Indication - Cancer
Tyrosine-protein kinase receptor (erbB-2) or human epidermal growth factor receptor 2 (HER-2) overexpression
Facility level:
Assay formats
IHC testing
Status history
First added in 2019
Changed in 2020
Purpose type
Aid to diagnosis, Prognosis
To aid in treatment and prognosis of breast cancer
Specimen types
Formalin-fixed paraffin-embedded tissue (FFPE) (Referred specimens must be fixed correctly before transport)
WHO prequalified or recommended products
WHO supporting documents
WHO classification of tumours of the breast. WHO classification of tumours, 4th edition, volume 4. https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/WHO-Classification-Of-Tumours-Of-The-Breast-2012 ; WHO list of priority medical devices for cancer management https://apps.who.int/iris/handle/10665/255262 ; WHO 20th eEssential mMedicines lList (2017) https://apps.who.int/iris/handle/10665/273826 ; WHO Guide for establishing a pathology laboratory in the context of cancer control. https://www.who.int/publications/i/item/guide-for-establishing-a-pathology-laboratory-in-the-context-of-cancer-control
ICD11 code: 2C6Z

Summary of evidence evaluation

There is no reference standard against which to compare immunohistochemistry for evaluation of overexpression of HER2 or the tyrosine–protein kinase erbB-2 receptor. Data from comparisons with other panels show that IHC detects about 70% of samples that are positive by any other method and do not indicate samples as positive that are not positive by any other method. There is strong evidence from trials of the benefit of HER2 testing for stratifying treatments for breast cancer according to HER2 status, which are summarized in the EML.

Summary of SAGE IVD deliberations

HER2 testing is essential for identification of breast cancer that can be treated with trastuzumab, which is on the WHO EML. Use of trastuzumab is associated with significant improvement in overall survival of HER2-positive breast cancer patients.

SAGE IVD recommendation

The SAGE IVD recommended inclusion of IHC for detecting overexpression of HER2 in patients with breast cancer to ensure appropriate treatment. The Group noted that trastuzumab, an anti-HER2 drug, is on the WHO EML. The SAGE IVD also recommended that WHO consider submissions for other endocrine diagnostics.

Details of submission from 2020


Disease condition and impact on patients: Breast cancer is the most prevalent cancer in women and the most frequent cause of death from cancer in women. According to IARC (1), worldwide, about 2.1 million cases of female breast cancer were newly diagnosed in 2018, accounting for almost one in four cancer cases among women. More than 50% of the deaths occur in LMICs. Does this test meet a medical need? HER2/erbB-2 protein overexpression dictates a worse prognosis and predicts the benefit of trastuzumab, a monoclonal antibody that blocks HER2. Trastuzumab is a valuable medicine for the treatment of this type of breast cancer, particularly in early and locally advanced stages, and is on the WHO EML. How this test is used: The kit is used to grade HER2 overexpression in neoplastic breast tissue that has been processed and paraffin-embedded routinely for histological evaluation. Testing for HER2 overexpression is required to prescribe trastuzumab.

Public health relevance

Prevalence: HER2 overexpression is found in 15–25% of cases of breast cancer. Socioeconomic impact: Breast cancer incidence and mortality are major causes of productivity loss. In Europe, breast cancer-related premature mortality was responsible for US$ 7 billion in losses (2). In a study of women in Brazil, China, India, the Russian Federation and South Africa, the total productivity loss was highest for breast cancer (US$ 2.1 billion) and cervical cancer (US$ 1.5 billion) (3). According to IARC (1), only 40% of new cases and 28% of mortality for breast cancer occur in high-income countries. Large disparities in breast cancer survival have also been reported, predominantly related to differences in time of presentation and different insurance schemes, resulting in diverse treatments and follow-up care (4). For instance, the mortality:incidence ratio for breast cancer in women in LMICs is 0.48, while that in high-income settings is 0.17.

WHO or other clinical guidelines relevant to the test

The test is on the WHO Priority list of medical devices for cancer management (5). The prognostic and predictive role of HER2 is described in WHO Classification of tumours of the breast (6).

Evidence for clinical usefulness and impact

Over-expression of HER2 in breast cancer is a recognized risk factor for an increased risk of relapse in resected primary tumours and overall mortality, as shown in both high-income and LMICs (7, 8). In current guidelines for the diagnosis of breast cancer, the HER2 immunochemistry test gives one of three possible scores: no over-expression (0 and 1+), over-expression (3+) or equivocal (2+). In the case of an equivocal score, which is found in 20–25% of cases tested, in-situ hybridization is recommended for confirmation of HER2 status (9); no benefit of trastuzumab has been reported in cases of equivocal tests (2+) with non-amplified HER2. Overexpression of HER2 defines appropriate treatment. All women with radically resected breast cancer are eligible for adjuvant chemotherapy in combination with an anti-HER2 agent and/or trastuzumab if they have metastases. Trastuzumab is the first approved anti-HER2 agent and is on the 20th WHO EML for use in both early (adjuvant) treatment and for metastatic cancer (palliative use). Biosimilars are undergoing WHO prequalification. The indication is supported by clinical guidelines for breast cancer management (10– 14). Use of trastuzumab is associated with a significant improvement in overall survival of women with HER2-positive breast cancer (15, 16). On the basis of data from the HERA trial (17), the European Society for Medical Oncology evaluated the absolute benefit and safety of trastuzumab as an adjuvant and concluded that it is a priority drug, scoring it “A” (priority medicine) for adjuvant use. The reviewers underlined the critical importance of a test for quality, including an assurance scheme or protocol; ASCO and CAP guidelines for high-quality HER2 testing and assurance were discussed (18).

Evidence for economic impact and/or cost–effectiveness

Use of trastuzumab as an adjuvant has been considered cost–effective by the principal health and technology assessment agencies. The cost of trastuzumab per QALY was £ 2387 (US$ 3122) (19). Use of the HER2 kit requires a laboratory technician for incubation and staining on an automatic stainer, and a trained pathologist for reading slides and interpreting the results. Immunohistochemistry for HER2 testing is appropriate for most health systems. In-situ hybridization tests require reagents that are significantly more expensive (US$ 140 versus US$ 10) and require a longer testing time (36 h versus 4 h) and a longer interpretation time (7 min versus 45 s) (20).

Ethical issues, equity and human rights issues

Consent is required to obtain a breast tissue sample. Disparities in the accessibility and affordability of trastuzumab have been reported in global surveys, partially related to issues in accessing HER2 testing. Access to HER2 testing should be ensured for patients likely to benefit from trastuzumab (21).
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