To update the American Society of Clinical Oncology–College of American Pathologists (ASCO-CAP) recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer. An Update Panel is aware that a new generation of antibody-drug conjugates targeting the HER2 protein is active against breast cancers that lack protein overexpression or gene amplification.
The Update Panel conducted a systematic literature review to identify signals for updating recommendations.
The search identified 173 abstracts. Of 5 potential publications reviewed, none constituted a signal for revising existing recommendations.
The 2018 ASCO-CAP recommendations for HER2 testing are affirmed.
HER2 testing guidelines have focused on identifying HER2 protein overexpression or gene amplification in breast cancer to identify patients for therapies that disrupt HER2 signaling. This update acknowledges a new indication for trastuzumab deruxtecan when HER2 is not overexpressed or amplified but is immunohistochemistry (IHC) 1+ or 2+ without amplification by in situ hybridization. Clinical trial data on tumors that tested IHC 0 are limited (excluded from DESTINY-Breast04), and evidence is lacking that these cancers behave differently or do not respond similarly to newer HER2 antibody-drug conjugates. Although current data do not support a new IHC 0 versus 1+ prognostic or predictive threshold for response to trastuzumab deruxtecan, this threshold is now relevant because of the trial entry criteria that supported its new regulatory approval. Therefore, although it is premature to create new result categories of HER2 expression (eg, HER2-Low, HER2-Ultra-Low), best practices to distinguish IHC 0 from 1+ are now clinically relevant. This update affirms prior HER2 reporting recommendations and offers a new HER2 testing reporting comment to highlight the current relevance of IHC 0 versus 1+ results and best practice recommendations to distinguish these often subtle differences. Additional information is available at www.asco.org/breast-cancer-guidelines.
The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) first published a practice guideline on human epidermal growth factor receptor 2 (HER2) testing in breast cancer in 2007.1 The guideline was updated in 2013,2 and again in 2018,3 based on targeted literature searching, Panel expertise, and new signals.4 These guidelines were developed to standardize and ensure accurate detection of HER2 gene amplified or protein overexpressed breast cancers for prediction of benefit from HER2-targeted therapies. The clinical utility of HER2 testing to identify patients for therapy with the HER2 antibody trastuzumab has since expanded to other antibodies (pertuzumab added to trastuzumab, margetuximab), small molecule tyrosine kinase inhibitors (lapatinib, neratinib, or tucatinib), and antibody-drug conjugates (ADCs) (trastuzumab emtansine or trastuzumab deruxtecan).
The impetus for revisiting the ASCO-CAP guideline was the 2022 publication of the DESTINY-Breast04 trial. Modi et al5 showed in an open-label phase III study a significant improvement in survival in patients with breast cancers without HER2 overexpression or amplification, but with immunohistochemistry (IHC) 1+ or IHC 2+ with in situ hybridization (ISH) not-amplified results, treated with the ADC fam-trastuzumab-deruxtecan-nxki compared with physician’s choice of chemotherapy after progression on other therapies for metastatic disease. Participants in the control arm did not have access to trastuzumab deruxtecan after progression, and patients with IHC 0 results were excluded from the trial.
These data extended the US Food and Drug Administration–approved label indication of this drug and resulted in premarket approval of the monoclonal IHC antibody testing system used in DESTINY-Breast04 (Ventana PATHWAY anti-HER2/neu 4B5 rabbit monoclonal antibody on the BenchMark ULTRA instrument) for a new use as a semiquantitative assay, to identify patients with breast cancer without HER2 overexpression or amplification who could be eligible for treatment with trastuzumab deruxtecan.6 The implications of these data for the ASCO-CAP breast cancer HER2 testing guideline recommendations were reviewed.
Although there is clearly a new role for IHC assays to most accurately identify tumors that test HER2 IHC 1+ or 2+/ISH not-amplified, this clinical need is based on DESTINY-Breast04 clinical trial entry criteria rather than the demonstration of a new predictive or prognostic threshold for HER2 IHC test results below overexpression (IHC 3+).5 As patients whose cancers tested IHC 0 in a central laboratory were ineligible for the trial, and trial data did not identify a differential benefit between patients with IHC 1+ and 2+/ISH not-amplified treated with trastuzumab deruxtecan, no new predictive biomarker threshold for response (yes or no) has been identified among tumors historically classified as HER2-negative for overexpression or amplification. Instead, a new threshold has been artifactually created between a result of IHC 0 and IHC at least 1+ to determine access to the drug based on trial eligibility.
The terminology HER2-Low was used in the trial as shorthand for IHC 1+ or 2+/ISH not-amplified cases. However, other than renaming test results to fit trial eligibility for this new treatment indication, there is no evidence that HER2-Low is a new or reproducibly defined subtype of breast cancer with distinct prognostic or predictive implications.7–13 HER2 IHC 0 versus Low status also appears to be unstable across patient samples, with close to 40% of cases switching between IHC 0 and IHC 1+ or 2+/ISH not-amplified (HER2-Low) results when paired primary and metastatic are compared.8
There are data to suggest that IHC 0 cases may also have low levels of HER2 protein expression by more sensitive testing methods.11 Higher frequencies of HER2 protein detection in fresh tissue samples also suggest that preanalytic factors during tissue processing likely affect protein detection rates at low levels.14 Data from one single-arm phase II study (the DAISY trial [ClinicalTrials.gov identifier: NCT04132960] reported in abstract form) suggest that IHC 0 and HER2-Low cancers have similar response to trastuzumab deruxtecan. Although these results require confirmation, they suggest that an IHC 0 result may not truly mean a cancer has no targetable HER2 protein present, as HER2 assays are semiquantitative and were optimized to detect overexpression. Additional clinical trial data are needed to determine if IHC 0 samples also include targetable levels of HER2 protein needed for clinical response, to test if new, more sensitive assays can accurately quantify it, and to investigate if there is differential clinical benefit based on protein expression levels. Currently, there is a risk that available IHC assays are suboptimal for the detection of these low levels of protein expression and could result in false-negative and false-positive test determinations around the IHC 0/IHC 1+ threshold that would incorrectly influence treatment recommendations and potentially impact data from ongoing clinical trials that still rely on them.
The Expert Panel (see Appendix) also notes that adoption of HER2-Low terminology in IHC reporting is problematic because it would require changing the reporting schema for IHC 2+ results (currently reported as equivocal for protein overexpression with reflex ISH testing required to determine gene amplification status), such that the final IHC result category could not be reported (as HER2-Low versus HER2-positive) until reflex ISH results are back. Since the DESTINY-Breast04 trial used current standard IHC scoring definitions for 0, 1+, 2+, and 3+, there is also no evidence to support changing these at this time.
Based on the lack of new data to support a change to current HER2 scoring and reporting recommendations, the prior HER2 guideline recommendations for classic anti-HER2 therapies are affirmed, and no new reporting terminology is adopted. However, a new HER2 testing reporting footnote and additional best practices to identify candidates that may be eligible for trastuzumab deruxtecan are offered (see The Bottom Line).
The recommendations in previous (2013 and 2018) ASCO-CAP HER2 testing guideline updates are affirmed for classic anti-HER2 therapies that conventionally target HER2 signaling (Table). Although no changes are made to prior recommendations, there should be awareness that, for metastatic patients without HER2 overexpression or gene amplification, an IHC 1+ or 2+ result may make patients eligible for treatment targeting nonamplified/nonoverexpressed levels of HER2 expression (and IHC 0 results would not), for which trastuzumab-deruxtecan is the only currently available agent. A new HER2 testing reporting footnote and best practices for identification and reporting of IHC 0 versus IHC 1+ results are offered in the bulleted Bottom Line box.
The Clinical Practice Guidelines and other guidance published herein are provided by the ASCO and the CAP to assist providers in clinical decision-making. The information herein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified therein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Further, the information is not intended to substitute for the independent professional judgment of the treating provider, as the information does not account for individual variation among patients. Recommendations specify the level of confidence that the recommendation reflects the net effect of a given course of action. The use of words like “must,” “must not,” “should,” and “should not” indicates that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating provider in the context of treating the individual patient. Use of the information is voluntary. ASCO and the CAP do not endorse third-party drugs, devices, services, or therapies used to diagnose, treat, monitor, manage, or alleviate health conditions. Any use of a brand or trade name is for identification purposes only. ASCO and the CAP provide this information on an “as is” basis and make no warranty, express or implied, regarding the information. ASCO and the CAP specifically disclaim any warranties of merchantability or fitness for a particular use or purpose. ASCO and the CAP assume no responsibility for any injury or damage to persons or property arising out of or related to any use of this information, or for any errors or omissions.
Guideline and Conflicts of Interest
The Expert Panel was assembled in accordance with ASCO’s Conflict of Interest Policy Implementation for Clinical Practice Guidelines (“Policy,” found at www.asco.org/guideline-methodology). All members of the Expert Panel completed ASCO’s disclosure form, which requires disclosure of financial and other interests, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as a result of promulgation of the guideline. Categories for disclosure include employment; leadership; stock or other ownership; honoraria, consulting, or advisory role; speaker’s bureau; research funding; patents, royalties, other intellectual property; expert testimony; travel, accommodations, expenses; and other relationships. In accordance with the Policy, the majority of the members of the Expert Panel did not disclose any relationships constituting a conflict under the Policy.
More information, including a supplement with additional evidence tables, slide sets, and clinical tools and resources, is available at www.asco.org/breast-cancer-guidelines. The Methodology Manual (available at www.asco.org/guideline-methodology) provides additional information about the methods used to develop this guideline. Patient information is available at www.cancer.net.
ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients should have the opportunity to participate.
RELATED ASCO GUIDELINES
This ASCO and CAP Clinical Practice Guideline provides recommendations, with comprehensive review and analyses of the relevant literature for each recommendation. Additional information, including a supplement with additional evidence tables, slide sets, clinical tools and resources, and links to patient information at www.cancer.net, is available at www.asco.org/survivorship-guidelines.
Conception and design: Antonio C. Wolff, Mitchell Dowsett, M. Elizabeth H. Hammond, Daniel F. Hayes, Kimberly H. Allison
Administrative support: Mark R. Somerfield
Collection and assembly of data: Antonio C. Wolff, Mark R. Somerfield, Kimberly H. Allison
Data analysis and interpretation: Antonio C. Wolff, Mark R. Somerfield, Mitchell Dowsett, M. Elizabeth H. Hammond, Lisa M. McShane, Thomas J. Saphner, Patricia A. Spears, Kimberly H. Allison
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO–College of American Pathologists Guideline Update
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians.
Antonio C. Wolff
Research Funding: Genentech (Inst), Merck Sharp & Dohme (Inst), Array BioPharma (Inst)
Patents, Royalties, Other Intellectual Property: A.C.W. has been named as inventor on one or more issued patents or pending patent applications relating to methylation in breast cancer, and has assigned his rights to Johns Hopkins University (JHU), and participates in a royalty sharing agreement with JHU.
Consulting or Advisory Role: AstraZeneca/MedImmune, Besins Healthcare, Roche, Rovi, Lilly
Research Funding: Lilly (Inst)
Patents, Royalties, Other Intellectual Property: AIR-CIS—a molecular profile for predicting sensitivity of breast cancer patients to CDK4/6 inhibitors among patients resistant to an aromatase inhibitor (Inst), Share of royalties from the invention of abiraterone.
M. Elizabeth H. Hammond
Consulting or Advisory Role: Daiichi Sankyo/Astra Zeneca
Daniel F. Hayes
Stock and Other Ownership Interests: InBiomotion
Consulting or Advisory Role: Cepheid, Freenome, Epic Sciences, Cellworks, BioVica, Oncocyte, Turnstone Bio, Predictus Biosciences, Guardant Health, L-Nutra, Macrogenics, Tempus, Xilis, Exact Sciences
Research Funding: AstraZeneca (Inst), Pfizer (Inst), Menarini Silicon Biosystems (Inst), Cepheid/Danaher (Inst)
Patents, Royalties, Other Intellectual Property: Royalties from licensed technology, Diagnosis and Treatment of Breast Cancer. Patent No.: US 8,790,878 B2. Date of Patent: July 29, 2014. Applicant Proprietor: University of Michigan. D.F.H. is designated as inventor/coinventor, Circulating Tumor Cell Capturing Techniques and Devices. Patent No.: US 8,951,484 B2. Date of Patent: February 10, 2015. Applicant Proprietor: University of Michigan. D.F.H. is designated as inventor/coinventor, Title: A method for predicting progression free and overall survival at each follow-up timepoint during therapy of metastatic breast cancer patients using circulating tumor cells. Patent No.: 05725638.0-1223-US2005008602
Other Relationship: Menarini, UpToDate
Uncompensated Relationships: UpToDate
Patricia A. Spears
Consulting or Advisory Role: Pfizer
Kimberly H. Allison
Consulting or Advisory Role: Mammotome
Expert Testimony: Kaiser Permanente
No other potential conflicts of interest were reported.
The Expert Panel wishes to thank Alexi A. Wright, MD, MPH; Praveen Vikas, MBBS; and the Evidence Based Medicine Committee for their thoughtful reviews of and insightful comments on this guideline.
Wolff and Allison were Expert Panel cochairs.
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Authors’ disclosures of potential conflicts of interest are shown after the references.