Molecular markers associated with response to chemotherapy in gastro-entero-pancreatic neuroendocrine tumors

Response rates to cytotoxics in gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) vary; recent trials demonstrated lack of objective response rates in up to 70% of patients. Identification of predictive therapeutic biomarkers would be beneficial in the treatment of GEP. Selected markers with known or suspected capability of predicting response to cytotoxics or prognosis (Ki-67, p53, multidrug resistance protein-1 (MDR1), Akt, thymidylate synthase (TS), phosphatase and tensin homolog (PTEN), CA9, cluster of differentiation 34 (CD34), vascular endothelial growth factor(VEGF), hypoxia-inducible factor (HIF)-1, mismatch repair gene - human mutL homolog 1 (hLMH1), and Bcl-2) were analyzed using immunohistochemisrtry in 60 treatment-naive patients receiving chemotherapy (n = 46) or chemoembolization (n = 14) for inoperable advanced and/or metastatic GEP and correlated with prognosis (survival and response rates). Therapy included systemic chemotherapy with streptozotocin (n = 28), doxorubicin (n = 14), 5-fluorouracil (n = 18), and etoposide/cisplatinum (n = 16), or chemoembolization (streptozotocin, 9; doxorubicin, 5). Factors associated with overall survival in the entire cohort were Ki-67, P < 0.001; tumor grade, P < 0.001; tumor differentiation, P < 0.001; CA9, P = 0.004; Akt, P = 0.01; HIF-1, P < 0.001; p53, P < 0.0001; and hMLH1, P = 0.005. Markers associated with treatment response included overall group: Akt and PTEN (P = 0.05 and 0.05 respectively); streptozotocin: Akt (P = 0.07), TS (P = 0.02), and PTEN (P = 0.017); doxorubicin: Ki-67 (P = 0.05), Akt (P = 0.06), and CA9 (P = 0.02). At multivariate analysis, Akt was significantly associated with a nonresponse to therapy (objective response (OR): 0.2 (0.05-0.8)). For patients receiving only systemic chemotherapy (n = 46), PTEN (0.04) and hLMH1 (0.03) were correlated with treatment response and for individual molecules were streptozotocin: PTEN (P = 0.008) and hLMH1 (0.07); doxorubicin: Akt (P = 0.09), CA9 (P = 0.09), and hLMH1 (P = 0.09). These results demonstrate a number of new prognostic biomarkers in GEP-NET, and in addition, response to chemotherapy was correlated with a simple panel of selected markers (such as CA9, Akt, PTEN, TS, and hLMH1). Endocrine-Related Cancer (2010) 17 847-856