Expression of HER2 and GRB7 in Upper Gastrointestinal Tract Carcinomas
Georgios Deftereos, Uma Krishnamurti, Patrick Storto, Jan F Silverman, Mark L Bunker. Allegheny General Hospital, Pittsburgh, PA; Western Pennsylvania Hospital, Pittsburgh, PA
Background: Overexpression of HER2 is identified in a subset of gastric and gastroesophageal junction carcinomas, leading to use of trastuzumab based therapy. GRB7, a signaling molecule implicated in tumorigenesis and trastuzumab resistance, is located on the 17q12 amplicon near HER2 and is frequently co-amplified with HER2. The aim of this study was to evaluate immunohistochemical expression of HER2 and GRB7 in upper gastrointestinal tract carcinomas and to correlate these with pathologic stage.
Design: 60 cases of gastroesophageal junction and 34 cases of gastric carcinoma between 1991 and 2006 were selected and immunostained for HER2 and GRB7. HER2 IHC scoring was per published FDA guidelines. 3+ score was considered positive, 0 and 1+ negative and 2+ equivocal. HER2 2+ cases and one GRB7 + HER2 1+ case were submitted for FISH for HER2 amplification. For GRB7 percentage of positively staining cells and intensity of staining were noted. Less than 10% cells with weak staining was considered negative. Results of HER2 and GRB7 were correlated with pathologic stage.
Results: Of the 60 GE junction carcinomas 6 cases (10.0%) were HER2 3+ positive and 7 (11.7%) were HER2 2+ equivocal. GRB7 was positive in 9 cases, distributed as follows: 6 HER2 3+, 2 HER2 2+, 1 HER2 1+. Of the 34 gastric carcinomas 2 cases (6.5%) were HER2 3+ positive and 1 case was HER2 2+ equivocal (2.9%). GRB7 was positive in one case which was also HER2 3+. Overall, GRB7 expression was only seen in conjunction with non-zero HER2 expression, typically at high level (3+, 70%). Of the remaining GRB7+ cases, FISH confirmed amplification in 2 (1 HER2 2+ and 1 HER2 1+, HER2/CEP17 3.79 and 9.36) and showed chromosome 17 polysomy in 1 (HER2 2+ CEP17 3.63). These results indicate that GRB7 is highly specific (90%) for HER2 amplification, with polysomy a possible cause of false positivity.
Overall, lymph node positivity was 6/7 (86%) in GRB7 positive cases versus only 37/74 (54%) in GRB7 negative cases, though not statistically significant (p=0.11), possibly due to the relative rarity of GRB7 expression.
Conclusions: GRB7 expression is detected in a subset of HER2-amplified cases of upper gastro-intestinal carcinoma, and is rare in unamplified cases. Used in a panel, GRB7 could be used to select cases for FISH when HER2 IHC is 2+ or 1+. Further, this study could be useful for identifying patients who might benefit from potential targeted anti-GRB7 therapy.
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 54, Tuesday Afternoon