O 6-Methylguanine DNA Methyltransferase Deficiency and Response to Temozolomide-Based Therapy in Patients with Neuroendocrine Tumors

Abstract

Purpose Recent studies suggest that temozolomide has activity in neuroendocrine tumors. Low levels of the DNA repair enzyme, O6-methylguanine DNA methyltransferase (MGMT), are associated with sensitivity to temozolomide in other tumor types. We evaluated the prevalence of MGMT deficiency in neuroendocrine tumors and correlated MGMT deficiency with treatment response to temozolomide-based regimens. Experimental Design The prevalence of MGMT deficiency, measured by immunohistochemistry, was assessed in 97 archival neuroendocrine tumor specimens. Rates of treatment response and survival were next evaluated in a cohort of 101 consecutive neuroendocrine tumor patients who had received treatment with a temozolomide-based regimen at one of three institutions. MGMT expression was directly correlated with treatment response in 21 patients who had available tumor tissue and response data. Results In archival specimens, MGMT deficiency was observed in 19 of 37 (51%) pancreatic neuroendocrine tumors and 0 of 60 (0%) carcinoid tumors (P < 0.0001). In the clinical cohort, 18 of 53 (34%) patients with pancreatic neuroendocrine tumors but only 1 of 44 (2%) patients with carcinoid tumors (P < 0.001) experienced a partial or complete response to temozolomide-based therapy. Among 21 patients with evaluable tumor tissue who had also received treatment with temozolomide, 4 of 5 patients with MGMT-deficient tumors (all pancreatic neuroendocrine tumors) and 0 of 16 patients with tumors showing intact MGMT expression responded to treatment (P = 0.001). Conclusions MGMT deficiency, measured by immunohistochemistry, is more common in pancreatic neuroendocrine tumors than in carcinoid tumors as is treatment response to temozolomide-based therapy. Absence of MGMT may explain the sensitivity of some pancreatic neuroendocrine tumors to treatment.

PAX8 expression reliably distinguishes pancreatic well-differentiated neuroendocrine tumors from ileal and pulmonary well-differentiated neuroendocrine tumors and pancreatic acinar cell carcinoma

“…Recent clinical trials have demonstrated that patients with pancreatic neuroendocrine tumors more often benefit from temozolimide-based therapies compared with neuroendocrine tumors from non-pancreatic sites of origin. 26,27 Thus, an immunohistochemical marker that can reliably determine the primary site of origin for a metastatic neuroendocrine tumor would have tremendous diagnostic utility. …”

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

“…Identification of markers capable of predicting responders or nonresponders to therapy could allow for a tailored approach to therapy and avoid use of potential toxic protocols in predictable nonresponders. Indeed, such an approach was recently described in pancreatic GEP where a low level O6-methylguanine-DNA methyltransferase (MGMT), a key enzyme in DNA repair, was suggested to be responsible for the lack of response to temozolamide (Kulke et al 2009). Further studies examining MGMT status are currently underway.…”

Neuroendocrine tumor disease: an evolving landscape

“…Despite the limitations of the latter study, recent retrospective and small prospective studies have demonstrated the efficacy of this regimen with reports of tumor remissions of w40% (Kouvaraki et al 2005, Turner et al 2010. Smaller, phase II trials support the efficacy of temozolomide-based chemotherapy in PNENs (Kulke et al 2009). In a retrospective study on patients with metastatic PNENs treated with first-line chemotherapy with a combination of capecitabine and temozolamide, a response rate of 70% and a median progression-free survival of 18 months were achieved compared with a response rate of 39% and a median progression-free survival of 9.3 months achieved with a triple combination of streptozotocin, doxorubicin, and 5-FU (Strosberg et al 2011).…”