Abstract
[Background] Colorectal neuroendocrine tumors (NETs) may cause distant unresectable metastases, for which no effective chemotherapy has been established. Trastuzumab, which targets HER2/neu, has been effective in the treatment of advanced tumors that overexpress the target molecule. Bevacizumab, which targets VEGF, is moderately effective against advanced tumors, but the predictor of efficacy for this drug is unknown. Specifically, it is unclear whether these target molecules are involved in colorectal NETs. Furthermore, the expression patterns of EGFR and SSTR have not been fully characterized in NETs. [Objective] To assess the possibility of molecular-targeted therapies against colorectal NETs, we classified NET specimens according to the new WHO 2010 classification criteria and examined the expression of HER2/neu, VEGF, EGFR, and SSTR. [Specimens] Thirty-six paraffin-embedded specimens of colorectal NET excised from 2000 to 2010. [Methods] Each specimen was classified according to the new WHO 2010 classification criteria and examined for the expression of HER2/neu, VEGF, EGFR, and SSTR2A (a subtype of SSTR) by immunohistochemistry. [Results] 1. WHO classification: Of the 36 specimens, 31 were classified into NET G1, 1 into NET G2, and 4 into NEC. 2. Immunohistochemical staining: The overall proportions of the stained specimens (and proportion by WHO class) were as follows: 5% (G1: 0%, G2: 0%, NEC: 50%) for HER2/neu, 78% (G1: 80%, G2: 100%, NEC: 50%) for VEGF, 0% for EGFR, and 16.6% (G1: 19%, G2: 0%, NEC: 0%) for SSTR2A. [Discussion] Among colorectal NETs, HER2/neu was expressed in highly proliferative tumors.While trastuzumab is expected to be effective against these unresectable advanced tumors, its efficacy may be limited due to low HER2/neu expression levels (rated as 1+). VEGF was expressed in 78% of the tested specimens, indicating that bevacizumab monotherapy is effective in these tumors. However, more basic studies are required to clarify the role of VEGF in tumor proliferation. Sunitinib, a VEGFR-1,2,3-TKI drug, has been reported to be effective against PNET, and its potential efficacy against colorectal NEC should be assessed in future studies. Because EGFR was not detected in any specimen, cetuximab should not be effective. SSTR2A expressionwas inversely correlated with malignancy, suggesting that SSTR degrades as the proliferative capacity increases. Thus, SSTR will not serve as a target molecule for highly malignant colorectal NETs.
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