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Oncology/Hematology
HER2 Testing Guide Clarifies Rules, Process

Published: Oct 7, 2013 | Updated: Oct 8, 2013
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By Charles Bankhead, Staff Writer, MedPage Today
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points

An updated clinical guideline states that oncologists should determine HER2 status for every invasive breast cancer, including recurrent disease, and adhere to specific histologic criteria to define positive, equivocal, and negative results.
Note that the guideline recommends that breast cancer specialists recommend HER2-targeted therapy if the test is positive and delay a decision about HER2-targeted therapy if the initial HER2 test result is equivocal.

Oncologists should determine HER2 status for every invasive breast cancer, including recurrent disease, and adhere to specific histologic criteria to define positive, equivocal, and negative results, according to an updated clinical guideline.
Every tumor must be tested for HER2 protein expression by immunohistochemistry (IHC) or for HER2 gene expression by single- or dual-probe in situ hybridization (ISH) assay, using only validated tests, preferably those approved by the FDA, according to the guideline developed by the American Society of Clinical Oncology and the College of American Pathologists.
The guideline defines a positive test as IHC 3+ or ISH positive, equivocal as IHC 2+ or ISH equivocal, and negative as IHC 1+ or IHC 0 or ISH negative.
As compared with a 2007 version of the guideline, the update establishes more specific criteria for the histologic categories, such as the percentage of involved cells in a specimen, reported CAP co-chair Antonio C. Wolff, MD, of Johns Hopkins Kimmel Comprehensive Cancer Center, ASCO co-chair Elizabeth Hammond, MD, of the University of Utah in Salt Lake City, and colleagues, simultaneously online in the Journal of Clinical Oncology and Archives of Pathology & Laboratory Medicine.
"Since publication of the 2007 guideline, new diagnostic strategies, like measures of HER2 amplification by bright-field in situ hybridization, DNA expression by microarray, or mRNA expression reverse-transcriptase polymerase chain reaction, have been introduced into practice, and the Update Committee felt these required evidence-based review," the guideline panel noted.
"The Update Committee wishes to re-emphasize that it is important that any new test methodology, for the same clinical use, be compared with a reference test that assays for the same analyte and for which there are high levels of evidence that use of the test leads to clinical benefit for the patient," they wrote.
The updated guideline defines a positive test for HER2 as "when, on observing within an area of tumor that amounts to >10% of contiguous and homogeneous tumor cells, there is evidence of protein overexpression (IHC) or gene amplification (HER2 copy number orHER2/CEP17 ratio by ISH based on counting at least 20 cells within an area)."
In summarizing the guideline, committee members cited six key recommendations for oncologists and a dozen for pathologists. According to the the oncologist-directed recommendations, breast cancer specialists:

Must request HER2 testing for every primary invasive cancer (and on the metastatic site if stage IV)
Should recommend HER2-targeted therapy if the test is positive
Must delay a decision about HER2-targeted therapy if the initial HER2 test result is equivocal
Must not recommend anti-HER2 therapy for patients who have negative tests
Should delay a decision about anti-HER2 therapy if the test cannot be confirmed as positive or negative
May consider HER2-targeted therapy if a test result remains equivocal, even after reflex testing with an alternative assay

In addition to assuring the that tests are performed and reported appropriately, pathologists:

Must report test results as indeterminate if technical issues with IHC and/or ISH preclude a determination of positive, negative, or equivocal
Should interpret bright-field ISH results on the basis of a comparison between normal breast cells and tumor cells
Should ensure adherence to a specific protocol for preparing specimens for testing
Should ensure laboratory adherence to CAP standards
Should consider additional testing, in consultation with oncologists, if evidence of histopathologic discordance is observed, and document the decision-making process and results in the pathology report
Should consider results IHC or ISH equivocal if uncommon situations arise involving creation of HER2-status categories not covered by the guideline definitions

The update does not represent a dramatic overhaul of the previous version but instead clarifies test criteria, definitions, and processes, said Eric Winer, MD, a breast cancer specialist in the Susan F. Smith Center for Women's Cancers at Dana-Farber Cancer Institute in Boston.
"My sense is the guideline is a bit more explicit about the testing methodology, and also a bit clearer about how much HER2-positive disease has to be present for a specimen to be called truly HER2 positive as opposed to equivocal," Winer, who was not a member of the guideline panel, told MedPage Today. "What this guideline states is that if more than 10% of the tumor meets the criteria for HER2 positivity, then it is called HER2 positive."
The guideline update was supported by ASCO and CAP.
One or more members of the update committee disclosed relationships with Clarient-GE Healthcare, Roche, Genomic Health, Dako, and Abbott.