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Implementation of the 2018 Human Epidermal Growth Factor Receptor 2 Guideline by American Society of Clinical Oncology/College of American Pathologists Will Reduce False-Positive Tests.

To the Editor.--We highly appreciated the recent publication on the update of human epidermal growth factor receptor 2 (HER2) testing guideline for breast cancer by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) in Journal of Clinical Oncology. (1) The new guideline introduces a more rigorous diagnostic approach, compared with the previous ASCO/CAP 2013 recommendations, (2) regarding the HER2 testing algorithm for a subset of ambiguous and difficult cases that may be observed by using a dual-probe in situ hybridization assay, namely (1) low-level HER2 gene amplification defined by HER2/chromosome enumeration probe 17 (CEP17) ratio [greater than or equal to] 2.0 and average copy number < 4.0 per cell, (2) HER2 copy number gain defined by HER2/CEP17 ratio < 2.0 and average copy number [greater than or equal to] 6.0, and (3) equivocal HER2 status characterized by HER2/CEP17 ratio < 2.0 and average copy number [greater than or equal to] 4.0 and < 6.0.

The new evaluation criteria will most likely have an important clinical impact because the HER2-equivocal patients defined according to the previous recommendations will be redistributed in HER2-positive and HER2-negative test results. From their introduction in 2013, equivocal cases, detected at a not negligible frequency of up to 20%, generated uncertainty regarding clinical management, posing the challenge to oncologists of whether to recommend HER2-targeted therapy. (1, 2) In our practice, a choice in favor of treatment was made for tumors showing aggressive clinical-morphologic features (young age, advanced stage, high grade, high Ki-67 index), resulting in about one third of equivocal patients being treated with HER2-targeted therapy. However, there is a complete lack of clinical information about benefits in this group (these patients were not eligible for treatment in the original pivotal trials (1,3)), and it is possible that anti-HER2 treatment in these patients generated false expectations, increased costs, and unnecessary adverse effects. To face these issues, ASCO/CAP 2013 recommended the use of reflex tests to classify equivocal cases. (2) Many laboratories have relied on alternative and not clinically validated chromosome 17 fluorescent in situ hybridization (FISH) probes, which turned into positive almost one half of equivocal cases (30% to 50%), (1, 3, 4) but, because no evidence of therapy efficacy has been reported in this subgroup, the 2018 Expert Panel has taken a strong position against using this approach as a routine strategy. (1) We totally agree that this approach is unreliable because we observed that the alternative D17S122 probe tested in a series of 265 HER2-negative cases (ratio < 2.0, HER2 copy number < 4.0) detected 27 patients (10%) with a false-positive HER2 test, thus indicating that the introduction of this probe in clinical practice had possibly generated a considerable number of false-positive tests in equivocal cases as well (unpublished data).

To quantify the impact of the new ASCO/CAP guideline in daily practice, we applied the HER2 FISH classifications criteria produced in 2007, 2013, and 2018 (1, 2, 5) to a consecutive series of 880 breast cancer samples collected during the past 4 years in our institution and selected for FISH analysis according to in-house policy (6) or as requested by clinicians (Figure). Equivocal cases (97 of 880 [11%]) were turned into HER2 negative in 92 patients (95%) according to the 2018 guideline, confirming that the application of the new criteria will avoid redundant reflex testing and overtreatment in a relevant number of patients, with a clear improvement in terms of cost effectiveness.

In addition, the ASCO/CAP 2018 guideline has changed the evaluation criteria for cases with nonclassical HER2 amplification, namely low-level HER2 amplification and HER2 copy number gain. In our series, we observed that 12 of 250 HER2-positive patients (5%) according to the 2013 guideline were reclassified as negative because of the absence of HER2 overexpression (scores 1 and 2). Among these patients, 10 (83%) showed HER2 copy number gain, and only 2 (17%) showed low level of HER2 amplification.

We conclude that the introduction into clinical practice of the ASCO/ CAP 2018 classification will generate a considerable increase in negative cases compared with the ASCO/CAP 2013 guideline, coming from false-positive patients previously classified as equivocal or as with nonclassical amplification, without overexpression of HER2 protein. No or slight changes will be observed in the overall rate of positive patients because the 2018-positive shifted from 2013-equivocal will balance the 2013-positive lost when reclassified according to the 2018 guideline. However, the ASCO/ CAP 2018 HER2-positive patients will have a different HER2 status compared with positive patients selected on the basis of the 2013 criteria because the new algorithm more rigorously selects HER2-driven tumors.

Accurate HER2 assessment for clinical decision-making in patients with invasive breast carcinoma is fundamental for patient care. Our experience supports the expectation that the combined in situ hybridization-immunohistochemistry approach recommended by ASCO/CAP 2018 will result in a more accurate selection of patients eligible for targeted therapy, closely reflecting the original guideline published in 2007. (5)

Vittoria Martin, Alexandra Valera, Melissa De Joffrey, Sara Banfi, Luca Mazzucchelli

Institute of Pathology, Locarno, Switzerland

(1.) Wolff AC, Hammond MEH, Allison KH, 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. J Clin Oncol 36: 2105-2122, 2018 https://doi.org/10.1200/JCO. 2018.77.8738 PubMed

(2.) Wolff AC, Hammond MEH, Hicks DG, 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 31:3997-4013, 2013 https://doi.org/10. 1200/JCO.2013.50.9984 PubMed

(3.) Shah MV, Wiktor AE, Meyer RG, et al: Change in pattern of HER2 fluorescent in situ hybridization (FISH) results in breast cancers submitted for FISH testing: Experience of a reference laboratory using US Food and Drug Administration criteria and American Society of Clinical Oncology and College of American Pathologists guidelines. J Clin Oncol 34:3502-3510, 2016 https://doi.org/10.1200/JCO. 2015.61.8983 PubMed

(4.) Donaldson AR, Shetty S, Wang Z, et al: Impact of an alternative chromosome 17 probe and the 2013 American Society of Clinical Oncology and College of American Pathologists guidelines on fluorescence in situ hybridization for the determination of HER2 gene amplification in breast cancer. Cancer 123:2230-2239, 2017 https://doi.org/10. 1002/cncr.30592 PubMed

(5.) Wolff AC, Hammond MEH, Schwartz JN, et al: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118-145, 2007 https://doi.org/10.1200/JCO.2006.09.2775 PubMed

(6.) Martin V, Camponovo A, Ghisletta M, et al: Internal quality assurance program for ERBB2 (HER2) testing improves the selection of breast cancer patients for treatment with trastuzumab. Pathol Res Int 2012:261857, 2012 https://doi.org/ 10.1155/2012/261857 PubMed

Accepted for publication November 21, 2018.

Published online January 3, 2019.

The authors have no relevant financial interest in the products or companies described in this article.

Copyright 2018 College of American Pathologists and American Society of Clinical Oncology. This letter is being jointly published by invitation and consent in the Archives of Pathology & Laboratory Medicine and the Journal of Clinical Oncology. This letter has been edited in accordance with style standards established at the Journal of Clinical Oncology. All rights reserved.

doi: 10.5858/arpa.2018-0904-LE
Human epidermal growth factor receptor 2 (HER2) test results
distribution applying 2007, 2013, and 2018 American Society
of Clinical Oncology (ASCO)/College of American Pathologists
(CAP) guidelines on a series of 880 patients with invasive
breast cancer selected for in situ hybridization analysis
performed with dual-probe US Food and Drug Administration--approved
fluorescent in situ hybridization assay (PathVysion, Abbott,
Abbott Park, IL).

                HER2-Positive   HER2-Negative   HER2-Equivocal

ASCO/CAP 2007        24              28              28
ASCO/CAP 2013        74              61              72
ASCO/CAP 2018         2              11               0

Note: Table made from bar graph.
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Title Annotation:Letters to the Editor
Author:Martin, Vittoria; Valera, Alexandra; de Joffrey, Melissa; Banfi, Sara; Mazzucchelli, Luca
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Letter to the editor
Date:Apr 1, 2019
Words:1335
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