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Year : 2021  |  Volume : 64  |  Issue : 4  |  Page : 677-682
HER2 testing by immunohistochemistry in breast cancer: A multicenter proficiency ring study

1 Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
2 Department of Community Health, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
3 Department of Pathology, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
4 Department of Pathology, University Malaya Medical Centre, Lembah Pantai, Kuala Lumpur, Kuala Lumpur
5 Department of Pathology, Hospital Raja Permaisuri Bainun, 30450 Ipoh, Perak, Malaysia
6 Department of Pathology, Sarawak General Hospital, 93586 Kuching, Sarawak, Malaysia
7 Subang Jaya Medical Centre, 47500 Subang Jaya, Selangor, Malaysia

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Date of Submission15-Aug-2020
Date of Decision30-Sep-2020
Date of Acceptance25-Oct-2020
Date of Web Publication20-Oct-2021


Background: Human epidermal growth factor receptor 2 (HER2) over-expression in breast cancer is associated with aggressive tumor behavior and predicts response to targeted therapy. Accurate HER2 result is paramount for optimal patient management. However, routine HER2 immunohistochemistry (IHC) testing are subjected to intra- and inter-laboratory variability. Objective: This study aims to determine inter-laboratory variation in HER2 IHC testing through a slide-exchange program between five main reference laboratories. Method: A total of 20 breast carcinoma cases with different known HER2 expression and gene status were selected by the central laboratory in five testing rounds. Three unstained tissue sections from each case were sent to participating laboratories, which immunostained and interpreted the HER2 immunohistochemistry result. One of the stained slides was sent to one designated participating laboratory for evaluation. Results were analyzed by the central laboratory. Results: A complete concordance was achieved in six IHC-positive and six IHC-negative cases, its gene status of which was confirmed by in-situ-hybridization (ISH) study. The discordant results were observed in six equivocal cases, one negative case and one positive case with a concordance rate of 50–88.3%. Interestingly, the negative discordant case actually displays tumor heterogeneity. Good inter-observer agreement was achieved for all participating laboratories (k = 0.713-1.0). Conclusion: Standardization of HER2 testing method is important to achieve optimum inter-laboratory concordance. Discordant results were seen mainly in equivocal cases. Intra-tumoral heterogeneity may impact the final HER2 IHC scoring. The continuous quality evaluation is therefore paramount to achieve reliable HER2 results.

Keywords: Breast cancer, HER2 immunohistochemistry, proficiency study, quality control, ring study

How to cite this article:
Md Pauzi SH, Masir N, Yahaya A, Mohammed F, Tizen Laim NM, Mustangin M, Aizudin AN, Talib A, Teoh KH, Karim N, Oy-Leng JW, Rajadurai P. HER2 testing by immunohistochemistry in breast cancer: A multicenter proficiency ring study. Indian J Pathol Microbiol 2021;64:677-82

How to cite this URL:
Md Pauzi SH, Masir N, Yahaya A, Mohammed F, Tizen Laim NM, Mustangin M, Aizudin AN, Talib A, Teoh KH, Karim N, Oy-Leng JW, Rajadurai P. HER2 testing by immunohistochemistry in breast cancer: A multicenter proficiency ring study. Indian J Pathol Microbiol [serial online] 2021 [cited 2023 Jan 31];64:677-82. Available from:

   Introduction Top

Human epidermal growth factor receptor type 2 (HER2) gene encodes a cell surface receptor protein that possesses tyrosine kinase activity.[1] It has been shown that this gene is amplified in 15–30% of cases of primary breast cancer.[2],[3],[4]

HER2 positivity in breast cancer confers a prognostic factor in which over-amplified HER2 gene is associated with aggressive tumor behavior and poor prognosis, especially in patients with nodal metastasis.[2],[4],[5],[6] It is also a predictive marker in estimating responses to trastuzumab (Herceptin) treatment.[1],[2] It has been suggested that HER2 status may also predict response to hormonal and chemotherapy.[2] HER2 serve as both prognostic and predictive marker; knowing its status guides the oncologists in choosing the best systemic therapies for breast cancer patients.

Early and accurate HER2 testing is essential in primary breast cancer for optimal patient management. Trastuzumab was proven to increase progression-free survival and overall survival in the metastatic disease. However, this therapy is not without risk as it also has toxic side effects apart from its expensive treatment cost.[3] Considering this, an accurate HER2 result is paramount to breast cancer management as false-negative results may hamper proper treatment while a false positive result would lead to the administration of potentially toxic, ineffective treatment.[3]

A HER2 testing algorithm for breast cancer cases recommended by the American Society of Clinical Oncology/College of American Pathologist was recently updated in 2013 (ASCO/CAP guideline).[3],[7] This guideline has been adapted in HER2 immunohistochemistry interpretation in our laboratories with further in-situ-hybridization (ISH) study to confirm HER2 gene amplification was performed for both positive (score 3+) and equivocal (score 2+) cases to select eligible patients for trastuzumab therapy.

HER2 immunohistochemistry testing is widely performed by histopathology laboratories in Malaysia with the confirmatory ISH study centralized to a few main reference laboratories. As with any laboratory test, HER2 immunohistochemistry test is subject to intra- and inter-laboratory variation. The main objective of this study was to determine the agreement of HER2 status evaluated by immunohistochemistry results by five reference laboratories and to detect the variation of HER2 scoring between the laboratories. Using the results of this study, we hope to identify factors that may contribute to the variation of HER2 results between laboratories as well as to evaluate the usage of slide-exchange programs as quality assessment tools.

   Materials and Methods Top

This was a slide-exchange program to correlate the results of HER2 protein expression by immunohistochemistry (IHC) in breast carcinoma between five reference histopathology laboratories in Malaysia that were routinely involved in HER2 testing (IHC and ISH). This study included five testing rounds at three-monthly intervals. The study was coordinated by a central laboratory which provided the cases for all five participating histopathological laboratories as well as analyzing the final results.

A total of 20 cases of breast carcinoma from mastectomy or wide local excision were assessed over the period of study. A mastectomy or wide local excision specimen was selected as the tumour area was larger for evaluation of HER2 immunohistochemistry with the possibility of heterogenous intratumoural HER2 protein expression will be better assessed. The selected cases were from routine surgical pathology practice at the central laboratory, which comprises of cases with variable HER2 protein expressions (score 0 to 3+). The cold ischaemic time for these specimens were around half an hour (less than one hour). As per routine laboratory protocol, the specimens received by the central laboratories were fixed in formalin for 24 hours before being processed and paraffin embedded. A 3-micrometre thick section from each selected tissue blocks were cut and mounted onto coated slides. Three unstained slides were provided for each case.

In each round, four breast carcinoma cases with different level of HER2 expression were randomly selected by the central laboratory. The central laboratory distributes three unstained sections from each case to all five participating laboratories.

The participating laboratories immunostained the sections for HER2 protein. Each laboratory utilized its own set of routine protocol and interpreted the score. The antibody (Ventana anti-HER2/neu rabbit monoclonal antibody, clone 4B5, catalogue number 790-4493) and detection kit (Ultra-view Universal DAB detection kit, catalogue number 760-500) used for this study was similar for all centers and was supplied by the central laboratory. One of the stained-slide was sent to one designated peer laboratory for interpretation. The same peer laboratory was designated for all five testing rounds [Figure 1].
Figure 1: Diagram of Study Design

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The HER2 protein expression by immunohistochemistry was evaluated manually by the respective laboratories and was scored as 0 (negative), 1+ (negative), 2+ (equivocal), and 3+ (positive) according to the ASCO/CAP guideline of HER2 testing 2013.[5] The final the scoring results (interpretation of staining of the respective laboratory staining as well as the peer laboratory's scoring) were sent back to the central laboratory. A final analysis of the results was performed upon completion of all five testing rounds. The information regarding the method of antigen retrieval and the type of automated staining platform protocol used by each center were also obtained. The diagram of the study is shown in [Figure 1] [Figure 1].

   Results Top

Descriptions on staining method employed by participating laboratories

As all the participating laboratories were using their own routine methods for IHC staining, the information on the staining method was also submitted to the central laboratory. All five participating laboratories employed heat-mediated antigen retrieval method. Control tissues were also tested for each run and were evaluated to be positive and working well before the interpretation of the test results was made.

All five laboratories used an automated staining platform, out of which four laboratories (Lab A, B, C, and E) were using Ventana Ultra while one laboratory (Lab D) used Ventana Benchmark XT [Table 1].
Table 1: Method of antigen retrieval and type of automated staining platform

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Analysis of Inter-laboratory concordance of immunohistochemistry (IHC) score

A complete 100% concordance between all five participating laboratories were achieved in 18 out of 20 cases, out of which 6 cases were scored as positive (score 3+), one case scored equivocal (score 2+) and 11 cases as negative (score 1+ or 0) [Table 2].
Table 2: Analysis of Immunohistochemistry: Concordance among testing laboratories

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All 20 cases were tested by DDISH study to confirm the HER2 gene amplification status. The HER2 gene was noted to be amplified in all 6 IHC-positive cases while 10 out of 11 IHC-negative cases show non-amplified HER2 gene. Interestingly, one case (case number 8) that was scored to be IHC-negative by all 5 laboratories was shown to have gene amplification by DDISH study. HER2 gene amplification was also proved in the single IHC-equivocal case. [Table 2].

Further information was also retrieved for case number 8, where the DDISH study showed a low level of gene amplification with a HER2/CEP17 ratio of 2.50.

Analysis of inter-observer agreement of HER2 IHC score between participating laboratories

As part of the study, one IHC-stained slide from each case was sent to a designated peer laboratory for interpretation [Figure 1]. The laboratories were grouped into five different groups, each of which comprised of one reference laboratory and one designated peer laboratory. The grouping was similar for all five testing rounds [Figure 1] and [Table 3]. Each of these groups had evaluated HER2 IHC test based on the slides stained by their peer laboratory and their agreement were assessed.
Table 3: Inter-laboratory Agreement in IHC Scoring

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Two out of five groups achieved a complete agreement in their IHC scoring with a kappa value of 1.0 while an almost perfect agreement was seen in group 1 (kappa value = 0.923). Two other groups showed a substantial IHC scoring agreement with a kappa value of 0.713 and 0.720, respectively [Table 3].

Analysis of discordant cases

All five participating laboratories had submitted one of their stained slides to the central laboratory, where the researchers there selected the two discrepant cases with concordance less than 100% (i.e., case number 12 and 19) [Table 2]. Three researchers (from the central laboratory) reviewed the stained slides together under a multi-headed microscope to review possible causes for this discordance.

In case number 12, it was revealing to observe that the tumor actually had regional heterogeneous HER2 expression with only a small focal area (<10% of tumor cells) showing complete membrane staining, which was according to 2013 ASCO/CAP guideline, interpreted as equivocal (score 2+) [Figure 2]. While the majority of the tumor area in this particular case did not express HER2 (score 0) [Figure 3], the ISH study revealed that this focal area showed amplified gene with a HER2/CEP17 ratio of 5.97. Nonetheless, the majority of the tumor showed a non-amplified gene status with a HER2/CEP17 ratio of 1.40.
Figure 2: HER-2 positive sub clone of tumor cells are seen focally in less than 10% of the tumor area in one case (original magnification, 100x)

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Figure 3: The majority of the tumor cells from the case illustrated in Figure 2 were immunohistochemically-negative for HER2 (original magnification, 200x)

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The researchers in the central laboratory had also reached a consensus of negative IHC score (score 0) for case number 19, as the case showed weak and incomplete membranous staining in <10% of the tumor cells.

   Discussion Top

A reliable and precise HER2 result is essential in ensuring an accurate course of treatment is being administered as well as preventing deprivation of beneficial targeted therapy in the management of breast cancer. It is thus of paramount importance that reference laboratories provide an accurate HER2 test result. This study managed to show that under standardized circumstances, an acceptable agreement can be obtained across many laboratories.

The 2013 ASCO/CAP guideline was followed by all laboratories[7] in the interpretation of the HER2 score as the 2018 guideline was yet to be released at the time the study commenced. The updated recommendation in the 2018 guideline[8] mainly focused on the definition of IHC 2+ which was defined as invasive cancer with weak to moderate complete staining that was observed in >10% of tumor cells with recommendation of reflex in-situ hybridization (ISH) testing on the same specimen or new testing by IHC or ISH on a new specimen if available.

The findings in this study showed a high level of concordance in HER2 IHC interpretation in almost all cases (90%). However, most of the concordant cases were IHC-positive (3+) and IHC negative (1+/0). It is known that inter-observer interpretation variability may occur at different staining intensity. This observation was noted in another study which showed good inter-observer agreement for IHC score of 0 and 3+ but poor agreement in IHC score 1+ and 2+.[9] Correct determination of staining of HER2 IHC score is clinically significant as in the present setting, only cases with IHC score of 2+ and 3+ were subjected to DDISH study to confirm gene amplification. Misinterpretation of 2+ cases as negative (1+) may lead to deprivation of possible targeted therapy to IHC-equivocal (2+), gene-amplified cases.

The above phenomenon was also noted in the current study. One case (case number 8) was scored as negative (score 0 or 1+) by all five participating laboratories. However, DDISH study performed for this case has confirmed HER2 gene amplification with a HER2/CEP17 ratio of 2.50. Under routine service protocol, further testing would not be performed for IHC-negative cases, rendering these patients non-eligible for trastuzumab therapy. Upon further review of the stained slides (for the above case number 8) from all five laboratories by researchers in the central laboratory, a consensus on negative IHC interpretation (score 0/1+) was achieved, thus eliminating the possibility of inter-laboratory and inter-observer variability in the interpretation of HER2 staining. Although all laboratories used sections from the same tissue blocks with standardized conditions as mentioned above, getting a detailed information on the technical aspect of the staining procedures, which was not investigated in this study (e.g. temperature of antibody incubation, duration of antigen retrieval and duration of antibody incubation), would be beneficial to assess possible causes of staining discrepancy.

Perez et al. (2006) suggested that discordant between local and central laboratory results may also occur in the testing archival specimen that has been stored for long durations due to the possibility of epitope degradation.[9],[10] The duration of storage for tumor tissue blocks used for this study ranged from 1-3 years in central laboratory archive. Although this factor may affect the immunohistochemical staining, other cases in the same testing rounds showed a good concordance in IHC staining and interpretation.

An excellent inter-laboratory agreement was also obtained in one study that utilized the same primary antibody across two laboratories even though no standardization of methods were performed. Nevertheless, the authors had recommended standardization of testing method between laboratories to achieve the highest level of concordance.[11] A similar recommendation of HER2 test standardization was also proposed by Gancberg et al. in 2002 in achieving reproducible results.[14]

Thomas et al. (2001) had concluded in their study that IHC scores 1+ and 2+ were not reliable to foretell the gene amplification status while IHC scores 0 and 3+ were highly predictive of HER2 gene status.[12] The authors thus recommended further in-situ-hybridization (ISH) testing in both IHC 1+ and 2+.[12]

According to the latest recommendation by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) 2018, there is no situation in which HER2 IHC score 0 or 1+ can be considered as positive. Therefore, this recommendation removes the need for routine additional ISH-test for this category of IHC-negative tumours.[8] Furthermore, the NSABP-47 trial that has looked into the value of trastuzumab in HER2-negative breast cancer patients (IHC score 1+ or 2+ with ISH ratio <2 or HER gene copy number <4) has found no added benefits of anti HER2 therapy to this group of patient.[13] Therefore, this finding further support the recommendation by ASCO/CAP to refrain from further testing of HER2 IHC-negative tumors.

A similar observation was also noted in one study by Suria Hayati et al. (2019) which showed 105 out 106 IHC-negative cases or 96.3% of those scored 0/1+ were proved to have non-amplified HER2 gene by ISH study.[5] All these observations have further emphasized the importance of reliable and accurate HER2 immunohistochemistry test.

Discordant results were expected in IHC-equivocal cases even between reference laboratories. A study by Perez et al. (2006) also showed HER2 IHC 2+ was a nonreliable predictor of HER2 status, irrespective of testing locality, whether the test was performed by a local or central laboratory.[10]

True gene amplification in equivocal (IHC score 2+) cases were reported to range from 18 to 69%. Probability of survival was reported to be comparable between ISH-negative/IHC-positive patients to that of ISH-negative/IHC-negative. Whereby, the survival was also noted to be similar among ISH-positive/IHC-negative patients to that of ISH-positive/IHC-positive.[9] These facts further emphasize the role of in-situ-hybridization study (ISH) to confirm the gene amplification status.

True tumoral heterogeneity in HER2 expression is not frequently encountered.[15],[16] Tumor heterogeneity is suggested to occur in 1% of all breast malignancy,[2],[16] while one study reported a percentage of 36% among the gene-amplified cases.[11] Case 12 in the current study highlighted this issue in which the focus of tumor cells exhibiting IHC-positive, gene-amplified status was found to contribute to the discordant scoring interpretation among laboratories. Therefore, the difference in staining pattern should not be ignored or presumed to be a technical fault with further testing with ISH as indicated in this situation. HER2-overexpression in ductal carcinoma in-situ (DCIS) with the negative invasive component is nonetheless not considered to have intra-tumoral heterogeneity. The presence of tumor sub clone which is HER2-positive in true intra-tumoral heterogeneity is clinically significant as it may reflect a different patient's response to therapy.[16]

Eliminating the improperly-treated patient with false-positive HER2 status by achieving accurate determination of HER2 status will have a significant impact in the long run.[17] Even though HER2 amplification can be detected via other diagnostic assays such as polymerase chain reaction (PCR),[18],[19] both IHC and ISH testing which can be performed on the formalin-fixed, paraffin-embedded tissue specimen is more appropriate for routine surgical pathology practice. Furthermore, the outcome of Transtuzumab clinical trials has been based on HER2 status tested by IHC and ISH.[17],[20]

In the present study, although a certain degree of standardized conditions was ensured, discrepancies were still observed among the reference laboratories albeit a few. As a consequence, laboratories that carried out a small number of HER2 testing are expected to have discrepancies as compared with the results obtained by the central or reference laboratory which perform tests in much larger volumes.[10] A study by Paik et al. (2002) hypothesized that the discordance may be attributed to overestimation of HER2-positive cases by the pathologist in laboratories that perform infrequent HER2 test.[21] Furthermore, problems in methodology and variability in the interpretation of HER2 results were likely encountered in low-volume laboratories. These factors emphasize the importance to centralize the HER2 testing to high-volume laboratories.[10],[21] Usage of image-analysis software to analyze the IHC-stained slides may also aid in achieving better concordance results.[2]

In conclusion, precise HER2 results are paramount to select eligible patients that may benefit from targeted therapy. HER2 testing methods require a high standard of validation to ensure the reliability of results. Our study has shown that under certain standardized condition, an excellent inter-laboratory agreement can be achieved. A continuous in-house evaluation, participation in slide-exchange program and participation in external quality assurance program will also be beneficial to ensure good laboratory performance.

Financial support and sponsorship

This study was supported by an external grant by Roche (Malaysia) Sdn Bhd which provide the financial funding for the study. The funders had no role in the design of the study, the collection, analysis or interpretation of the data, the writing of the manuscript and the decision to publish the manuscript. The study is approved by the Ethical Committee of Universiti Kebangsaan Malaysia Medical Centre, Project Code: FF-2017-078.

Conflicts of interest

There are no conflicts of interest.

   References Top

Umemura S, Osamura RY, Akiyama F, Honma K, Kurosumi M, Sasano H, et al. What causes discrepancies in HER2 testing for breast cancer? A Japanese ring study in conjunction with the global standard. Am J Clin Pathol 2008;130:883-91.  Back to cited text no. 1
Dowsett M, Hanna WM, Kockx M, Penault-Llorca F, Ruschoff J, Gutjahr T, et al. Standardization of HER2 testing: Results of an international proficiency-testing ring study. Mod Pathol 2007;20:584-91.  Back to cited text no. 2
Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 2013;31:3997-4013.  Back to cited text no. 3
van de Vijver M, Bilous M, Hanna W, Hofmann M, Kristel P, Penault-Llorca F, et al. Chromogenic in situ hybridisation for the assessment of HER2 status in breast cancer: An international validation ring study. Breast Cancer Res 2007;9:R68.  Back to cited text no. 4
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Gancberg D, Järvinen T, Di Leo A, Rouas G, Cardosol F, Paesman M, et al. Evaluation of HER-2/NEU protein expression in breast cancer by immunohistochemistry: An interlaboratory study assessing the reproducibility of HER-2/NEU testing. Breast Cancer Res Treat 2002;74:113-20.  Back to cited text no. 14
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Hillig T, Thode J, Breinholt MF, Franzmann MB, Pedersen C, Lund F, et al. Assessing HER 2 amplification by IHC, FISH, and real-time polymerase chain reaction analysis (real-time PCR) following LCM in formalin-fixed paraffin embedded tissue from 40 women with ovarian cancer. APMIS 2012;120:1000-7.  Back to cited text no. 18
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Hofmann M, Stoss O, Gaiser T, Kneitz H, Heinmoller P, Gutjahr T, et al. Central HER2 IHC and FISH analysis in a trastuzumab (Herceptin) phase II monotherapy study: Assessment of test sensitivity and impact of chromosome 17 polysomy. J Clin Pathol 2008;61:89-94.  Back to cited text no. 20
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Correspondence Address:
Suria Hayati Md Pauzi
Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_983_20

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