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DESCRIPTIONNovel assays that quantitatively measure total HER2 protein expression and homodimers have been developed in an effort to improve the accuracy and consistency of HER2 testing.
The HER-family of receptor tyrosine kinases (EGFR/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4) plays a major role in the pathogenesis of many solid tumors. In approximately 25-30% of breast cancers, overexpression of HER2 has been linked to shorter disease-free (DFS) and overall survival (OS), lack of responsiveness to tamoxifen antiestrogen therapy and altered responsiveness to a variety of cytotoxic chemotherapy regimens.
Trastuzumab, a monoclonal antibody directed at the extracellular domain of HER2 has offered significant DFS and OS advantages in the metastatic and adjuvant settings in HER2-overexpressing patients, although not all patients respond. Fewer than 50% of patients with metastatic HER2-positive breast cancer show initial benefit from trastuzumab treatment, and many of those eventually develop resistance.
Current methodologies for the selection of HER2-positive patients include immunohistochemistry (IHC) to detect HER2 protein overexpression, and fluorescence in situ hybridization (FISH) to detect HER2 gene amplification. However, controversy still exists regarding the accuracy, reliability, and interobserver variability of these assay methods. IHC provides a semiquantitative measure of protein levels (scored as 0, 1+, 2+, and 3+) and the interpretation may be subjective. FISH is a quantitative measurement of gene amplification, in which the HER2 gene copy number is counted. However, FISH, which is considered to be more quantitative analytically, is not always representative of protein expression, and multiple studies have failed to demonstate a relationship between HER2 gene copy number and response to trastuzumab. Whereas patients who overexpress HER2 protein (IHC) or show evidence of HER2 gene amplification (FISH) have been slow to experience better outcomes on trastuzumab than those scored negative by those assays, differences in the degree of expression or amplification by these methods have generally not been shown to discriminate between groups with different outcomes. IHC and FISH testing may be affected by interlaboratory variability, and neither test provides quantitative data that reflect the activation state of signaling pathways in tumors, which may limit their utility in patient selection. Most laboratories in North America and Europe use IHC to determine HER2 protein status, with equivocal category results (2+) confirmed by FISH (or more recently by chromogenic in situ hybridization (CISH).
Normally, HER2 activates signaling pathways by dimerizing with ligand-bound EGFR-family members such as HER1 and HER3. A HER2 ligand has not been identified, but overexpressed HER2 is constitutively active. When HER2 is pathologically overexpressed, the receptor may homodimerize and activate signaling cascades in the absence of the normal regulatory control imposed by the requirement for ligand binding of its heterodimerization partners.
A novel assay (HERmark® Breast Cancer Assay, Monogram Biosciences, South San Francisco, CA) was developed to quantify total HER2 protein expression (H2T) and HER2 homodimers (H2D) in formalin-fixed, paraffin-embedded (FFPE) tissue samples.
No U.S. Food and Drug Administration (FDA)‒approved proximity ligation assays for quantifying total HER2 protein expression or HER2 homodimers were identified. HERmark® is a laboratory-developed test (LDT). Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; LDTs must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). HERmark® is available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, FDA does not require any regulatory review of this test.
POLICYThe assessment of HER2 status by quantitative total HER2 protein expression and HER2 homodimer measurement is considered investigational.
POLICY GUIDELINESInvestigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY03/22/2012: Approved by Medical Policy Advisory Committee.
12/13/2012: Policy reviewed; no changes.
12/13/2013: Policy reviewed; no changes.
11/19/2014: Policy reviewed; description updated regarding laboratory-developed tests. Policy statement unchanged.
08/14/2015: Code Reference section updated for ICD-10.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.04.76
CODE REFERENCEThis may not be a comprehensive list of codes applicable to this policy.