Breast Carcinomas with Equivocal HER2/Neu Amplification: Morphologic Features, CEP17 Polysomy and HER2 Genetic Heterogeneity
Kristine Astvatsaturyan, Shikha Bose. Cedars-Sinai Medical Center, Los Angeles, CA
Background: Her2/neu (HER2) status determines eligibility for targeted therapy with the anti-HER2-humanized monoclonal antibody, Trastuzumab in breast carcinoma. Expression is commonly assessed by immunohistochemistry (IHC) and amplification by fluorescent in situ hybridization (FISH). Amplification determines patient selection for therapy in breast carcinoma with equivocal IHC results. An equivocal FISH result, however causes uncertainty amongst clinicians regarding therapeutic options. The recent ASCO/CAP guidelines recommend additional testing for final determination. This study aims at determining the characteristics of breast carcinomas with equivocal HER2 amplification (average HER2/CEP17 ratio of 1.8-2.2) (EqHER2) and the role of chromosome 17 polysomy (CEP17P) and/or HER2 genotypic heterogeneity (GH).
Design: Our anatomic pathology database was searched for cases diagnosed as EqHER2 on FISH analysis between April 2010 and August, 2011. Breast carcinomas were fixed and evaluated in accordance with the 2007 ASCO/CAP guidelines. ER, PR, HER2 and Ki-67 expression was evaluated by IHC using image analysis while HER2 and CEP 17 copy number were evaluated by FISH. EqHER2 cases were charted to determine incidence and histopathologic features including tumor size, tumor grade, axillary lymph node metastasis, ER, PR, Ki-67, and HER2 expression, amplification, GH and presence of CEP17P (≥3 CEP17 signals/cell).
Results: 20 of 671 (3%) breast carcinomas were reported as EqHER2. Tumors varied in size from 7-50 mm (median 20.5 mm), with Bloom Richardson scores of 4-9 (median 8). 18 (90%) were ER positive, 13 (65%) were PR positive with high Ki67 proliferation index (2-68%, median 31%). Axillary lymph node metastasis was present in 8 of the 13 (62%) cases with axillary dissections. Two of the cases demonstrated overexpression (IHC3+), one of which contained >6 HER2 signals/cell. One additional case with >6 HER2/cell (IHC 2+) was present in this cohort. 6 (30%) cases demonstrated CEP17P. GH was noted in 15 (75%) cases with 15 to 50% (median 23%) of the neoplastic cells demonstrating HER2 amplification. Overall 12 (60%) cases demonstrated GH in the absence of CEP17P. There were 3 cases with CEP17P alone (without GH) and 3 with GH.
Conclusions: Breast carcinomas with EqHER2
- are rare, constituting 3% of invasive carcinomas
- are larger, poorly differentiated, positive for ER and PR with high proliferation rates (luminal B phenotype)
- demonstrate GH in 75% cases and polysomy in 30%.
Wednesday, March 21, 2012 1:00 PM
Poster Session VI # 6, Wednesday Afternoon