Impact of the 2018 ASCO/CAP HER2 Guideline Focused Update

Adlin M. Gordian-Arroyo; Debra L. Zynger, MD; Gary H. Tozbikian, MD


Am J Clin Pathol. 2019;152(1):17-26. 

In This Article

Abstract and Introduction


Objectives: The 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) human epidermal growth factor receptor 2 (HER2) guideline focused update revises the HER2 scoring criteria. We evaluated the impact on HER2 rates in breast carcinoma diagnosed at our center.

Methods: In a retrospective series of breast core biopsies with invasive carcinoma diagnosed between 2014 and 2017 (n = 1,350), HER2 status was classified according to 2013 and 2018 ASCO/CAP guidelines and changes in HER2 status identified.

Results: The 2018 guidelines reclassified the HER2 status of 6% of patients. Most changed from HER2 equivocal status (equivocal by immunohistochemistry and fluorescence in situ hybridization under the 2013 guidelines) to HER2-negative status (2018 guidelines). The HER2-positive rate decreased by 0.4%.

Conclusions: The 2018 guidelines decrease the rate of HER2 equivocal and positive breast cancer and reduce repeat HER2 testing on excision specimens. Approximately 0.4% of patients will become newly ineligible for anti-HER2 therapy.


Human epidermal growth factor receptor 2 (HER2) is a predictive and prognostic biomarker that is overexpressed in up to 15% to 20% of invasive breast carcinomas.[1] HER2 status is critically important in clinical decision making, as it informs the use of systemic chemotherapy and anti-HER2 targeted therapy. In 2018, the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) revised the HER2 guideline recommendations and interpretation criteria for both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays.[2] In comparison to the 2013 ASCO/CAP HER2 guideline (2013 guidelines),[3] the 2018 ASCO/CAP HER2 guideline focused update (2018 guidelines) further refines the HER2 evaluation algorithms by addressing tumors with uncommon HER2 in situ hybridization (ISH) amplification patterns that carry uncertain biological and clinical significance.[2] Additionally, the 2018 guidelines increase the emphasis on coordination between IHC and ISH results, soften the recommendations for repeat HER2 testing of grade 3 tumors initially found to be HER2 negative, discontinue the option of using alternate probe HER2 FISH for clinical HER2 assessment, and raise the thresholds for categorizing a patient as HER2 positive. As a result, the 2018 guidelines have the potential to recategorize the HER2 status of some patients by eliminating equivocal results, decreasing the rate of HER2-positive results, and reducing the numbers of cases subjected to repeat HER2 testing. While the 2018 guidelines[2] estimate that 5% of cases could have ISH results reclassified, the actual impact of the 2018 guidelines on HER2 rates is unknown.

Under the 2018 guidelines, tumors with uncommon HER2 ISH amplification patterns are subjected to a more complicated workup that requires concomitant review with the HER2 IHC. If the IHC result is equivocal, a blinded ISH recount is required utilizing the HER2 IHC slide to direct the selection of the region of the tumor to rescore HER2. Under the 2018 guidelines, both IHC and FISH should be conducted in the same institution to ensure parallel review and quality.[2] One main advantage of the integration of HER2 IHC and ISH is that this approach better addresses the tumors that demonstrate intratumoral heterogeneity for HER2 expression, which may potentially cause a false-negative result.

In our study we investigated the potential impact of the 2018 guidelines on the HER2 rates in primary invasive breast carcinomas diagnosed at our center. We conducted a retrospective search of breast core needle biopsy (CNB) specimens performed at our institution from 2014 to 2017 with a diagnosis of primary invasive breast carcinoma. The standard HER2 testing protocol that was used in our institution during this period closely approximates the testing algorithm provided in the 2018 guidelines in several key aspects. Simultaneous testing of HER2 using both IHC and dual-probe ISH was routinely performed and interpreted in parallel and within the same institution, with a minimum of 90 tumor cells assessed per case. The HER2 IHC slide was used to direct the selection of tumor region to score HER2 ISH in all cases showing intratumoral heterogeneity. As such, we were able to rescore all cases utilizing the 2018 guidelines and analyze the impact on HER2 rates in our institution.