Abstract ES1-1: What is a HER2-positive in breast cancer in 2018?
Authors: Schnitt S 
Published: May 2019

Abstract
Remarkable progress has been made in the treatment of patients with HER2-positive breast cancer since trastuzumab was approved by the U.S. Food and Drug Administration 20 years ago. Among patients with HER2-positive disease, HER2-targeted therapy has been associated with substantial improvements in overall survival in the adjuvant setting, a high rate of pathologic complete response (pCR) after neoadjuvant therapy, and improvements in survival in patients with metastatic disease. While much of these improvements in outcome is due to more effective therapies, improvements in patient selection as a result of more accurate HER2 testing has also contributed to the better prognosis of patients with this disease. Data from clinical trials examining the benefit of trastuzumab in the adjuvant setting and published in the early 2000s (e.g., NSABP B31; NCCTG 9831) demonstrated that up to 25% of community-based assays reported as HER2-positive by immunohistochemistry (IHC) and up to 15% reported as HER2-positive by fluorescence in situ hybridization (FISH) could not be confirmed upon central laboratory testing. To address this high frequency of false-positive results and to improve the accuracy of HER2 testing, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) in 2007 published guideline recommendations for HER2 testing. These guidelines were subsequently updated in 2013 and, more recently, in 2018. Since the implementation of these guidelines, the accuracy of HER2 testing has improved. In fact, in current clinical practice, when HER2 IHC and FISH testing are performed according to the ASCO-CAP guidelines, approximately 95% of breast cancers can ultimately be categorized as either unequivocally HER2-positive or HER2-negative. In the remainder of the cases, combined IHC and FISH assay results provide a less straightforward picture of the HER2 status and, in turn, create uncertainty regarding the likelihood of benefit from HER2-targeted therapy. These include cases which on dual-probe FISH testing show: 1) HER2/CEP17 ratio &gt;2.0 and an average HER2 copy number &lt;4.0 signals/cell (monosomy); 2) HER2/CEP17 ratio &lt;2.0 and an average HER2 copy number &gt;6.0 signals/cell (polysomy); and 3) HER2/CEP17 ratio &lt;2.0 and an average HER2 copy number &gt;4.0 and &lt;6.0 signals/cell. However, the most recent (2018) update of the ASCO-CAP guidelines provides pragmatic recommendations to resolve the HER2 status of such cases, and this, in turn, should result in even fewer cases in which the HER2 status remains in doubt. It should be noted, however, that not all patients whose tumors are HER2-positive by IHC and/or FISH respond similarly to HER2-targeted therapy and that some patients who initially respond subsequently develop resistance. Active efforts are underway to understand the mechanisms of de novo and acquired resistance to HER2-targeted treatments and to identify biomarkers that can predict resistance to therapy. Thus, the clinically relevant question in 2018 is not “what is a HER2-positive breast cancer ”? Rather, the question that now needs to be addressed is “which HER2-positive breast cancers will respond to HER2 targeted-treatments and to which HER2-targeted treatments are they most likely to respond? ”.
Citation Format: Schnitt S. What is a HER2-positive in breast cancer in 2018? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES1-1.