adenocarcinoma (3.2024) recommend testing for potentially actionable somatic findings including NTRK fusions for patients with locally advanced/metastatic disease. (p. PANC-1A) In addition, patients with resectable or borderline resectable disease who are considering systemic therapy are recommended to consider testing for somatic findings including NTRK fusions. (p. PANC-F, 1 of 12) For individuals who are NTRK

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gene fusion-positive, NCCN lists the following biomarker-directed therapies: entrectinib, larotrectinib, and repotrectinib. (p. PANC-F 3 of 12)

The NCCN guidelines for Vaginal Cancer (1.2025) recommend consideration of NTRK fusion testing for recurrent or metastatic vaginal cancer. (p. VAG-5, VAG-6, VAG-A 2 of 2)

The NCCN guidelines for Gastrointestinal Stromal Tumors (2.2024) lists the following biomarker-directed therapies for individuals with unresectable, progressive or metastatic disease: entrectinib, larotrectinib, and repotrectinib. (p. GIST-E 1 of 4)

Food and Drug Administration

The FDA label for Augtyro (repotrectinib) includes indications and usage information for the treatment of the following:

• “adult patients with locally advanced or metastatic ROS1-positive nonsmall cell lung cancer (NSCLC). (1.1)
• adult and pediatric patients 12 years of age and older with solid tumors that: ○ have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion and ○ are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity.

have progressed following treatment or have no satisfactory alternative therapy.

Tumor Specific PD-L1 Protein Analysis National Comprehensive Cancer Network (NCCN)

The NCCN Gastric Cancer guidelines (2.2024) recommends PD-L1 testing during the workup for documented or suspected metastatic adenocarcinoma. (p. GAST-1)

The NCCN Head and Neck Cancers guidelines (4.2024) state recommendations for first line therapy which could include PD-L1 inhibitors for recurrent, unresectable, oligometastatic, or metastatic cancer of the nasopharynx. (p. NASO-B 1 of 3)

The NCCN Bladder Cancer guidelines (4.2024) states recommendations for specific therapies for individuals with locally advanced or metastatic (stage IV) bladder cancer, which can include PD- L1 inhibitors. (p. BL-G 2 of 7)

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The NCCN Vulvar Cancer guidelines (4.2024) recommends consideration of PD-L1 testing for individuals with recurrent, progressive, or metastatic squamous cell carcinoma of the vulva. (p. VULVA-A 2 of 4)

The NCCN Esophageal and Esophagogastric Junction Cancers guidelines (4.2024) recommends PD-L1 testing for individuals during the workup phase for documented or suspected metastatic esophageal and esophagogastric junction cancers. (p. ESOPH-1)

The NCCN Cervical Cancer guidelines (3.2024) recommends PD-L1 testing for individuals with recurrent, progressive, or metastatic cervical cancer of the following pathologies: squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. (p. CERV-A 1 of 7)

NCCN Non-Small Cell Lung Cancer guidelines (7.2024) recommend PD-L1 testing in patients with stage IB-IIIA, IIIB [T3, N2] non-small cell lung cancer perioperatively (p. NSCL-E, 1 of 5) or for advanced or metastatic adenocarcinoma, large cell, squamous cell, and NSCLC not otherwise specified (NOS). (p. NSCL-19)

The NCCN Breast Cancer guidelines (4.2024) states recommendations for treatments for recurrent unresectable or stage IV triple negative breast cancer based on PD-L1 tumor status. (p. BINV-Q 2 of 14)

NCCN guidelines for Vaginal Cancer (1.2025) recommend consideration of PD-L1 testing for recurrent or metastatic vaginal cancer. (p. VAG-5, VAG-6, VAG-A 2 of 2).

Food and Drug Administration (FDA)

The FDA’s list of cleared or approved companion diagnostic devices lists several cancer types approved for testing via the immunohistochemistry assay for PD-L1 for the purposes of treatment decision-making. These cancer types include, in part: head and neck squamous cell carcinoma, urothelial carcinoma (PMA number 150013, supplement number S014), and triple negative breast cancer (PMA number 150013, supplement number S020).

Tumor Specific FOLR1 Protein Analysis National Comprehensive Cancer Network (NCCN)

NCCN guidelines for Ovarian Cancer/Fallopian Tube Cancer/Primary Peritoneal Cancer (3.2024) indicate that the preferred treatment regimen for platinum resistant recurrent disease includes mirvetuximab soravtansine if the tumor expresses folate receptor alpha (i.e., FOLR1). Therefore, tumor molecular analysis for this cancer type is recommended to include, at a minimum, tests to identify potential benefit from targeted therapeutics that have tumor-specific or tumor-agnostic benefit, including folate receptor alpha (FOLR1). (p. OV-C, 9 and 10 of 12)

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In the setting of recurrent disease, tumor molecular analysis is also recommended to include folate receptor alpha (FOLR1) if prior testing did not include this marker. (p. OV-6)

Tumor Specific PML/RARA Gene Rearrangement (Qualitative FISH and PCR) National Comprehensive Cancer Network (NCCN)

NCCN Acute Myeloid Leukemia guidelines (3.2024) state that many different types of gene mutations are associated with specific prognoses, helping to guide medical management decisions, and/or may indicate that specific therapeutic agents are useful. Therefore, all patients with AML should be tested for these mutations. (p. EVAL-1). The discussion section of this guideline states that PML-RAR alpha is included in this group of genetic markers that should be tested in all patients. (p. MS-4)

Tumor Specific RET Gene Rearrangement Tests (FISH) National Comprehensive Cancer Network (NCCN)

The NCCN guidelines on Thyroid Carcinoma (3.2024) recommend that patients with recurrent or persistent medullary thyroid carcinoma have somatic RET testing if germline wild type or germline unknown (p. MEDU-6). The guideline also recommends that individuals with anaplastic thyroid cancer and/or locally recurrent, advanced and/or metastatic papillary, follicular, or oncocytic carcinoma that cannot be treated with radioactive iodine should undergo molecular testing including BRAF, NTRK, ALK, RET and tumor mutational burden if not previously done. (p. ANAP-3, PAP-10, FOLL-9, ONC-9)

The NCCN guideline on Non-Small Cell Lung Cancer (7.2024) recommends analysis for RET gene rearrangements in patients with advanced or metastatic adenocarcinoma of the lung, large cell carcinoma of the lung, or NSCLC not otherwise specified and recommends consideration of RET gene testing for patients with advanced or metastatic squamous cell carcinoma of the lung (p. NSCL-19), 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 8)

The NCCN guideline for Cervical Cancer (3.2024) recommends consideration of RET gene fusion testing for patients with locally advanced or metastatic cervical cancer of the following pathologies: squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. (p. CERV-A, 1 of 7)

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NCCN guidelines for Breast Cancer (4.2024) list RET fusion as a biomarker with an FDA approved therapy for any subtype of recurrent unresectable or stage IV disease. Either tumor tissue or blood can be used for detection. (p. BINV-Q, 6 of 14)

NCCN guidelines for Colon Cancer (4.2024) recommend broad molecular profiling including RET fusion detection as part of the workup for suspected or proven metastatic adenocarcinoma. (p. COL-2)

NCCN guidelines for Pancreatic Adenocarcinoma (3.2024) recommends consideration of testing for potentially actionable somatic mutations including RET fusions for resectable or borderline resectable disease when systemic therapy is being considered (p. PANC-F, 1 of 12) and recommends this testing for locally advanced/metastatic disease. (p. PANC-1A)

NCCN guidelines for Esophageal and Esophagogastric Junction Cancers (4.2024) recommend biomarker testing for patients with locally advanced, recurrent or metastatic esophageal or esophagogastric junction cancer and lists RET gene fusion as a targeted biomarker. (p. ESOPH-B, 5 of 6)

NCCN guidelines for Gastric Cancer (2.2024) recommend biomarker testing for patients with locally advanced, recurrent or metastatic gastric cancer and lists RET gene fusion as a targeted biomarker. (p. GAST-B, of 6)

NCCN guidelines for Vaginal Cancer (1.2025) recommend consideration of RET fusion testing for recurrent or metastatic vaginal cancer. (p. VAG-A 2 of 2)

Tumor Specific ROS1 Gene Rearrangement

National Comprehensive Cancer Network (NCCN)

NCCN Non-Small Cell Lung Cancer guidelines (7.2024) recommend ROS1 rearrangement testing in patients with advanced or metastatic disease of the following lung cancer pathologies: Adenocarcinoma, Large Cell, and NSCLC not otherwise specified (NOS) and recommends consideration of this testing for patients with squamous cell carcinoma of the lung. (p. NSCL-19)

NCCN guidelines for Ampullary Adenocarcinoma (2.2024) recommend consideration of tumor molecular profiling, including ROS1 fusions, for patients with locally advanced or metastatic disease who are considering systemic therapy. (p. AMP-3)

NCCN guidelines for Pancreatic Adenocarcinoma (3.2024) recommends consideration of tumor molecular profiling including ROS1 fusions for patients with resectable or borderline resectable disease in advance of systemic therapy (p. PANC-F, 1 of 12) and recommends this testing for locally advanced or metastatic disease. (p. PANC-1A)

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NCCN guidelines for Pediatric Central Nervous System Cancers (1.2024) state that broad molecular testing is required for comprehensive classification of pediatric diffuse high-grade gliomas, including detection of fusions involving ROS1. (p. PGLIO-B, 2 of 4)

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Concert Genetic Oncology: Cytogenetic Testing V1.2025 Date of Last Revision: 11/2024

REFERENCES

1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 7.2024. https://www.nccn.org/professional/gls/pdf/nscl.pdf
2. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 4.2024. https://www.nccn.org/professionals/physician_gls/PDF/colon.pdf
3. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer. Version 3.2024. https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf
4. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. Version 3.2024. https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf
5. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf
6. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Esophageal and Esophagogastric Junction Cancer. Version 4.2024. https://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf
7. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia. Version 3.2024. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf
8. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Acute Lymphoblastic Leukemia. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf
9. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Pediatric Acute Lymphoblastic Leukemia. Version 6.2024. https://www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf
10. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia. Version 3.2024. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf
11. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 4.2024. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf

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12. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. Version 4.2024. https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf
13. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. Version 4.2024. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf
14. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. Version 4.2024. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf
15. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Vulvar Cancer. Version 4.2024. https://www.nccn.org/professionals/physician_gls/pdf/vulvar.pdf
16. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Occult Primary (Cancer of Unknown Primary [CUP]). Version 1.2025. https://www.nccn.org/professionals/physician_gls/pdf/occult.pdf
17. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Uterine Neoplasms. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf
18. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf
19. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Neuroendocrine and Adrenal Tumors. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf
20. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer, Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 3.2024. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf
21. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma. Version 3.2024. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
22. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Ampullary Adenocarcinoma. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/ampullary.pdf
23. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Pediatric Central Nervous System Cancers. Version 1.2024. https://www.nccn.org/professionals/physician_gls/pdf/ped_cns.pdf
24. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Hepatocellular Carcinoma. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/hcc.pdf

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25. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Small Bowel Adenocarcinoma. Version 4.2024. https://www.nccn.org/professionals/physician_gls/pdf/small_bowel.pdf
26. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Histiocytic Neoplasms. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/histiocytic_neoplasms.pdf
27. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Vaginal Cancer. Version 1.2025. https://www.nccn.org/professionals/physician_gls/pdf/vaginal.pdf
28. US Food and Drug Administration (FDA). Premarket Approval Document for PD-L1 IHC 22C3 pharmDx. (PMA Number: 150013. Supplement Number: S014). Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P150013S014
29. US Food and Drug Administration (FDA). Premarket Approval Document for PD-L1 IHC 22C3 pharmDx. (PMA Number: 150013. Supplement Number: S020). Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P150013S020
30. Centers for Medicare & Medicaid Services. Medicare Coverage Database: Lab: Bladder/Urothelial Tumor Markers. (L33420). Available at: https://www.cms.gov/medicare-coverage-database/database/view/lcd.aspx?Idcd=33420
31. Centers for Medicare & Medicaid Services. Medicare Coverage Database: Billing and Coding Article. MoIDx: Billing and Coding: Lab: Bladder/Urothelial Tumor Markers. (A53095). Available at: https://www.cms.gov/medicare-coverage-database/view/articleId=53095&ver=25
32. Bristol-Myers Squibb Company. Augtyro (repotrectinib). U.S. Food and Drug Administration. Website: https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/218213s001lbl.pdf Accessed 8/16/2024
33. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Gastrointestinal Stromal Tumors. Version 2.2024. https://www.nccn.org/professionals/physician_gls/pdf/gist.pdf

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

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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 member/enrollees. This clinical policy is not intended to recommend treatment for member/enrollees. Member/enrollees should consult with their treating physician in connection with diagnosis and treatment decisions.

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. Unauthorized copying, use, and distribution of this clinical policy or any information contained herein are strictly prohibited. Providers, member/enrollees, and their representatives are bound to the terms and conditions expressed herein through the terms of their contracts. Where no such contract exists, providers, member/enrollees and their representatives agree to be bound by such terms and conditions by providing services to member/enrollees and/or submitting claims for payment for such services.

Note: For Medicaid member/enrollees, when state Medicaid coverage provisions conflict with the coverage provisions in this clinical policy, state Medicaid coverage provisions take precedence. Please refer to the state Medicaid manual for any coverage provisions pertaining to this clinical policy.

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Note: For Medicare member/enrollees, to ensure consistency with the Medicare National Coverage Determinations (NCD) and Local Coverage Determinations (LCD), all applicable NCDs and 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.

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