The Her-2/Neu (Erbb2) Oncogene In Breast Cancer: Prognostic Factor, Predictive Factor and Target of Therapy

INTRODUCTION

During the past few decades, with the explosion of molecular technology and understanding of the biology of breast cancer, numerous studies have been performed to identify prognostic and predictive factors in breast cancer, with mixed success.

Approximately, 15 percent of all newly diagnosed breast cancers are HER2-positive, meaning that the tumors have extra copies of the HER2 gene and/or high levels of the HER2 protein, which controls Breast Cancer cell growth and spread. HER2-positive tumors usually grow faster compared to HER2-negative tumors.

The purpose of HER2 testing is to identify patients who could benefit from effective HER2-targeted therapies, such as trastuzumab (Herceptin), lapatinib (Tykerb), pertuzumab (Perjeta), and T-DM1 (Kadcyla).

These treatments can substantially improve survival in patients with HER2-positive invasive Breast Cancer. It is therefore important to accurately determine the HER2 status to ensure that patients most likely to benefit are offered a HER2-targeted treatment. At the same time, those that are unlikely to benefit can avoid side effects and costs associated with those drugs.

The American Society of Clinical oncology recommends routine measurement of Her-2/neu over-expression and possibly amplification for all patients for breast cancer diagnosis.

The ASCO guideline recommends the following*:

• Always test HER2 status on all newly diagnosed invasive breast cancers (primary site and/or metastatic site). Ensure that at least one tumor sample is tested for either HER2 protein expression (immunohistochemistry [IHC] assay) or (in situ hybridization FISH assay]) for HER2 gene amplification.
• Discuss the role of HER2-targeted therapy if the HER2 test result is positive and if there is no apparent histopathologic discordance with HER2
• Delay the decision to recommend HER2-targeted therapy if the HER2 test result is Mandatory retesting should be done on the same specimen using the alternative test if the initial HER2 test result is equivocal or on an alternative specimen.
• Do not administer HER2-targeted therapy if the HER2 test result is If there is apparent histopathologic discordance with the HER2 test result, additional HER2 testing should be considered.
• Report a HER2 test result as indeterminate if technical issues prevent one or both tests (IHC and ISH) from being done in a tumor specimen, or prevent the test (or tests) from being reported as positive, negative, or
• Confirm that the testing laboratory conforms to standards set for accreditation by CAP or an equivalent accreditation

INDIAN SCENARIO

Collectively, US, India and China account for almost one third of the global breast cancer burden.

India accounts for 25% to 31% of all cancers in women in Indian cities. (Source: PBCR 2009 – 2011)

For India in the year 2012:

• 144,937 women were newly detected with breast cancer
• 70,218 women died of breast cancer
• 144937 / 70218 = 06 = round it off to 2. So roughly, in India, for every 2 women newly diagnosed with breast cancer, one lady is dying of it

THE HER-2/neu ONCOGENE

The gene encoding HER2 is located on chromosome 17 and is a member of the EGF/erbB growth factor receptor gene family, which also includes epidermal growth factor receptor (EGFR, or HER1), HER3/erbB3 and HER4/erbB4. All of these genes encode transmembrane growth factor receptors, which are tyrosine kinase type 1 receptors with growth stimulating potential. Activation of HER family members generally occurs when the ligand and a dimer of the same monomer or other member of the HER family are bound together. HER2 has no known ligand. Once activation has occurred, tyrosine autophoshorylation of cytoplasmic signal proteins transmit signals to the nucleus, thus regulating aspects of cell growth, division, differentiation and migration.

Overexpression of HER2 receptors results in receptors transmitting excessive signals for cell proliferation to the nucleus. This may lead to more aggressive growth of the transformed cell. Data supports the hypothesis that the HER2- overexpression cells directly contribute to the pathogenesis and clinical aggressiveness of tumors. This overexpression is associated with poor prognosis, including reduced relapse-free and overall survival.

Figure 1 : Representation of HER2 family

OTHER USES OF HER-2/neu IN BREAST CANCER

Antibodies to the HER-2/neu protein have been used for radionucleotide imaging in breast cancer. In a 1994 study, Allan and coworkers used Tc99m-labeled monoclonal antibodies to HER-2 protein and reported encouraging results3. In addition to a potential use as a detector of occult metastasis, this approach may also allow for antibody-targeted chemo or radiation therapy in patients with recurrent or metastatic disease.

HER-2 NEU TESTING IHC and FISH

Immunohistochemistry (IHC) measures the level of HER2 receptor overexpression, while Fluorescence In-Situ Hybridization (FISH) quantifies the level of HER2 gene amplification. Together they are the most commonly used methods of determining HER2 status in routine diagnostic settings.

ADVANTAGES OF FLUORESCENCE IN SITU HYBRIDIZATION FOR HER-2/NEU STATUS IN BREAST CANCER

1. DNA target is more stable after tissue
2. Objective Slide scoring
3. Built in internal control (2 gene copies on average demonstrated in non amplified benign and malignant cells).
4. Rapid, sensitive, and specific detection and characterization of chromosome abnormalities.
5. Ability to test metaphase chromosomes from cultured samples and interphase cells from specimens that cannot be
6. Direct-labeled probes, as compared to indirect labeling methods, mean:

-Less background signal, thereby simplifying interpretation.

-Reduced costs associated with labeling reagents and technician time.

7. Dual colored probes for most

CONCLUSION

The FISH technique has out-performed a number of solid matrix blotting techniques designed to detect HER-2/neu DNA and RNA as well as immunohistochemistry designed to detect HER-2/neu protein in formalin-fixed paraffin- embedded tissues1. The FISH technique has been described as a rapid, reproducible and extremely reliable method of detecting HER-2/neu gene amplification [48]. In addition, FISH can readily be performed on archived paraffin blocks stored for long periods and has been successfully applied to fine-needle aspiration biopsies2.

SUMMARY

The testing of newly diagnosed Breast Cancer specimens for HER-2 neu status has now achieved standard of practice status for the management of breast cancer.

The discussion as to the best method to determine HER-2 neu status comes to a stop with the FISH Method gaining popularity due the advantages and recent evidence that it in comparison with IHC , may be more accurately predict clinical responses to trastuzumab-based therapies.

However with the other gene based CISH technique waiting in the wings, the story of HER-2/neu testing in breast cancer will continue to unfold over next coming years.

TEST RANGE AVAILABLE FOR BREAST CANCER

REFERENCES

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