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HER-2/Neu Alterations in Non-Small Cell Lung Cancer

A Comprehensive Evaluation by Real Time Reverse Transcription-PCR, Fluorescence in Situ Hybridization, and Immunohistochemistry¹

Division of Pathology [C. P., M. F., B. C., G. C., S. B.], Division of Medical Genetic [M. M.], Department of Medicine, Surgery and Dental Sciences, University of Milan, A.O. S. Paolo and IRCCS Ospedale Maggiore, 20142 Milan; Interuniversity Center of Cancer Research, Milan [G. C.]; Department of Oncology and Neurosciences, University of Chieti, Chieti [A. M., F. B.]; and Department of Medicine, Surgery and Dental Sciences, University of Milan, Istituto Clinico Humanitas, Rozzano (Milan) [M. R.], Italy

Purpose: Amplification and/or overexpression of HER2/neu have been documented in many types of epithelial tumor, and HER2/neu evaluation is now gaining importance, because this mechanisms of disease can be inhibited in vivo using humanized monoclonal antibodies. The main purpose of our investigation includes the evaluation of the prevalence of HER2/neu alterations in non-small cell lung cancer (NSCLC) at different molecular levels.

Experimental Design: We performed a comprehensive investigation of HER2/neu alterations in a series of 115 NSCLC, using fluorescence in situ hybridization (FISH), real time reverse transcription (RT)-PCR, and immunohistochemistry.

Results: HER2/neu immunoreactivity was detected in 26 of 115 of specimens (23%), with 5 carcinomas (4%) showing intense staining. Real time RT-PCR demonstrated HER2/neu mRNA in all samples analyzed, with levels above normal in 54 of 115 of carcinomas (47%). FISH documented HER2/neu gene amplification in 9 of 41 carcinomas (22%).

Conclusions: These results demonstrate that HER2/neu alterations occur in NSCLC, albeit with significantly different prevalence depending on the technical assay used for the assessment. It is therefore likely that inhibitory monoclonal antibodies will be appropriate in the treatment of a subgroup of NSCLC patients. The results suggest that other mechanisms unrelated to gene amplification could be responsible for HER2/neu mRNA or protein overexpression. FISH, real time RT-PCR, and immunohistochemistry are complementary techniques for the evaluation of HER2/neu activation, useful for the identification of the subgroup of patients to be treated. The real time RT-PCR assay is very sensitive and requires minimal amounts of tissue for testing, and additional studies should evaluate its clinical application for patient evaluation.

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