Updated HER2+ Breast Cancer Guidelines Offer Additional Insight, But Questions Remain


Clinical guidelines have been necessary to help oncologists stay current in the face of rapidly evolving knowledge in HER2-positive breast cancer.

K.P. Siziopikou, MD, PhD

K.P. Siziopikou, MD, PhD

K.P. Siziopikou, MD, PhD

As HER2 status has become an ever-increasing aspect of breast cancer diagnosis and management during the past two decades, clinical guidelines have been necessary to help oncologists stay current in the face of rapidly evolving knowledge.

The most recent HER2 guideline from the ASCO/College of American Pathologists (CAP), published in 2018, addressed several previous oversights, but also leaves some important clinical questions in need of further clarification, Kalliopi Siziopikou, MD, PhD, said in a presentation at the 2019 Lynn Sage Breast Cancer Symposium.1

Siziopikou, director of Breast Pathology at Northwestern University’s Robert H. Lurie Comprehensive Cancer Center in Chicago, began by reminding colleagues that HER2 targeted therapy significantly improves outcomes for patients with HER2-positive breast carcinomas in adjuvant, neoadjuvant, and metastatic settings, and that HER2 gene amplification/protein overexpression occurs in 15% to 20% of invasive breast cancers, not the 25% to 30% initially reported.

Pathology labs use immunohistochemistry (IHC) to test for HER2 overexpression or in situ hybridization (ISH) to detect HER2 gene amplification. “One advantage to IHC and ISH is that the signals are interpreted in the context of the histopathology on tissue sections, permitting specific scoring in morphologically confirmed invasive cancer cells,” Siziopikou said. “Additionally, standard FFPE [formalin-fixed, paraffin-embedded] tissues are acceptable specimens, easily obtainable in most laboratory settings.”

Siziopikou emphasized that the focus of the 2007 ASCO/CAP guidelines was to limit false positives. “A number of studies showed a significant discordance rate between community labs and central testing, as high as 26% in one case,” she said. “The main problem in the early days was the lack of standardization of pre-analytic, analytic, and post-analytic factors.”

By the time the first major ASCO/CAP guideline revision occurred in 2013, the focus had shifted to limiting false negatives. As a result of this guideline, some laboratories adopted the use of alternative chromosome 17 probe testing for equivocal fluorescence in situ hybridization (FISH) results, Siziopikou noted.

In 2018, the Journal of Clinical Oncology published the newest ASCO/CAP guideline.2 “The focus of the 2018 ASCO/CAP guidelines was to give guidance for less common FISH patterns, groups 2-4, which together constitute 5% of all cases,” Siziopikou said.

Additionally, the guidelines answered five common clinical questions and further clarified previous recommendations, including the use of alternative chromosome 17 probe testing. “There was also an attempt to address less common HER2v result patterns and attempt to reclassify these cases, as well as other equivocal cases into either HER2-negative or -positive groups,” Siziopikou said, before walking colleagues through the key questions asked and answered in the guideline.

Clinical Cases

Clinical question 1 addressed the issue of an appropriate definition for the IHC “equivocal” category (IHC 2+): “Revised definition of IHC 2+ (equivocal) is ‘invasive breast cancer with weak to moderate complete membrane staining observed in >10% of tumor cells.’” In other words, the FISH equivocal category has been eliminated, Siziopikou noted.

Clinical question 2 asked if HER2 testing of a surgical specimen must be repeated if the initial core biopsy was negative. The answer: “On the basis of some criteria (including a tumor grade 3), if the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may be ordered on the excision specimen.”

Siziopikou explained that IHC HER2 negative cases on core biopsy (Score 0 or 1+), are generally accurate and do not need repeating on excisions. She elaborated by noting several possible exceptions, such as the possibility of repeating IHC when the tumor is histologic grade 3, there is a small amount of high-grade tissue on the core, or the resection contains high-grade component not present on the core. Conversely, do not repeat IHC when the tumor is histologic grade 1; infiltrating ductal or lobular carcinoma that is strongly ER/PR positive; or tubular, mucinous, or cribriform carcinoma that is >90% pure.

Clinical questions 3 to 5 all elicited the same answer: “a definitive diagnosis will be rendered based on additional workup.”

Clinical question 3 asked if invasive cancers with a HER2 enumeration probe 17 (CEP 17) ratio of ≥2.0 but the average HER2 signals per cell is <4.0, should be considered ISH positive.

Additionally, the guideline states that if the IHC result is not 3+ positive, it is recommended that the specimen be considered HER2 negative because of the low HER2 copy number by ISH and the lack of protein overexpression.

Clinical question 4 asked whether invasive cancers with an average of ≥6.0 HER2 signals per cell with a HER2/CEP17 ratio of <2.0 should be considered ISH-positive.

Siziopikou highlighted additional guidance from the guidelines committee: “When concurrent IHC results are negative (0 or 1+), it is recommended that the specimen be considered HER2 negative.”

Clinical question 5 probed the diagnosis for cases with an average HER2 signals per tumor cell of ≥ 4.0 and <6.0 and the HER2/CEP17 ratio of <2.0, formerly diagnosed as ISH equivocal for HER2. For this question, the guidelines committee offered this clarification: “When IHC results are not 3+ positive, it is recommended that the sample be considered HER2 negative without additional testing on the same specimen.”

Finally, the 2018 guideline considered whether alternative ISH probe testing should be used in order to assign HER2 status. “Clinical information about benefit from HER2-targeted therapy in [high CEP 17] patients is not available because these patients would not have been eligible for the original pivotal trials,” Siziopikou said. “Additionally, many of the alternative probes are not analytically or clinically validated, so the 2018 Expert Panel strongly recommends against alternate probe testing as a routine testing strategy.”

“A clinicopathological correlation and/or a second opinion are more helpful,” she added.


  1. Siziopikou KP. Understanding the new HER2 testing guidelines. Presented at: 2019 Lynn Sage Breast Cancer Symposium; October 3-6, 2019; Chicago, IL.
  2. Wolff AC, Hale Hammond ME, Allison KH, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update. J Clin Oncol. 2018;36(20):2105-2122. doi: 10.1200/JCO.2018.77.8738.

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