MOLECULAR MARKERS FOR CHEMOTHERAPY RESPONSE IN GEPs

Endocr Relat Cancer. 2010 Jun 22. [Epub ahead of print]
Molecular markers associated with response to chemotherapy in gastro-entero-pancreatic neuroendocrine tumors (GEP).
O'Toole D, Couvelard A, Rebours V, Zappa M, Hentic O, Hammel P, Levy P, Bedossa P, Raymond E, Ruszniewski P.

D O'Toole, Department of Clinical Medicine & Gastroenterology, Trinity College Dublin, Dublin, P.O. Box 580, Ireland.
Abstract

Response rates to cytotoxics in gastro-entero-pancreatic (GEP) neuroendocrine tumors 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, MDR1, Akt, TS, PTEN, CA-9, CD34, VEGF, HIF1, hLMH1, Bcl2) were analyzed using immunohistochemisrtry in 60 treatment-naive patients receiving chemotherapy (n=46) or chemoembolisation (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-FU (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; hMLH1, p=0.005. Markers associated with treatment response included: overall group: Akt and PTEN (p=0.05 and p=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 CA-9 (p=0.02). At multivariate analysis, Akt was significantly associated with a non-response to therapy (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), hLMH1 (0.07); doxorubicin: Akt (p=0.09), CA-9 (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).