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Expert Sheds Light on Issues With ASCO-CAP HER2 Guidelines

Laura Panjwani
Published: Tuesday, Sep 27, 2016

Michael F. Press, MD, PhD

Michael F. Press, MD, PhD

Due to discrepancies in HER2-testing results, ASCO and the College of American Pathologists (ASCO-CAP) recently released new guidelines for the use of fluorescence in situ hybridization (FISH) testing for HER2 in breast cancer.

The guidelines separate in situ hybridization (ISH) into 5 groups based on HER2 FISH ratio and average HER2 gene copy number per tumor cell. According to the ASCO-CAP guidelines, breast cancers in groups 1, 2, and 3 are interpreted as ISH-positive, group 4 as ISH-equivocal, and group 5 as ISH-negative. These classifications differ from the original FDA-approved criteria for HER2 gene amplification.

Using data from 3 Breast Cancer International Research Group studies, researchers at the University of Southern California conducted a retrospective study comparing the original FDA-approved criteria for HER2 gene amplification with the current ASCO-CAP guidelines. Their findings support the original categorizations of HER2 by FISH status.

“The most significant thing we learned is that compared to the original FDA-guidelines, we did not find an advantage to the current ASCO-CAP guidelines in predicting correlations, either with HER2 protein expression or with patient outcomes in terms of overall and disease-free survival,” said lead study author Michael F. Press, MD, PhD, a professor in the Department of Pathology and co-leader of the Women’s Cancers Program at Norris Comprehensive Cancer Center. “The FDA approach is perfectly adequate and we do not have reason in most cases to diverge.”

To learn more about the study, OncLive spoke with Press about the trial design and exactly how the 2 sets of guidelines differ from one another.

OncLive: How was the study conducted?

Press: We looked at samples from over 10,000 women from 3 clinical trials and stratified them according to HER2 FISH status as either HER2-amplified or HER2 nonamplified. Current ASCO-CAP guidelines include a category that they call “HER2-equivocal,” which is HER2 unknown.

In our original screening using the FDA-approved guidelines, they were sorted into 2 different groups, amplified or nonamplified. Since we had these data on HER2 by FISH and we also have the data of HER2 by immunohistochemistry (IHC), we could re-sort these cases according to the current ASCO-CAP FISH guidelines, which includes 5 different groups that they have categorized.

These groups are then determined to be ISH-positive, ISH-negative, or ISH-equivocal. They have 3 categories and we usually only use 2. Therefore, we validated with FISH and sorted our cases into the 5 categories that they have, calling them groups 1 through 5, and then analyzed the data that was downstream of those patients, in terms of their clinical outcome and in terms of the tissue samples—how they were categorized by IHC. Our findings were that IHC was more strongly correlated with the original HER2-gene amplification status determined by the FDA guidelines rather than the ASCO-CAP guidelines.

Having said that, it is important to keep in mind that there is about a 95% agreement rate between breast cancers analyzed by either of these approaches. The differences are in about 5% of women. Therefore, it is not a huge difference, and the differences are in groups 2, 3, and 4, which are basically the groups created by the ASCO-CAP guidelines that are not part of the original FDA guidelines.

What are the biggest differences between the original FDA-approved guidelines and the ASCO-CAP guidelines?

The first big difference was seen in group 2. To understand the differences, you need to understand that the number of HER2 gene copies is represented as an average, and that is compared to a control that is on the same chromosome, ideally, as the HER2 gene. The standard approach is to use chromosome 17 centromere, which is an approach that has been used since about 1991. When the ratio between HER2 and chromosome 17 centromere is greater than 2, it is referred to as HER2 gene amplification.

What the ASCO-CAP guidelines did is break this up into 2 groups: one group where the average HER2 copy number is greater than or equal to 4 and one in which it is less than 4. HER2 gene amplification represents a substantial increase in the number of copies of the HER2 gene. Four is not a substantial increase, but 20 or 30 are substantial increases.

Our previous data that we published in 1997 suggested that the behavior of breast cancers in women that did not have at least 4 copies of HER2 was relatively less aggressive, like that of women who had conventional HER2 nonamplified breast cancer. Since 1997 we have, in our consultation practice, called attention to these patients that are so-called “HER2-positive” patients with a ratio rate of HER2 but probably not gene amplification.

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