Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Lab Test: Hepsin Biomarker Testing

Description:

Hepsin is a protein produced by tumor cells. A blood draw is used to detect the level of hepsin in a patient’s blood. If a high level of hepsin is found, it suggests a tumor is present.

Hepsin biomarker testing is used to detect many tumor types, but the main focus has been on prostate cancer, endometrial cancer, breast and ovarian cancer.

Coding

There is no specific CPT code for this test. Hepsin biomarker testing will likely be billed with 81479.

Policy/
Coverage:

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Hepsin biomarker testing for the diagnosis, monitoring and risk assessment of cancer does not meet benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. This includes, but is not limited to the following:

Breast cancer
Endometrial cancer
Cervical cancer
Ovarian cancer
Gastric cancer
Esophageal cancer
Prostate cancer

For members with contracts without primary coverage criteria, hepsin biomarker testing for the diagnosis, monitoring and risk assessment of cancer is considered investigational. Investigational services are exclusions in most member benefit certificates of coverage.

The use of hepsin biomarker testing for any indication does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, hepsin biomarker testing for any indication is considered investigational. Investigational services are exclusions in most member benefit certificates of coverage.

Rationale:

This policy was developed in response to a provider request for coverage of hepsin biomarker testing for the diagnosis, monitoring and risk assessment of cancer including, but not limited to breast cancer, endometrial cancer, cervical cancer, ovarian cancer, gastric cancer, esophageal cancer and prostate cancer.

A literature search using the MEDLINE database through September 2018 revealed limited data.No documented randomized controlled or nonrandomized controlled trials were found. The key identified literature is summarized below.

Hepsin Expression in Breast Cancer

A study on the clinical and biological significance of hepsin expression in breast cancer, by Peng et al examined 4 pairs of fresh breast tumor samples and corresponding nontumor cancer breast tissues by Western blotting. Additionally, immunohistochemistry for hepsin was performed on 215 archival breast cancer samples. The clinical significance of hepsin expression was analyzed. They found hepsin was overexpressed in breast cancer tissues relative to adjacent nontumor tissues. Knockdown of hepsin expression was performed in 2 breast cancer cell lines, MDA-MB-231 and HER18, with a high abundance of endogenous hepsin, and the effects of hepsin silencing on cell invasion and proliferation were evaluated. Its overexpression was significantly associated with tumor stage (P = 0.037), lymph node metastasis (P = 0.010), estrogen receptor positivity (P = 0.019), and progesterone receptor positivity (P < 0.0001) in patients with breast cancer. Down-regulation of hepsin expression by small interfering RNA (siRNA) significantly reduced cell proliferation and invasion in both the MDA-MB-231 and HER18 cells compared to nonspecific control small interference RNA. Their data demonstrated that hepsin expression is often up-regulated in breast cancer tissues, which is associated with tumor growth and progression (Peng, 2011).

Tervonen et al showed that hepsin protein was highly expressed in 40% of all examined breast cancer subtypes and 60% of triple-negative breast cancers examined (Tervonen, 2015). The findings highlight the role of hepsin overexpression in tumorigenesis and progression to clinical metastasis. (Tervonen, 2015)

Hepsin Expression in Cervical Cancer

In 2017, Cheng et al assessed the hypothesis that the protein levels of high mobility group box 1 (HMGB1) and hepsin can be used as markers for diagnosis and prognosis in cervical carcinoma. Seventy patients with cervical cancer who were hospitalized in Xuzhou Central Hospital from May 2008 to June 2010 and underwent surgical treatment were selected for the observation group. At the same time, 20 patients with cervical benign lesions who underwent tumor stripping or accessory resection were selected for the control group.

Immunohistochemical (SP) detection methods were used to detect hepsin and HMGB1 protein levels in tissues. The positive rates of HMGB1 cells in normal, paracancerous and cancerous cervical tissues were 5.0% (1/20), 22.9% (16/70) and 95.7% (67/70) (F=24.581, P=0.001) respectively. The positive rates of hepsin in normal, paracancerous and cancerous cervical tissues were respectively 10% (2/20), 61% (43/70) and 90% (63/70) (F=11.538, P=0.001). The HMGB1 expression level was related to the degree of tumor differentiation, lymph node metastasis and TNM stage (P<0.05). While the level of hepsin expression was related to the degree of tumor differentiation, invasion depth, lymph node metastasis and TNM stage (P<0.05). Furthermore, a positive correlation between the levels of hepsin and HMGB1 was found (r=15.27, P<0.05). The overall 5-year survival rates of patients with high expression of HMGB1 (+++) and low expression of HMGB1 (+ to ++) were respectively 51.2 and 29.2% (HR=11.637, 95% CI=4.351–38.213; P=0.002). The overall 5-year survival rates of patients with high hepsin expression (+++) and low hepsin expression (+ to ++) were respectively 41.3 and 35.3% (HR=10.143, 95% CI=4.285–33.275; P=0.006). The results indicate the higher the levels of expression of hepsin and HMGB1 in tissues the higher the degree of invasiveness of the cervical cancers, and the worse the prognoses for the patient.

Hepsin Expression in Ovarian Cancer

In the study by Bignotti et al, the purpose was to identify genes that are highly differentially expressed in metastatic serous papillary ovarian tumors (MET) when compared with primary ovarian serous carcinomas (OSPC). An oligonucleotide microarray with probe sets complementary to >14,500 human genes was used to determine whether patterns of gene expression may differentiate OSPC from MET in 31 snap-frozen serous papillary ovarian carcinomas (ie, 14 primary OSPC and 17 omental metastasis [MET]). Hierarchic cluster analysis of gene expression in OSPC and MET identified 156 genes that exhibited > 2-fold differences (P < .05) and that distinguished OSPC from MET. A number of invasion and metastasis predictive genes (including plasminogen activator; matrix metalloproteinase; matrix structural constituent genes encoding products with collagen, heparin, and hyaluronic acid binding activity; genes encoding receptors for insulin-like growth factors; vascular endothelial growth factor; endothelin type A; fibroblast growth factor; thrombospondin 1 and 2; type A and B integrins, and chemokines [stromal cell-derived factor 1 (CXCL12)]) were found among the 120 genes that were highly differentially overexpressed in MET, when compared with OSPC. Down-regulated genes in MET compared with OSPC included hepsin and testisin. Overexpression of CXCL12, matrix metalloproteinase, plasminogen activator, type A and B integrins, and hepsin genes was validated by quantitative real-time polymerase chain reaction in all samples. Overexpression of CXCL12 in MET, when compared with OSPC, was validated at the protein level by immunohistochemistry. The authors concluded that gene expression profiling may differentiate metastatic ovarian cancer from primary OSPC. The identification of metastasis-associated genes may provide a foundation for the development of new type-specific diagnostic strategies and treatment for metastatic ovarian cancer. (Bignotti, 2007)

To gain insight into its function in ovarian cancer, Miao et al analyzed the expression and subcellular localization of hepsin protein in ovarian cancer cell lines and tumors. We showed that the membrane‐associated hepsin protein is present at desmosomal junctions, where it colocalizes with its putative proteolytic substrate hepatocyte growth factor. Consistent with the growing evidence that desmosomal junctions and their constituents play a role in cancer progression, the study demonstrated that overexpression of hepsin promotes ovarian tumor growth in a mouse model. The ability of ectopic hepsin to induce tumor growth in mice is abrogated by the mutation of 3 critical residues in the catalytic domain, thus implicating the enzymatic activity of hepsin in promoting tumor progression (Miao, 2008).

Hepsin Expression in Prostate Cancer

Dhanasekaran et al looked at characterization of gene-expression profiles that molecularly distinguish prostatic neoplasms to identify genes involved in prostate carcinogenesis, elucidate clinical biomarkers, and lead to an improved classification of prostate cancer. Using microarrays of complementary DNA, examined gene-expression profiles of more than 50 normal and neoplastic prostate specimens and three common prostate-cancer cell lines were examined. Signature expression profiles of normal adjacent prostate (NAP), BPH, localized prostate cancer, and metastatic, hormone-refractory prostate cancer were determined. Here we establish many associations between genes and prostate cancer. Two of these genes—hepsin, a transmembrane serine protease, and pim-1, a serine/threonine kinase—at the protein level using tissue microarrays consisting of over 700 clinically stratified prostate-cancer specimens were assessed. Expression of hepsin and pim-1 proteins was significantly correlated with measures of clinical outcome (Dhanasekaran, 2001).

The aim of the study by Goel et al in 2011 was to find out immuno-histochemistry based phenotypic expression of HPN in formalin fixed paraffin embedded sections of prostate cancer compared with that in benign prostatic hyperplasia, in a prospective clinical setting, to know the differential status of HPN expression in benign and malignant prostatic disease. Tissue biopsies of histologically proven cases of prostatic cancers (48), benign prostatic hyperplasia (42), benign prostatic hyperplasia with prostatic intraepithelial neoplasia (7) and 4 cases of benign prostatic hyperplasia with prostatitis, were subjected to immunohistochemical staining with HPN antibody by strepavidin biotin method. Hepsin expression was 100% in prostate carcinoma, 11.9% (5/42) in benign prostatic hyperplasia, 57.14% (4/7) in benign prostatic hyperplasia with prostatic intraepithelial neoplasia (PIN), and none in benign prostatic hyperplasia with prostatitis. Hepsin staining showed higher expression in high grade tumor in comparison to low grade tumor (Goel, 2011)

Hepsin Expression in Endometrial Cancer

Matsuo et al examined hepsin expression and evaluated its clinicopathological significance in endometrial cancer. Hepsin expression was examined by immunohistochemisty in 34 cases with normal endometrium as a control, 11 cases with endometrial hyperplasia, and 128 cases with endometrioid adenocarcinoma. Hepsin expression was found to be significantly higher in endometrial cancer compared to normal endometrium and endometrial hyperplasia. High levels of hepsin expression were associated with advanced stage (p<0.001), high grade (p=0.002), depth of myometrial invasion (p<0.001), cervical involvement (p=0.007), lymph node metastasis (p=0.001), lymph vascular space (LVS) involvement (p=0.006), ovarian metastasis (p=0.002), and peritoneal cytology (p=0.03) of endometrial cancer (Matsuo, 2008).

In a retrospective study by El-Rebey et al, 27 endometrial carcinoma and 18 endometrial hyperplasia cases were studied. Immunohistochemical expression of hepsin was evaluated in tissue specimens and results were correlated with the available clinicopathlogic parameters. Positive hepsin expression was seen in all (100%) carcinoma and 17/18 (94.44%) endometrial hyperplasia cases. The H-score of hepsin expression in endometrial carcinoma was significantly higher than that of hyperplasia cases (P=0.012). A significant negative association was found between hepsin expression in endometrial carcinoma cases regarding the grade and the size of tumors (P=0.018 and 0.008, respectively) as well as myometrial invasion (P=0.027) (El-Rebey, 2017).

Hepsin Expression in Gastric Cancer

The aim of the study conducted by Zhang et al was to describe the expression pattern and evaluate the clinical implication of hepsin in gastric cancer patients. The mRNA expression of hepsin was analyzed in 50 gastric cancer and matched non-tumor tissues, which was downregulated in 78% (39/50) of gastric cancer. By searching and analyzing four independent datasets from Oncomine, similar results were obtained. Furthermore, the hepsin expression by IHC in tissue microarray (TMA) containing 220 Gastric Cancer specimens was evaluated. Kaplan-Meier survival and Cox regression analyses were taken to access the prognosis of gastric cancer and predicted that hepsin protein expression was one of the significant and independent prognostic factors for overall survival of Gastric Cancer (Zhang, 2016).

2019 Update

Annual policy review completed with a literature search using the MEDLINE database through October 2019. No new literature was identified that would prompt a change in the coverage statement.

2020 Update

Annual policy review completed with a literature search using the MEDLINE database through October 2020. No new literature was 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 October 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 October 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 October 2023. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:

References:

Bignotti E, Tassi R, Calza S, et al.(2007) Gene expression profile of ovarian serous papillary carcinomas: identification of metastasis-associated genes. American Journal of Obstetrics & Gynecology. 2007;196(3):245.e1–245.e11.

Cheng H, Wang W, Zhang Y, et al.(2017) Expression levels and clinical significance of hepsin and HMGB1 proteins in cervical carcinoma. Oncology Letters. 2017;14(1):159-164. doi:10.3892/ol.2017.6116.

Dhanasekaran S, Barrette T, Ghosh D, et al.(2001) Delineation of prognostic biomarkers in prostate cancer. Nature International Journal of Science. 2001;412:822-826.

El-Rebey H, Kandil M, Samaka R, et al.(2017) The Role of Hepsin in Endometrial Carcinoma. Appl Immunohistochem Mol Morphol. 2017;25(9):624-631.

Goel M, Agrawal D, Natu S, et al.(2011) Hepsin immunohistochemical expression in prostate cancer in relation to Gleason’s grade and serum prostate specific antigen. Indian Journal of Pathology and Microbiology. 2011;54(3):476-481. DOI: 10.4103/0377-4929.85078 PMID: 21934206.

Matsuo T, Nakamura K, Takamoto N, et al.(2008) Expression of the serine protease hepsin and clinical outcome of human endometrial cancer. Anticancer Research. 2008; 28(1A):159-164.

Miao J, Mu D, Ergel G, et al.(2008) Hepsin colocalizes with desmosomes and induces progression of ovarian cancer in a mouse model. International Journal of Cancer. 2008;123(9):2041-2047

Tervonen T, Belitskin D, Pant S, et al.(2016) Deregulated hepsin protease activity confers oncogenicity by concomitantly augmenting HGF/MET signaling and disrupting epithelial cohesion. Oncogene. 2016;35:1832-1846.

Xing P, Li J, Jin F, et al.(2011) Clinical and Biological Significance of Hepsin Overexpression in Breast Cancer. Journal of Investigative Medicine. 2011;59:803-810.

Zhang M, Zhao J, Tang W, et al.(2016) High hepsin expression predicts poor prognosis in gastric cancer. Scientific Reports. 2016;6, 36902; doi: 10.1038/srep36902.

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.
CPT Codes Copyright © 2024 American Medical Association.