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HER2 Gene Testing Guidelines May Misclassify Patients

Allie Strickler @Alliejayes
Published: Monday, Mar 13, 2017

Michael F. Press, MD, PhD

Michael F. Press, MD, PhD

New guidelines for the way patients with breast cancer should be classified are a concern, as a small subset of patients are liable to be misclassified and receive the wrong treatment, said Michael F. Press, MD, PhD, a member of the College of American Pathologists (CAP). He has recommended changes to updated ASCO-CAP guidelines on assessment of HER2 amplification by fluorescence in situ hybridization (FISH).

Press, the Harold E. Lee Chair for Cancer Research in the Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California, discussed the new ASCO-CAP guidelines for HER2 FISH testing at the 2017 Miami Breast Cancer Conference. Although the updates have resulted in no changes for approximately 90% to 95% of cases, they will result in potential disagreements for approximately 5% of HER2 breast cancer cases, according to Press.

OncLive: What is controversial about the HER2 oncogene right now in breast cancer?

Press: The guidelines were published in 2013 and 2014 and did not recommend many changes related to testing for the HER2 protein using immunohistochemistry [IHC]. Some minor revisions were made, but they didn’t substantially impact the way in which HER2 is evaluated by IHC. On the other hand, the ASCO-CAP guidelines committee did make a number of changes in the way the HER2 gene is evaluated by FISH for gene amplification. These changes have created confusion about whether or not some FISH subgroups are HER2 amplified, known as in situ hybridization (ISH)-positive, or HER2 not amplified, known as ISH-negative. This confusion impacts approximately 5% of women with breast cancer.

Approximately 20% to 25% of breast cancers in women have the HER2 gene alteration, also known as gene amplification. This means that the cancer cells have increased the number of copies of the HER2 gene in each tumor cell. Whereas normal cells have 2 copies of the HER2 gene, cancer cells often have greater than 20 copies per tumor cell. This leads to a great increase in such things as cell migration, cell invasion, and increased cell division. It stimulates the production of new blood vessels, and these cancer cells are much more aggressive than cancers that lack this particular alteration.

The good news is that there are several different HER2-targeted therapies that interfere with the actions of the overexpressed protein on the cell surface. And one class of these would be monoclonal antibodies that are directed against the extracellular domain, such as trastuzumab (Herceptin) and pertuzumab (Perjeta). There are also antibody–drug conjugates (ADCs). There’s T-DM1 (trastuzumab emtansine; Kadcyla), which is linked to a biological toxin, so that the drug is directed to tumor cells that overexpress HER2. When the membrane is internalized, the poison that’s linked to trastuzumab damages and destroys the tumor cells. Another class of agents is anti-HER2 small molecule inhibitors. Either one of these classes of drugs prevent the continuous stimulation of HER2 in tumor cells.

Because there are drugs that are aimed at HER2 gene amplification and overexpression, it’s important to know who among patients with breast cancers has this alteration and who doesn’t. In the absence of gene amplification, there is no HER2 overexpression. The ASCO-CAP guidelines for HER2 testing by FISH have created new definitions of what is HER2-positive and what is HER2-negative. And I think these new definitions are problematic.

How are these definitions changing, and what makes them so problematic?

In the past, women were enrolled in clinical trials of HER2-targeted drugs if they had HER2-positive breast cancers. The definition of HER2-positive by FISH in the past referred to a ratio between the number of copies of the HER2 gene, compared with a control gene on the same chromosome arm that was greater than 2. The centromere is the usual control gene for calculation of this ratio. When the ratio of the HER2 gene compared with the centromere (CEP17) is greater than 2, these breast cancers are referred to as HER2-amplified.

The current ASCO-CAP guidelines for HER2 testing by FISH require consideration of both the HER2-to-CEP17 ratio and the average HER2 gene copy number per tumor cell. Because the clinical trials used for FDA approval of HER2-targeted therapies did not use this definition, it was not clear how the current ASCO-CAP guidelines definitions correspond to the previous definition of HER2 amplification used for enrollment in the clinical trials.


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Online CME Activities
TitleExpiration DateCME Credits
Miami Breast Cancer Conference®: Attendee Tumor Board OnlineNov 30, 20181.5
Community Practice Connections™: 1st Annual Paris Breast Cancer Conference™Dec 31, 20181.5
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