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Findings from the DESTINY-Breast04 trial necessitated a tweak to human epidermal growth factor receptor 2 (HER2) testing guidelines from ASCO and the College of American Pathologists (CAP).

An update published in the affirmed the prior HER2 reporting recommendations, but suggested a new HER2 testing reporting comment to highlight the relevance of immunohistochemistry (IHC) 0 versus 1+ results.

"This update acknowledges a new indication for trastuzumab deruxtecan when HER2 is not overexpressed or amplified but is IHC 1+ or 2+ without amplification by in situ hybridization," wrote Expert Panel co-chairs Antonio C. Wolff, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, and Kimberly H. Allison, MD, of Stanford University School of Medicine in California, and co-authors.

The following Q&A discusses the details of the update. (None of the authors were available for an interview, and the answers are excerpted from the text.)

What were the new findings that led to a review of the HER2 testing guidelines?

The impetus for revisiting the ASCO-CAP guideline was the 2022 publication of the trial. Shanu Modi et al. 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 IHC 1+ or IHC 2+ with in situ hybridization (ISH) not-amplified results, treated with the antibody-drug conjugate 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.

What new approvals were based on this trial?

These data extended the U.S. 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 ( PATHWAY anti-HER2/neu 4B5 rabbit monoclonal antibody on the BenchMark ULTRA instrument) for a new use as a semi quantitative assay, to identify patients with breast cancer without HER2 overexpression or amplification who could be eligible for treatment with trastuzumab deruxtecan.

The implications of these data for the ASCO-CAP breast cancer HER2 testing guideline recommendations were reviewed.

What did you determine in your review?

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+).

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.

How did you decide to modify your recommendations?

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. 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 in the .

Why did you decide it was premature to create a new category of HER2 expression, such as HER2-Low?

The terminology of 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.

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.

Read the guideline update here.