Abstracts
2000 Digestive Disease Week

# 2455 Herceptin Treatment - a Novel Treatment Modality in Pancreatic Cancer.
Peter Buechler, Joe O. Hines, Manuela C. Buechler, Helmut Friess, Mendel M. Roth, William H. Isacoff, Howard A Reber, Bern, Switzerland, Los Angeles, CA

Background: Pancreatic cancer is an aggressive tumor with limited response to conventional treatment. Overexpression of the proto-oncogene Her2/ neu has been identified in 50-70% of PaCa. A humanized anti-HER2/neu antibody (HerceptinTM, Genentech) has been shown to be clinically active in breast cancer. Aim: The purpose of this study was to determine the activity of Herceptin in the treatment of pancreatic cancer. Methods: In vitro human pancreatic cancer cell lines AsPc-1, Capan-1, HPAF-2 (HP2), MIA PaCa-2 (MP2) and PANC-1 were characterized for HER2/ neu expression according to standard pathological grading techniques. Growth analysis was done in both anchorage dependent and independent assays. Flow cytometry was used to study cell cycle progression. Tumor growth in vivo was studied with MP2 (n=8) and HP2 (n=8) cell lines in an orthotopic murine model of pancreatic cancer. HerceptinTM treatment was initiated after a period of 7 weeks of extensive tumor formation and was administered three times a week in a dose of 10mg/kg i.p. until death. Control animals received a nonspecific antibody (rhu IgG1). Results: All cell lines tested expressed HER2/neu antigen. Highest HER2/ neu levels were seen in MP2 cells and lowest in HP2 cells by immunostaining. Anchorage dependent cell proliferation was not inhibited in any of the cell lines at various doses of Herceptin. Herceptin treatment had no effect on cell cycle progression. Anchorage independent growth, however, was significantly reduced in cell lines expressing high HER2/neu levels with increasing doses of Herceptin (*p<0.05) HER2/neu Anchorage Independent Growth Assay (Colonies) expression 0 µg/ml 1 µg/ml 10 µg/ml 50 µg/ml Herceptin AsPc-1 ++ 17.8±1.6 15.8±1.2 7.44±0.5* 7.0±0.3* HPAF-2 - 7.3±1.6 16.6±8.9 9.7±0.6 7.9±1.4 MIA PaCa-2 +++ 27.0±1.3 18.7±0.7* 11.3±1.7* 4.3±1.5* PANC-1 ++ 20.9±2.1 19.6±0.9 17.5±1.1* 15.2±1.4* In vivo Herceptin significantly (p<0.05) improved survival of MP2 tumor bearing animals (36.3 ± 3 vs. 17.3 ± 2.7 days). Although animals bearing HP2 tumors survived longer (45.5 ± 10.5 vs. 27.6 ± 5.1days), this was not significant. Conclusion: The proto-oncogene HER2/neu is expressed on human pancreatic cancer cell lines. Cell lines expressing high levels of HER2/neu showed a significant growth inhibition in vitro and, more importantly, in vivo upon Herceptin treatment. This novel therapeutic concept appears to be of particular value for those patients overexpression HER2/neu, and therefore may be of immediate value for patients with pancreatic cancer.