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Hellenic Archives of Pathology, Volume 21, Issues 1-3, 2007, 26-37
Potential involvement of PTEN expression
in resistance
to anti-HER2 targeted therapies
in pancreatic ductal adenocarcinoma:
A combined chromogenic in situ hybridization
and immunohistochemistry analysis
based
on tissue microarrays
Tsiambas E.1, Karameris A.1, Tiniakos D.2, Karakitsos P.2, Patsouris E.3, Kittas Ch.2
1Department of Pathology, 417 VA (NIMTS) Hospital, Athens, Greece,
2Lab of Histology & Embryology, Medical School, National and Kapodestrian University of Athens, Greece,
3Department of Pathology, Medical School, National and Kapodestrian University of Athens, Greece
Background/Aim: HER2/neu overexpression is observed in different proportions of pancreatic ductal adenocarcinomas (PDAC). However, the specific mechanisms of gene deregulation and chemo resistance to novel targeted therapeutic agents remain under investigation. Our aim was to identify HER2/neu gene alterations in PDAC correlating them to its protein levels and also to PTEN suppressor gene expression, which normally opposes the activation of PI3K-Akt-m TOR signaling pathway.
Materials and Methods: Using tissue microarray technology, fifty (n=50) paraffin embedded tissue samples of histologically confirmed primary PDACs were cored at a diameter of 1 mm and re-embedded into one final recipient block. Ten (n=10) samples of normal epithelia, adjacent to cancerous tissue were used as normal control group. Immunohistochemistry was performed by the use of anti-HER2/neu monoclonal antibody (TAB 250) and anti-PTEN polyclonal antibody. Chromogenic in situ hybridization was applied based on the use of HER2/neu gene and 17 centromeric probes, respectively. Protein expression levels were evaluated using an image analysis system. SPSS (chi square test and interrater kappa) was performed for statistical analysis.
Results: HER2/neu protein over expression was observed in 10/50 (20%) and was correlated only to tumor grade (p=0.019). Low levels or loss of PTEN protein expression were observed in 17/50 (34%) cases and were significantly associated to tumor grade and stage (p=0.044 and p=0.02, respectively) Gene analysis identified 8/50 (16%) HER2/neu low-level gene amplified cases. Chromosome 17 analysis detected aneuploidy in 19/50 (38%) cases. Simultaneous HER2/neu overexpression and reduced PTEN expression was observed in 7 cases, whereas six of them demonstrated HER2/neu gene amplification (overall 95 % CI kappa=0.12). In the control group, HER2/neu protein overexpression was identified in one case, whereas two cases demonstrated low-level PTEN protein expression.
Conclusions: Our results indicate that a subset of PDAC is characterized by simultaneous HER2/neu over- and PTEN reduced expression including sporadic cases of HER2/neu gene amplification. The efficacy of targeted therapeutic strategies with monoclonal antibodies, such as trastuzumab, which, on binding to the HER2/neu receptor, stabilize and activate PTEN, may be reduced by the loss of PTEN expression in PDACs. In cases of HER2/neu gene amplification, which in breast cancer are associated to therapeutic response to these agents, the potential survival benefit for the PDAC patients is possibly lost.
Key words: Pancreatic cancer, tissue microarrays, HER2/neu, PTEN, HER2/neu and PTEN in ductal pancreatic adenocarcinoma.
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