New Recommendations Improve Accuracy of HER2 Status Designation

Jason Harris
Published: Friday, Aug 17, 2018
Antonio C. Wolff, MD

Antonio C. Wolff, MD

The guidelines for establishing HER2 status for patients with breast cancer with unclear results on initial testing have been fine-tuned in an update that the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) recently issued.

ASCO and CAP first established HER2 testing guidelines in 2007 and published an update in 2013. The 2018 Focused Update addresses uncommon clinical scenarios and seeks to explain how to handle HER2 testing results that are borderline, or “equivocal,” as previously defined in the guidelines,1 by immunohistochemistry (IHC) or in situ hybridization (ISH) (Table 1).2

An expert panel consisting of members of both organizations revised the diagnostic approach for patients who fall into groups categorized as 2, 3, and 4 by ISH testing (Table 21) to include more rigorous interpretation criteria for dual-probe ISH testing, and require an accompanying IHC review. The combined interpretation of the ISH and IHC assays is meant to improve the accuracy of HER2 status designation.

Only an estimated 5% of specimens will fall into the equivocal classification. Most specimens, about 95%, will be clearly HER2 positive (group 1) or clearly HER2 negative (group 5) and those will generally only require ISH or IHC testing.1

Although current outcomes data from clinical trials are of “limited statistical power,” Antonio C. Wolff, MD, professor of oncology at Johns Hopkins University School of Medicine and co-chair of the expert panel, said the goal was to better define the expected prognostic and predicted behavior of specimens tested by a dual-probe ISH that falls into one of the equivocal HER2 groups.

During an interview on the ASCO Guidelines Podcast Series episode, “HER2 Testing in Breast Cancer Guidelines,” Wolff said several labs and clinical investigators have reported on the practical implications of the 2013 guideline update and the observed frequency of equivocal cases.

M. Elizabeth H. Hammond, MD, emeritus professor of pathology at the University of Utah School of Medicine in Salt Lake City and co-chair of the expert panel, said in an interview with OncologyLive® that the guidelines are updated whenever new evidence becomes available or if there is confusion about the previous recommendations. In this case, a letter to the editor published by the Journal of Clinical Oncology led the panel to clear up some confusion regarding categorization of specimens that were neither clearly negative nor positive.2

Some Recommendations Changed

The panel has changed a recommendation regarding repeat HER2 testing of a surgical specimen. If the initial core biopsy is negative, a repeat test on the excision specimen is now optional rather than mandatory. Hammond said that clinical evidence shows the result is unlikely to change with a second test and may result in misdiagnosis.

“If you do a lot of repeat testing on the same sample, statistically what you do is increase the [odds] that you will have the wrong answer just by chance,” she said. “Repeat testing, in and of itself, is not a good idea.

Table 1. Clinical Questions Addressed in Updated HER2 Guidelines2

Table 1. Clinical Questions Addressed in Updated HER2 Guidelines2
The panel also recommends that the same institution should perform the concomitant review to ensure “parallel interpretation and quality of the 2 assays.” Wolff said that very few group 2 specimens will be IHC 3+ and so will not be confirmed as HER2 positive. Most group 4 specimens will be confirmed HER2 negative without the need for additional testing using alternative probes, he added.

“Group 3 specimens will produce mixed results, with a small number of cases shown to be amplified and a larger number of cases not shown to be amplified,” he said. “So, for these dual-probe ISH group 3 cases, the panel allows specimens that are IHC 2+ to be considered HER2 positive.”

Hammond said clinicians dislike terms like “equivocal” to describe IHC 2+ results because they don’t know how to treat the patient.

“What we’re trying to do with this new guideline is make it so that we don’t use those words very often,” she added. “It’ll be vanishingly rare that we would use those words because now we can sort those cases into either positive or negative [categories].”

The updated guideline reverts to the FDA-approved definition of IHC 2+: invasive breast cancer with weak to moderate complete membrane staining observed in >10% of tumor cells.

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