HER-2 testing is used to predict 5-year disease-free and overall survival in patients with breast cancer, assess eligibility for trastuzumab (Herceptin^®) treatment, assist in dose selection for certain drugs, and predict response to drug therapies.

The HER-2/neu (human epidermal growth factor receptor 2) proto-oncogene, 1 of a family of 4 closely related growth factor receptor genes, encodes a 185-kd tyrosine kinase. HER-2/neu gene amplification can lead to overproduction of the HER-2 protein and to tumor development through enhanced cell proliferation, survival, motility, and adhesion. HER-2/neu amplification and overexpression are observed in approximately 20% of invasive breast cancers and are associated with an aggressive disease course and decreased disease-free and overall survival.^1,2

HER-2 status is most often used to determine patient eligibility for trastuzumab immunotherapy. Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of HER-2, inhibits proliferation of human tumors cells that overexpress HER-2. Documentation of HER-2 overexpression, either directly with immunohistochemistry (IHC) or indirectly with fluorescence in situ hybridization (FISH), is therefore recommended before prescribing trastuzumab therapy.³ Patients whose breast tumors amplify the HER-2 gene and/or overexpress the HER-2 protein are suitable candidates for this treatment.^4-6

HER-2 amplification or overexpression status can also be helpful when considering other types of therapy. HER-2-positive tumors have been associated with increased sensitivity to anthracycline (eg, doxorubicin [Adriamycin^®]) and cyclophosphamide/doxorubicin/5-fluorouracil (CAF) chemotherapy.^7-10 Conversely, such patients do not benefit as much from cyclophosphamide/methotrexate/5-fluorouracil (CMF) regimens as do those with HER-2-negative tumors.^11-14 HER-2-positive patients also tend to have diminished sensitivity to endocrine therapy (eg, tamoxifen); however, the data are somewhat conflicting, and decisions regarding endocrine treatment should not be based on the results of HER-2 testing.¹⁵ Similarly, the data regarding HER-2 status and taxanes are insufficient for clinical use, although the tendency is for HER-2-positive tumors to respond well to treatment.¹⁵ For example, a recent article reported benefit from the addition of paclitaxel after adjuvant doxorubicin/cyclophosphamide therapy in patients with node-positive, HER-2-positive breast cancer, while patients with node-positive, HER-2-negative breast cancer did not benefit.¹⁶

• Includes all patients with invasive breast cancer¹

There are several approaches for detecting HER-2/neu overexpression or amplification. Currently, the only FDA-cleared methods for assessing HER-2 status are IHC and FISH. Quest Diagnostics offers both methods and follows the testing and reporting recommendations of the expert American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) Panel.¹ The Panel expressed no preference of one method over the other. The figure portrays an algorithm for use and interpretation of IHC and FISH methods; the algorithm is based on the ASCO/CAP Panel recommendations.

IHC Method

The IHC method determines protein overexpression status of the invasive component of the cancer by using an anti-human HER-2 antibody. The stained tissue is visually examined by a board-certified pathologist and graded using a 4-point scale. Protein overexpression is indicated by a score of 3+. Staining variations between the in situ and invasive components may occur.

FISH Method

The FISH assay determines gene amplification status of the invasive component of the cancer by using probes specific for the HER-2/neu locus and CEP 17; CEP 17 is included as an internal control and to account for aneusomy of chromosome 17. Results are reported as the ratio of HER-2/neu signal to CEP 17 signal. A ratio of >2.2 indicates gene amplification. This cut-point is recommended by ASCO/CAP Panel and the NCCN,^1,17 even though some clinical trials used a ratio cut-point of ≥2.0.⁶

Comparative information for these 2 methods can be found in Table 1. Aliases for these assays include c-erbB-2, HER-2/neu, human epidermal growth factor receptor-2, and p185 (IHC only).

HER-2 IHC and FISH results are reported as shown in Table 1. HER-2 overexpression or amplification suggests patient eligibility for trastuzumab treatment (Figure). In addition, stage II, node-positive breast cancer patients with amplification may benefit from higher doses of CAF.^8,9

Lack of HER-2 protein overexpression or gene amplification suggests the patient will not respond to trastuzumab therapy; however, clinical trials are needed to confirm this presumption. Similarly, trastuzumab response, or lack thereof, in patients with confirmed equivocal HER-2 test results is uncertain. Trastuzumab is clinically indicated only for patients in whom HER-2 protein overexpression or gene amplification can be confirmed.