Coverage Policy Manual
Policy #: 2007024
Category: Laboratory
Initiated: December 2007
Last Review: April 2024
  Genetic Test: HER2 Testing
Description:
Herceptin is a monoclonal antibody, one of a group of drugs designed to attack specific cancer cells. Herceptin binds to a protein called HER2 or HER2/neu, which is found on the surface of some normal cells and plays a role in regulating cell growth. It is estimated that in the United States 18-22% of women diagnosed with metastatic breast cancer have tumors that produce excessive amounts of (over express) the HER2 protein.
 
The DAKO HercepTest was the first FDA test approved to measure HER2 protein in tumors to help identify patients who may benefit from Herceptin treatment. This test is being studied in other types of cancer but would not be approved for any use other than breast or gastric cancer. The test is performed on paraffin-embedded tissue and can be performed on older specimens.  There are two other FDA approved tests that utilize FISH technique, the INFORM HER-2/neu Test and the Path Vysion HER-2 DNA Probe Kit. The FDA has also allowed pathology laboratories to develop and implement so-called "home brew assays" using FDA approved analyte specific agents.  Some of these assays have not been well validated.  There is considerable controversy about the method of choice to determine whether a tumor is HER2 positive, there is difficulty replicating test results even in the same laboratory, and there is lack of test standardization.
 
In 2006 the American Society of Clinical Oncology and the College of American Pathologists collaborated to establish guideline recommendations for the testing of human epidermal growth factor receptor 2 gene ERBB2 (HER2) in breast cancer.  The superiority of either immunocytochemistry (IHC) or in situ hybridization (ISH) has not clearly been demonstrated when carefully validated testing has been done.
 
Recently concern has been voiced over the accuracy of the interpretation of HER2 immunohistochemistry tests, particularly in labs which have little experience with the procedure.
Policy/
Coverage:
For HER2 (ERBB2) gene testing for targeted therapy in non-small cell lung cancer see coverage policy 2015002.
 
Effective August 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Testing of human epidermal growth factor receptor 2 gene ERBB2 (HER2) meets primary coverage criteria for effectiveness for the following indications:
 
    • Breast Cancer
        • Members with newly diagnosed invasive breast cancer or recurrent invasive breast cancer; OR
    • Gastric cancer
        • Locally advanced (recurrent or metastatic) OR
    • Esophageal or Gastroesophageal Junction Adenocarcinoma OR
    • Head and Neck Cancers (Salivary Gland Tumors) OR
    • Non-Small Cell Lung Cancer (see policy 2015002) AND
    • Member must be a candidate for Trastuzumab
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Testing of human epidermal growth factor receptor 2 gene ERBB2 (HER2) in any cancer other than breast, gastric cancer, esophageal or gastroesophageal junction adenocarcinoma, head and neck cancers (salivary gland tumors) and non-small cell lung cancer, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, testing of human epidermal growth factor receptor 2 gene ERBB2 (HER2) for any cancer other than breast, gastric cancer, esophageal or gastroesophageal junction adenocarcinoma, head and neck cancers (salivary gland tumors) and non-small cell lung cancer, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective September to July 31, 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Testing of human epidermal growth factor receptor 2 gene ERBB2 (HER2) meets primary coverage criteria for effectiveness for:
 
    • Members with newly diagnosed invasive breast cancer or recurrent invasive breast cancer; OR
    • Locally advanced (recurrent or metastatic) gastric cancer, esophageal or gastroesophageal junction adenocarcinoma;
AND
    • Member must be a candidate for Trastuzumab.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Testing of human epidermal growth factor receptor 2 gene ERBB2 (HER2) in any cancer other than breast, gastric cancer, esophageal or gastroesophageal junction adenocarcinoma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, testing of human epidermal growth factor receptor 2 gene ERBB2 (HER2) for any cancer other than breast, gastric cancer, esophageal or gastroesophageal junction adenocarcinoma is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to September 2019
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Testing of human epidermal growth factor receptor 2 gene ERBB2 (HER2) meets primary coverage criteria for effectiveness for members with newly diagnosed invasive breast cancer or at the time of recurrence or members with locally advanced, recurrent or metastatic gastric cancer.  
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The testing of human epidermal growth factor receptor 2 gene ERBB2 (HER2) is being studied in other types of cancer but there are no guidelines for it's use in any cancer other than breast or gastric cancer.  Any use for other than breast or gastric cancer does not meet Primary Coverage Criteria for effectiveness.
 
The testing of human epidermal growth factor receptor 2 gene ERBB2 (HER2) for any cancer other than breast or gastric cancer would be considered investigational and not covered for contracts without Primary Coverage Criteria.  Investigational services are an exclusion in the member benefit certificate.
 
Effective Prior to April 2015
 
Testing of human epidermal growth factor receptor 2 gene ERBB2 (HER2) meets primary coverage criteria for effectiveness for members with newly diagnosed invasive breast cancer or at the time of recurrence or members with locally advanced, recurrent or metastatic gastric cancer.  A positive test is defined as:
    •  An IHC staining of 3+ (uniform intense membrane staining of > 30% of invasive tumor cells; OR
    • An in situ hybridization (ISH) ratio (HER2 gene signals to chromosome 17 signals) of more than 2.2.
 
The testing of human epidermal growth factor receptor 2 gene ERBB2 (HER2) is being studied in other types of cancer but there are no guidelines for it's use in any cancer other than breast or gastric cancer.  Any use for other than breast or gastric cancer does not meet Primary Coverage Criteria for effectiveness.
 
The testing of human epidermal growth factor receptor 2 gene ERBB2 (HER2) for any cancer other than breast or gastric cancer would be considered investigational and not covered for contracts without Primary Coverage Criteria.  Investigational services are an exclusion in the member benefit certificate.
Rationale:
There are several uses of HER2 status but accurate testing results are essential:
    • HER2 positivity is associated with a worse prognosis in in patients with newly diagnosed breast cancer who do not receive any adjuvant systemic therapy;
    • HER2 status may be predictive for several systemic therapies;
    • Agents that target HER2 are very effective in both the metastatic and adjuvant settings.
 
The American Society of Clinical Oncology (2006), and a technology assessment of the Agency for Health Research & Quality (2008) consider a HER 2-neu measurement using immunohistochemistry test or 0 or 1+ to be negative, a test of 3+ or greater to be positive, and a test of 2+ to be indeterminate.  For patients with an indeterminate test an in-situ hybridization test (e.g., FISH [Fluorescent in-situ hybridization]) result should be positive before trastuzumab is covered.
 
2009 Update
Gastric Carcinoma
HER-2 amplification occurs in 10%-20% of gastric adenocarcinomas (Marx, 2009).  Kim at al. (2007) reported measurements of HER-2 expression by FISH and real-time q-PCR and of HER-2 protein by IHC were highly concordant at determining HER-2 status in gastric carcinoma.
 
An abstract by Van Custem et al. was presented at the 2009 ASCO Annual Meeting.  This reported efficacy results from the ToGA trial.  Central testing of tumors for 3,807 patients determined  22.1% of them were HER2 positive.  594 patients were randomized 1:1 at sites in Europe, Latin America and Asia and received Herceptin and 5-fluorouracil or capecitabine and cisplatin (H+CT) or CT alone.  Median overall survival (OS) was 13.5 vs 11.1 months for H+CT and CT respectively.  Overall response rate was 47.3% for H+CT and 34.5% for CT.  Safety profiles were similar with no unexpected adverse events in the H+CT arm.
 
2011 Update
The National Academy of Clinical Biochemistry released guidelines for the use of biomarkers for the management of testicular, prostate, colorectal, breast, and ovarian cancer (Sturgeon, 2009).   The guidelines include the following recommendations for HER-2 testing for the management of breast cancer:
 
    • HER-2 should be measured in all patients with invasive breast cancer. The primary purpose of measuring HER-2 is to select patients with breast cancer that may be treated with trastuzumab [LOE, I; SOR, A].  
    • HER-2 may also identify patients that preferentially benefit from anthracycline-based adjuvant chemotherapy [LOE, II/III; SOR, B].
 
These recommendations do not prompt a change in the coverage statement.
 
Clinical Utility:
The clinical utility of a direct diagnostic genetic test for the detection of the presence of over expression of HER2/neu protein in patients with applicable forms of breast cancer or gastric cancer has been found to have little, if any, risks associated with it, and the benefits of this test can be invaluable in this selected population of patients in assisting with the selection of chemotherapy treatment.
 
2012 Update
A literature search was conducted through May 2012.  There was no new literature identified that would prompt a change in the coverage statement.
 
2014 Update
A literature search was conducted through February 2014.  There was no new literature identified that would prompt a change in the coverage statement.
  
2016 Update
A literature search conducted using the MEDLINE database did not reveal any new information that would prompt a change in the coverage statement.  
 
2017 Update
A literature search conducted through March 2017 did not reveal any new information that would prompt a change in the coverage statement.
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2018. No new literature was identified that would prompt a change in the coverage statement.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
A literature search was conducted through March 2020.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2023. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2024. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
88365In situ hybridization (eg, FISH), per specimen; initial single probe stain procedure
88366In situ hybridization (eg, FISH), per specimen; each multiplex probe stain procedure
88367Morphometric analysis, in situ hybridization (quantitative or semi quantitative), using computer assisted technology, per specimen; initial single probe stain procedure
88368Morphometric analysis, in situ hybridization (quantitative or semi quantitative), manual, per specimen; initial single probe stain procedure
88369Morphometric analysis, in situ hybridization (quantitative or semi quantitative), manual, per specimen; each additional single probe stain procedure (List separately in addition to code for primary procedure)
88373Morphometric analysis, in situ hybridization (quantitative or semi quantitative), using computer assisted technology, per specimen; each additional single probe stain procedure (List separately in addition to code for primary procedure)
88374Morphometric analysis, in situ hybridization (quantitative or semi quantitative), using computer assisted technology, per specimen; each multiplex probe stain procedure
88377Morphometric analysis, in situ hybridization (quantitative or semi quantitative), manual, per specimen; each multiplex probe stain procedure
References: Dendukuri N, Khetani K, et al.(2007) Testing for HER2-positive breast cancer: a systematic review and cost-effectiveness analysis. CMAJ, 2007; 176:429-34.

Harris L, Fritsche H, et al.(2007) American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol, 2007; 25:[epub ahead of print].

Hofmann M, Stoss O, et al.(2008) Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathol, 2008; 52(7):797-805.

Kim MA, Jung EJ, et al.(2007) Evaluation o fHER-2 gene status in gastric carcinoma using immunohistochemistry, fluorescence in situ hybridization, and real-time quantitative polymerase chain reaction. Hum Pathol, 2007; 38(9):1386-93.

Marx AH, Tharun L, et al.(2009) HER-2 amplification is highly homogenous in gastric cancer. Hum Path, 2009; 40(6):769-77.

Myers GL.(2009) Emerging biomarkers for primary prevention of cardiovascular disease and stroke. Washington (DC): National Academy of Clinical Biochemistry; 2009. 70 p.

National Comprehensive Cancer Institute (NCCN).(2021) NCCN 2021 Practice Guidelines in Oncology-Head and Neck Cancers v.3.2021. Available at https://www.nccn.org/professionals/physcician_gls/pdf/head-and-neck.pdf. Accessed August 27, 2021.

National Comprehensive Cancer Institute (NCCN).(2021) NCCN 2021 Practice Guidelines in Oncology-Non-Small Cell Lung Cancer v5.2021. Available at https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed August 27, 2021.

NCCN(2019) Guidelines for esophageal or gastroesophageal junction adenocarcinoma NCCN v.2.2019

Perez EA, Suman VJ, et al.(2006) HER2 testing by local, central, and reference laboratories in specimens from the North Central Cancer Treatment Group N9831 Intergroup Adjuvant Trial. J Clin Oncol, 2006; 24:3032-8.

Ross JS, Symmans WF, et al.(2007) Standardizing slide-based assays in breast cancer: homone receptors, HER2, and sentinel lymph nodes. Clin Cancer Res, 2007; 13:2831-5.

Seidenfeld J, Samson DJ, Rothenberg BM, et al.(2008) Her2 testing to manage patients with breast cancer and other solid tumors. Evidence Report/Technology Assessment #172, Agency for Health Research & Technology, October 2008.

Van Cutsem E, Kang Y, et al.(2009) Efficacy results from the ToGA trial: a phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidural growth factor receptor 2 (HER2)-positive advanced gastric cancer (GC). J Clin Oncol, 2009; 27:18s (suppl; abstract LBA4509).

Wolff AC, Hammond EH, et al.(2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for humam epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol, 2007; 25:118-45.
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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