Overexpression of the HER2/neu oncogene and receptor
protein has been reported in 20%-30% of patients with
breast cancer and is associated with a poor prognosis. HER2/neu expression in
breast cancer patients assessed by fluorescence in situ hybridization or immunohistochemistry is a predictor for response to
trastuzumab, a humanized
monoclonal antibody against the HER2/neu
cell-surface protein. Data regarding HER2/neu expression in
lung cancer are more limited, and there is little information regarding HER2/neu expression and response to
trastuzumab alone or in combination with chemotherapeutic agents.
Gemcitabine is an active agent against
non-small-cell lung cancer (NSCLC) and has demonstrated activity in
breast cancer as well. In vitro modified
tetrazolium salt growth assays were performed to determine whether the combination of
trastuzumab/
gemcitabine produced synergistic or additive effects on breast and
lung cancer cell lines. The effects of
trastuzumab alone,
gemcitabine alone, and the
trastuzumab/
gemcitabine combination was evaluated on 4 NSCLC cell lines, 1
small-cell lung cancer (SCLC) cell line, and 2
breast cancer cell lines. HER2/neu
surface protein expression was assessed by fluorescence flow cytometry and immunohistochemistry. Fluorescence in situ hybridization analysis was used to study gene expression.
Trastuzumab treatment alone resulted in growth inhibition in all cell lines expressing HER2/neu and the inhibitive effect correlated with the level of cell surface HER2/neu
protein expression. Treatment with
gemcitabine alone resulted in growth inhibition in both breast and NSCLC cell lines. A synergistic growth inhibition effect was seen with the
trastuzumab/
gemcitabine combination as indicated by combination index values < 1. The degree of synergy observed did not directly correlate with the level of
surface protein expression, as synergy was seen even in
cancer cell lines expressing low levels of HER2/neu. No treatment effect was seen in the SCLC cell line, which did not express HER2/neu. These preclinical studies indicate a need to study the clinical synergistic effects of the
gemcitabine/
trastuzumab combination in
breast cancer and NSCLC patients whose
tumors overexpress HER2/ neu.