O6-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, O(6)-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.

Fig. 1

Representative MGMT staining in carcinoid and pancreatic neuroendocrine tumors.

Fig. 2

PFS and OS for carcinoid and pancreatic neuroendocrine tumor patients treated with temozolomide-based therapy. A, median PFS was 13.6 mo for pancreatic neuroendocrine tumor patients and 9.6 mo for carcinoid tumor patients (P = 0.12). B, median OS was 35.3 mo for pancreatic neuroendocrine tumor patients and 19.4 mo for carcinoid tumor patients (P = 0.07).

Fig. 3

PFS and OS in patients with MGMT-intact or MGMT-deficient neuroendocrine tumors treated with temozolomide-based therapy. A, median PFS was 19.2 mo for MGMT-deficient neuroendocrine tumors and 9.3 mo for MGMT-intact tumors (P = 0.11). B, median OS for patients with MGMT-deficient tumors was not reached; median OS for patients with MGMT-intact tumors was 19.1 mo (P = 0.14).