Abstract P3-05-02: HER2 copy number on FISH as a predictor of disease severity in HER2- breast cancer
Authors: Abedin S , Kruse M , Brufsky A , Bhargava R 
Published: August 2014

Abstract
Background: HER2 overexpression in breast cancer has prognostic significance and predicts responsiveness to HER2 directed therapy. Recent studies suggest HER2 status may be misidentified in a small group of patients due to an overestimation of chromosome 17 polysomy using the CEP17 probe in FISH. This can lead to a low HER2/CEP17 ratio and HER2 negative status despite elevated HER2 gene copies. We examined HER2 negative/equivocal patients on FISH (HER2/CEP17&lt;2.2) who demonstrated CEP17 polysomy (CEP17 copy &gt;2.7). Identifying patients with 3-4 HER2 copies, and patients with &gt;4 HER2 copies on FISH, we determined hormone status, nodal status, progression free survival, and overall survival. We further compared the groups to determine any differences.
Methods: A retrospective review was performed on breast cancer patients treated at Magee Womens’ Hospital of UPMC who underwent diagnostic biopsy between 7/2007 and 8/2009. We initially screened patients with equivocal HER2 protein expression (2+ on IHC) that underwent FISH. Of these, 135 patients had evidence of CEP17 polysomy (average copy &gt;2.7) and elevated HER2 copy (&gt;3). Clinical and pathologic parameters including tumor size, lymph node status, ER/PR status, surgery, chemotherapy, relapse, and survival were recorded. Statistical analysis was performed using STATA 12.0. t-Tests were performed to determine associations, cumulative incidences and hazard ratios were calculated using the method of Fine and Gray with death as a competing risk.
Results: Patients demonstrating 3-4 HER2 copies had no difference in hormone receptor positivity (ER+ 88%, PR+82%) compared to patients with &gt;4 HER2 copies (ER+81%, PR+70%). There was no association between increased HER2 gene copy and nodal disease on diagnosis when bimodally dividing patients (node+; HER2&lt;4 = 36.7%, HER2&gt;4 = 48%, p = 0.25). However, further stratifying the groups yields an association (node+; HER2&lt;4 = 37%, HER2 4-6 = 42%, HER2&gt;6 = 75%, p = 0.05). Death in 3 years was significantly associated with HER2 gene copy (death rate; HER2&lt;4 = 0%, HER2&gt;4 = 5.5%, HR &gt;100). Further, examining 3 year risk of recurrence, there is a trend of increased recurrence with increased HER2 gene copy (recurrence rate; HER2&lt;4 = 8%, HER2&gt;4 = 17%, HR 2.15(0.7-6.54)) which persists on further stratification (recurrence rate; HER2&lt;4 = 8%, HER2 4-6 = 16%, HER2&gt;6 = 27%, HR 1.75(0.86-3.6)). Finally, in a subgroup of patients with node positive disease on diagnosis (n = 53), there is a trend of increased recurrence over 3 years with increased HER2 gene copy (recurrence rate: HER2&lt;4 = 18%, HER2&gt;4 = 35%, HR 2.08(0.58-7.4)).
Conclusions: In patients diagnosed with Her2- breast cancer, we found those with increased HER2 gene copy on FISH may demonstrate more aggressive disease characteristics. Initial lymph node spread was associated with increased HER2 gene copy as was risk of death. Finally, three year recurrence rates in patients with HER2 gene copy&gt;4 are comparable to historical rates of recurrence seen in HER2+ breast cancer. A potential implication of this study is that the 2007 ASCO/CAP single color probe guideline may be a better method to determine HER2 status. This could also identify additional patients that may benefit from more aggressive therapy, including possibly HER2 targeting agents.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-05-02.