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).
Dermot O'Toole, Anne Couvelard, Vinciane Rebours, Magali Zappa, Olivia Hentic, Pascal Hammel, Philippe Levy, Pierre Bedossa, Eric Raymond, and Philippe Ruszniewski
Louis de Mestier, Anne Couvelard, Anela Blazevic, Olivia Hentic, Wouter W de Herder, Vinciane Rebours, Valérie Paradis, Philippe Ruszniewski, Leo J Hofland, and Jérôme Cros
The efficacy of alkylating agents (temozolomide, dacarbazine, streptozotocin) in patients with advanced neuroendocrine tumors (NETs) has been well documented, especially in pancreatic NETs. Alkylating agents transfer methyl adducts on DNA bases. Among them, O6-methylguanine accounts for many of their cytotoxic effects and can be repaired by the O6-methylguanine-methyltransferase (MGMT). However, whether the tumor MGMT status could be a reliable biomarker of efficacy of alkylating agents in NETs is still a matter of debate. Herein, we sought to provide a critical appraisal of the role of the MGMT status in NETs. After reviewing the molecular mechanisms of repair of DNA damage induced by alkylating agents, we aimed to comprehensively review the methods of determination of the MGMT status and its impact on prognosis, prediction of objective response and progression-free survival in patients with advanced digestive NETs treated by alkylating agents. About half of pancreatic NETs are MGMT-deficient, as determined by impaired tumor MGMT expression or by MGMT promoter methylation. Overall, while published studies are heterogeneous and mostly limited in size, they advocate that MGMT deficiency may be a relevant biomarker for increased objective response rate, prolonged progression-fee survival and overall survival in patients with advanced NETs treated by alkylating agents. While these data require confirmation in prospective controlled studies, future research should focus on the standardization of MGMT status assessment. Additional mechanisms of repair of DNA damages induced by alkylating agents should be explored in order to identify biomarkers complementary to MGMT and targets for potential antitumor synergy, such as PARP.