title: Molecular markers associated with response to chemotherapy in gastro-entero-pancreatic neuroendocrine tumors.
abstract: 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).
authors.affiliation: Department of Clinical Medicine and Gastroenterology, St James's Hospital and Trinity College Dublin, James's Street, Dublin 8, Ireland. dermot.otoole@tcd.ie
authors.forename: Dermot
authors.initials: D
authors.lastname: O'Toole
authors.forename: Anne
authors.initials: A
authors.lastname: Couvelard
authors.forename: Vinciane
authors.initials: V
authors.lastname: Rebours
authors.forename: Magali
authors.initials: M
authors.lastname: Zappa
authors.forename: Olivia
authors.initials: O
authors.lastname: Hentic
authors.forename: Pascal
authors.initials: P
authors.lastname: Hammel
authors.forename: Philippe
authors.initials: P
authors.lastname: Levy
authors.forename: Pierre
authors.initials: P
authors.lastname: Bedossa
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
authors.forename: Philippe
authors.initials: P
authors.lastname: Ruszniewski
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor