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Indication -
Cancer
Tyrosine-protein kinase receptor (erbB-2) or human epidermal growth factor receptor 2 (HER-2) overexpression
Assay formats
IHC testing
Status history
First added in 2019
Changed in 2020
Purpose type
Aid to diagnosis, Prognosis
Purpose
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
N/A
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
Codes
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
Background
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).
1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clinicians. 2018;68(6):394–424.
2. Hanly P, Soerjomataram I, Sharp L. Measuring the societal burden of cancer: the cost of lost productivity due to premature cancer-related mortality in Europe. Int J Cancer. 2015; 136(4):136–45.
3. Pearce A, Sharp L, Hanly P, Barchuk A, Bray F, de Camargo Cancela M, et al. Productivity losses due to premature mortality from cancer in Brazil, Russia, India, China, and South Africa (BRICS): a population-based comparison. Cancer Epidemiol. 2018;53:27–34.
4. Silber JH, Rosenbaum PR, Ross RN, Reiter JG, Niknam BA, Hill AS, et al. Disparities in breast cancer survival by socioeconomic status despite Medicare and Medicaid insurance. Milbank Q. 2018;96(4):706–54.
5. Priority medical devices for cancer management (WHO Medical Device Technical Series). Geneva`: World Health Organization; 2017 (http://www.who.int/medical_devices/publications/priority_ med_dev_cancer_management/en/).
6. WHO classification of tumours of the breast. WHO Classification of Tumours, 4th Edition, Volume 4. Geneva: World Health Organization; 2012 (http://publications.iarc.fr/Book-And-Report-Series/ Who-Iarc-Classification-Of-Tumours/WHO-Classification-Of-Tumours-Of-The-Breast-2012).
7. Mejri N, Boussen H, Labidi S, Benna F, Afrit M, Raha K. Relapse profile of early breast cancer according to immunohistochemical subtypes: guidance for patient’s follow up? Ther Adv Med Oncol. 2015;7(3):144–52.
8. Katzorke N, Rack BK, Haeberle L, Neugebauer JK, Melcher CA, Hagenbeck C, et al. Prognostic value of HER2 on breast cancer survival. J Clin Oncol. 2013;31(15 Suppl):640.
9. Stenehjem DD, Yoo M, Unni SK, Singhal M, Bauer H, Saverno K, et al. Assessment of single- institution HER2 testing patterns, rate of HER2+ disease, and utilization of trastuzumab in early breast cancer. J Clin Oncol. 2013;31(Suppl):124.
10. Morigi G. Highlights from the 15th St Gallen International Breast Cancer Conference 15–18 March, 2017, Vienna: tailored treatments for patients with early breast cancer. ecancermedicalscience. 2017;11:732.
11. Curigliano G, Burstein HJ, Winer E, Gnant M, Dubsky P, Loibl S, et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol. 2017;28(8):1700–12.
12. Cardoso F, Senkus E, Costa A, Papadopoulos E, Aapro M, André F, et al. 4th ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4). Ann Oncol. 2018;29(8):1634–57.
13. Hu X, Li T, Wang B, Zhang J, Yu X, Shao Z. Comparison of 4th ESO-ESMO international consensus guidelines for advance breast cancer and Chinese anti-cancer association committee of Breast Cancer Society guideline. Breast. 2019;45:36–42.
14. Breast cancer. Guidelines for invasive breast cancer. Fort Washington (PA): National Comprehensive Cancer Network; 2018.
15. Cameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja, et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017;389(10075):1195–205.
16. Daniels B, Kiely BE, Lord SJ, Houssami N, Lu CY, Ward RL, et al. Long-term survival in trastuzumab- treated patients with HER2-positive metastatic breast cancer: real-world outcomes and treatment patterns in a whole-of-population Australian cohort (2001–2016). Breast Cancer Res Treat. 2018;171(1):151–9.
17. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659–72.
18. Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update. Arch Pathol Lab Med. 2018;142(11):1364–82.
19. Mayor S. NICE approves trastuzumab for early stage breast cancer. BMJ. 2006;332(7555):1409.
20. Yaziji H, Goldstein LC, Barry TS, Werling R, Hwang H, Ellis GK, et al. HER-2 testing in breast cancer using parallel tissue-based methods. JAMA. 2004;291(16):1972–7.
21. Cherny NI, Sullivan R, Torode J, Saar M, Eniu A. ESMO International Consortium study on the availability, out-of-pocket costs and accessibility of antineoplastic medicines in countries outside of Europe. Ann Oncol. 2017;28(11):2633–47.