Phenotypes of Breast Cancers Heterogeneous for HER2 Gene Amplification: Looking for Biologically Relevant Thresholds
Mark R Kilgore, Julie S Kranseler, Suzanne M Dintzis, Rodney A Schmidt, Paul E Swanson, Mara H Rendi, Hannah M Linden, Kimberly H Allison. University of Washington, Seattle, WA
Background: In 2009, a College of American Pathologists expert panel (CAP-EP) published supplemental HER2 testing recommendations suggesting that cases with between 5% and 50% individual cells amplified by fluorescence in situ hybridization (FISH) be reported as “heterogeneous for HER2 gene amplification.”
Design: Data from counting sheets of 1329 consecutive breast cancer cases analyzed by FISH for HER2 at our institution were imported to an SQL Server database for analysis and statistics. Cases were categorized as heterogeneous if between 5-50% of cells counted had HER2:CEP17 ratios > 2.2. For cases meeting criteria for heterogeneity the following parameters were analyzed when available: HER2 IHC, estrogen receptor (ER) and progesterone receptor (PR), Nottingham grade, age, and histologic type. The percentage of HER2 amplified cells per case was divided into 5% incremental bins beginning with 5-9% and ending with 45-49%. Each bin was analyzed with respect to the aforementioned parameters, as well as the cumulative averages across bins.
Results: Out of 1329 cases, 283 cases met the CAP-EP criteria for HER2 heterogeneity by FISH. Of these, 84.1% were not amplified by mean HER2:CEP17 ratios, 13.4% were equivocal, and 2.5% were amplified. Most cancers that met the CAP-EP definition of HER2 heterogeneous were in women older than 50 (73.1% > 50, 20.5% 40-50, 6.4% <40) and 93.7% were invasive ductal carcinoma (6.3% lobular). Of the 250 cases with ER/PR data available, 79.2% were ER positive and 43.2% were PR positive. Of 240 cases with Nottingham grade available, 44.6% were grade 3, 44.2% grade 2, and only 11.2% grade 1. Interestingly, all cases with between 35-49% HER2 amplified cells were equivocal or amplified by mean ratios. ER/PR status remains relatively consistent over the range of percent HER2 amplified cells but all cases with 35-49% amplified cells were grade 2-3 carcinomas. 18.8% of cases in the 35-49% amplified range occurred in women younger than 40 versus 5.6% of cases with < 35% of amplified cells.
Conclusions: When looking at minority HER2 positive cell populations by FISH, more aggressive features are associated with cancers with 35-49% amplified cells versus 5-34%. This higher threshold for the definition of HER2 heterogeneity should be examined for potential response to HER2 targeted therapies to determine if it is clinically relevant.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 25, Monday Morning