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New ASCO/CAP Guideline Enhances HER2 Testing in Breast Cancer

Silas Inman
Published Online: Monday, October 7, 2013
Dr. Antonio C. Wolff

Antonio C. Wolff, MD

The American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) have released updated recommendations for HER2 testing in breast cancer. The new guideline endorses HER2 testing for every primary, recurrent, and metastatic tumor. Additionally, the report advocates retesting in patients who previously tested HER2-negative but demonstrate clinical behavior suggestive of HER2-positive or triple-negative disease at the time of recurrence.

The accurate identification of patients with HER2-positive breast cancer remains an area of high interest, since HER2-targeted therapies can substantially improve their survival. The updated guideline follows counsel from a joint committee that performed an extensive literature review of more than 70 publications that had been published since the National Comprehensive Cancer Network, in collaboration with ASCO/CAP, published the first guideline in 2007.

"This guideline update strengthens and clarifies recommendations for HER2 testing based on new evidence,” said Antonio C. Wolff, MD, co-chair of the ASCO/CAP HER2 Testing in Breast Cancer Panel and professor of Oncology at the Johns Hopkins Kimmel Comprehensive Cancer Center, in a statement. “Our ability to identify cancer subtypes that will lead to more individualized therapeutic decisions and that are shown to improve clinical outcomes is rapidly improving. Consequently, and more than ever before, society must demand access to high-quality cancer biomarker tests that can help cancer specialists match the right treatments with the right patients.”

The interpretation of HER2 test results follows an algorithm that was modernized for both immunohistochemistry (IHC) and in-situ hybridization (ISH) based assays. The refurbished criteria focus on HER2-positive status, defined via IHC as protein overexpression or via ISH as gene amplification by either HER2 gene copy number or HER2/CEP17 ratio.

At the time of the 2007 guidelines, a leading concern was the number of false-positive rates. However, in recent years, this has largely been reversed toward a concern regarding false-negative results. As such, the amended guideline places more emphasis on ensuring that HER2-positive disease is accurately detected.

For patients who test HER2-negative but demonstrate apparent histopathologic discordance, three levels of testing are suggested. The HER2 test can be performed on a core biopsy or on a surgical specimen from a patient with newly diagnosed breast cancer. If there is discordance, a section of the tumor from the excisional specimen should be tested. If this test is negative and concerns remain, the updated guideline recommends retesting in a different block from the patient’s tumor. If all three tests are negative, no additional testing is recommended (See table for full histopathological features).

Table. Histopathologic Features Suggestive
of Possible HER2 Test Discordance

Retest if the following histopathologic findings occur and the initial HER2 test was positive:
Histologic grade 1 carcinoma of the following types:
  • Infiltrating ductal or lobular carcinoma, ER and PgR positive
  • Tubular (at least 90% pure)
  • Mucinous (at least 90% pure)
  • Cribriform (at least 90% pure)
  • Adenoid cystic carcinoma (90% pure) and often triple negative
If the core needle biopsy specimen is negative, a new HER2 test must be ordered on the excision specimen
If the following is true:
  • Tumor is grade 3
  • Amount of invasive tumor in the core biopsy is small
  • Resection specimen contains high-grade carcinoma that is morphologically distinct from that in the core
  • Core biopsy result is equivocal for HER2 after testing by both ISH and IHC
  • There is doubt about the specimen handling of the core biopsy (long ischemic time, short time in fixative, different fixative) or the test is suspected by the pathologist to be negative on the basis of testing error
Do not retest if the following histopathologic findings occur and the initial HER2 test was negative:
Histologic grade 1 carcinoma of the following types:
  • Infiltrating ductal or lobular carcinoma, ER and PgR positive
  • Tubular (at least 90% pure)
  • Mucinous (at least 90% pure)
  • Cribriform (at least 90% pure)
  • Adenoid cystic carcinoma (90% pure) and often triple negative

Sources: Adapted from Table 2 from Wolff AC et all. Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. Published in J Clin Oncol.



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