EGFR Expression and KRAS Mutation in Cholangiocarcinoma: Implication in EGFR-Targeted Therapies
LF Fan, V Datta, A Riley-Portuges, J Lopategui, F Lin, H Xu, HL Wang. Cedars-Sinai Medical Center, Los Angeles, CA; Geisinger Medical Center, Danville, PA; University of Rochester, Rochester, NY
Background: Cholangiocarcinoma is a highly aggressive malignancy with extremely poor patient survival. It shares many of the histologic and immunophenotypic features with pancreatic ductal adenocarcinoma (PDA) but may differ from it pathogenetically. Mutational activation of the KRAS oncogene is a very common event in PDA, reported in over 90% of the cases in some studies, and these patients would not benefit from anti–epidermal growth factor receptor (EGFR) therapies. EGFR expression and KRAS mutation have not been well characterized in cholangiocarcinoma, however.
Design: A total of 59 cases of surgically resected cholangiocarcinoma (48 intrahepatic and 11 extrahepatic) were immunohistochemically stained for EGFR expression utilizing a monoclonal antibody. A tumor was recorded positive when ≥1% of the tumor cells exhibited any membranous staining above background. Positive cases were further stratified as 1+ (weak), 2+ (moderate) and 3+ (strong), as well as focal (1-50% of tumor cells stained) and diffuse (>50%). EGFR gene amplification was analyzed by FISH using commercially available probes. In each case, 200 nuclei were assessed and EGFR was considered amplified when the ratio of EGFR signals to chromosome 7 centromere was >2. KRAS mutational testing was performed employing a 92-bp amplicon containing both codons 12 and 13 in exon 2 followed by high-resolution melting curve analysis using DNA extracted from formalin-fixed paraffin-embedded tumor tissue.
Results: Positive EGFR immunostaining was detected in 43 of 59 (73%) cholangiocarcinomas, among which 26 (60%) exhibited 2+ or 3+ and diffuse immunoreactivity. EGFR amplification was detected in only 1 of 12 (8%) cases that showed 2+ or 3+/diffuse EGFR expression. KRAS mutation was detected in 1 of 49 (2%) cases with amplifiable DNA and interpretable results. This case showed 2+/focal EGFR expression but did not exhibit EGFR amplification.
Conclusions: EGFR is frequently overexpressed in cholangiocarcinoma independent of gene amplification. In contrast to PDA, cholangiocarcinoma infrequently harbors KRAS mutations. These observations may have important therapeutic implications since EGFR-targeted therapies have shown promise for malignancies that lack KRAS mutations.
Category: Liver & Pancreas
Tuesday, March 23, 2010 1:00 PM
Poster Session IV # 191, Tuesday Afternoon