Evaluation of Mesothelin and c-Met Expression in Triple Negative Breast Carcinomas Reveals Mesothelin as an Ideal, and Novel, Therapeutic Target
Rena Xian, Julia Tchou, Amy Ziober, Robert Vonderheide, Ben Selvan, Carl June, Paul J Zhang. Hospital of the University of Pennsylvania, Philadelphia, PA
Background: Women with triple negative breast cancer (TNBC) derive no benefit from molecularly targeted treatments such as endocrine therapy or trastuzumab, thus a search for novel cell surface markers as potential therapeutic targets is highly desirable in TNBC. c-Met encodes for the tyrosine kinase receptor for hepatocyte growth factor (HGF). Over-expression/hyperactivation of c-MET/HGF occurs in various cancers. Small molecules and monoclonal antibodies against MET are now available for targeting MET-positive cancers. Mesothelin is a cell surface glycoprotein highly expressed in mesothelial cells and numerous malignancies. Mesothelin-specific antibodies and anti-mesothelin immunotoxins have been used to treat mesothelin-expressing carcinomas. Although c-MET expression has been reported in 25-60% of breast cancers (BRCA), mesothelin is generally considered not expressed by BRCA. Specifically, expression of these markers has not been extensively evaluated in TNBC.
Design: Expression of c-Met and mesothelin were evaluated in 98 BRCA (43 TNBC, 25 ER+/HER2- and 30 HER2+) by immunohistochemical (IHC) staining on formalin fixed paraffin sections. Anti-mesothelin (5B2, NeoMarker, 1:20) and anti-c-Met (S-10, R&D, 1:100) antibodies were used with standard IHC methods. Positive staining was scored as a product of staining extent (%) and intensity (1+, 2+, 3+) with a maximal score of 300. A score of 5 or greater was considered positive.
Results: Mesothelin is expressed in 67% of TNBCs (mean score of 59, range 5-225) as compared to 0% of ER+/HER2- cases, 3% (one case, score 200) of HER2+ cases and 0% of normal breast tissue. 42% of TNBCs showed staining scores of at least 25. Expression of c-Met in TBNCs and ER+/HER2- carcinomas was similar (67% vs 60%), with variable low level reactivity in normal mammary epithelium.
Conclusions: We report here, for the first time, that mesothelin is preferentially expressed in 2/3 of TNBCs but rarely in other BRCAs (2%), and not at all in normal mammary tissue. Although its oncogenic role in TNBCs is unknown, it could be a potential therapeutic target in TNBCs for which there are few available treatment options. Studies are currently underway to evaluate T-cell mediated killing of mesothelin-expressing breast carcinoma in vitro with promising results. While the expression of c-Met is not specific to TNBC, it might still be a therapeutic target in TNBC when conventional drugs have been exhausted.
Monday, March 19, 2012 1:00 PM
Poster Session II # 62, Monday Afternoon