Abstract P3-07-07: The updated ASCO/CAP guidelines for HER2 testing create more uncertainty for clinicians
Authors: Chen J , Klein P , Shao T 
Published: May 2016

Abstract
Background: Accurate assessment of the Human Epidermal Growth Factor Receptor 2 (HER2) status has been an integral part of clinical decision making in treatments of breast cancer. In 2007, American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) published a series of guidelines on how to determine the status of HER2. The guidelines were updated in 2013 with the goal of reducing the numbers of false negative cases. The new guidelines are based on a combination of HER2:CEP17 ratio and average HER2 copy number. We sought to assess the overall effect of the new guidelines.
Methods: We retrospectively identified all cases of invasive breast cancer with HER2 testing done in 2014 from the pathology database of Mount Sinai Beth Israel, Mount Sinai St. Luke's and Roosevelt Hospitals. Our pathology department guideline is to perform initial testing for HER2 with immunohistochemistry (IHC) by the HercepTest (Dako) method. Those with IHC of 2+ would be followed by reflex HER2 dual probe FISH. The HER2:CEP 17 ratio and average HER2 copy number were then reviewed for each IHC 2+ case using the 2013 guidelines. These cases were then rescored using the 2007 guidelines. All equivocal cases as determined by the new 2013 guidelines (HER2:CEP17 ratio &lt;2.0 with an average HER2 copy number ≥4.0 and &lt;6.0 signals/cell) were further evaluated to determine whether repeat HER2 testing was performed as suggested by the new guidelines and whether HER2 directed therapy was recommended for patient.
Results: Among 853 cases identified in the database, 337 were IHC 2+. Using 2007 guidelines, 27/337 cases (8.0%) were amplified (HER2:CEP 17 ratio &gt;2.2), 6 (1.8%) were equivocal (HER2:CEP 17 ratio 1.8-2.2), and 305 cases (90.2%) were non-amplified (HER2:CEP 17 ratio &lt;1.8). Using the 2013 guidelines, 29/337 cases (8.6%) were amplified (HER2:CEP 17 ratio ≥2 or HER2 copy number ≥6), 23 (6.8%) were equivocal (HER2:CEP17 ratio &lt;2.0 with an average HER2 copy number ≥4.0 and &lt;6.0), and 284 (84.3%) were non-amplified (HER2:CEP 17 ratio &lt;2 with an average HER2 copy number &lt;4.0). The new guidelines resulted in change in HER2 status in 24 cases (7.1%): 2 cases changed from equivocal to amplified, 1 case changed from equivocal to non-amplified, but 20 cases changed from non-amplified to equivocal. Of the 23 equivocal cases determined using the 2013 guidelines, only 13 cases had repeat HER2 analysis. On repeat HER2 testing, one case was found to be HER2 amplified, 4 cases were non-amplified, and 8 cases remained equivocal. Only one equivocal case received HER2 directed treatment.
Conclusion: The 2013 ASCO/CAP guidelines for HER2 assessment identified a slightly increased number of patients eligible for HER2 directed therapy, but also resulted in a significant increase in the number of equivocal cases. The new guidelines appear to have generated more uncertainty for the clinician due to the rise in equivocal cases. Further studies are needed to determine whether patients with equivocal HER2 status would benefit from HER2 directed therapy.
Citation Format: Chen J, Klein P, Shao T. The updated ASCO/CAP guidelines for HER2 testing create more uncertainty for clinicians. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-07.