HER2 Amplification Status in Breast Cancer: The Effect of Adjusting for "Polysomy 17"
Isabelle Gagne, Kenneth J Craddock, Anna Marie Mulligan. University Health Network, University of Toronto, Toronto, ON, Canada
Background: Correction of the HER2 gene copy number with the copy number of chromosome 17 centromere (CEP17) (believed to be a surrogate for Ch17 copy number) has long been believed to be necessary for determination of true HER2 gene amplification. Recent evidence suggests that polysomy 17 is a very rare event in breast cancer (BC): the centromere may be included in HER2 amplicons, which could lead to misleading HER2 amplification status and a misclassification of patients eligible for trastuzumab therapy, if the ratio is taken as the sole indicator. A recent policy change in Cancer Care Ontario states that patients with tumors showing polysomy 17 may be considered eligible for trastuzumab if the mean number of HER2 copies per cell is greater than 6, even though the ratio is less than 2. To assess the likely impact of this in clinical practice, we performed an audit on a series of BC on which HER2 FISH data was available.
Design: An audit was performed of a consecutive series of 961 tumors at a single institution between December 2008 and September 2012. ASCO/CAP guidelines to define amplification status based on ratio of HER2 to CEP17 copy number were followed. Polysomy and monosomy 17 were defined as CEP17 copy number > 3 and < 1.4 respectively.
Results: Of 961 cases, 808 had HER2 immunohistochemistry data available: 3.2% were negative (0/1+), 96% were equivocal (2+), and 0.6% were positive (3+). Of 961 tumors, 131 (13.6%) were amplified, 784 (81%) were non-amplified and 46 (4.8%) were equivocal. 11.6% cases showed polysomy and 8% showed monosomy. Of 784 non-amplified cases, 11 (1.4%) had more than 6 copies of HER2. All had polysomy (CEP17 copy number range: 3.5-5.2). Of 131 amplified cases, 30 had a HER2 copy number ≤ 6 (23%), 9 of which showed monosomy (CEP17 copy number range:1.1-2.4). Of 77 monosomy 17 cases, 62 were non-amplified, 3 were equivocal and 12 were amplified. Amongst the 12 monosomy 17 amplified cases, only 3 had > 6 HER2 gene copies and 9 had ≤ 6 HER2 gene copies.
Conclusions: We found that just 1.4% of patients with tumors considered non-amplified according to HER2:CEP17 ratio had > 6 copies of HER2 and would now be considered eligible for trastuzumab therapy under new Ontario guidelines. 23% of patients with tumors considered amplified based on ratio had < 6 copies of HER2. Routine reporting of HER2 copy number is recommended and patients with non-amplified ratios but >6 copy numbers should be included in trials testing anti-HER2 therapies to determine the clinical significance in terms of response to therapy.
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 41, Tuesday Afternoon