Prognostic significance of MTOR pathway component expression in neuroendocrine tumors.

PURPOSE: Clinical studies have implicated the mechanistic target of rapamycin (serine/threonine kinase; MTOR) pathway in the regulation of neuroendocrine tumor (NET) growth. We explored whether expression of MTOR pathway components has prognostic significance in NET patients. PATIENTS AND METHODS: We evaluated immunohistochemical expression of MTOR and phospho (p) -MTOR; its downstream targets RPS6KB1, RPS6, and EIF4EBP1; and its upstream regulators, in a cohort of 195 archival neuroendocrine tumors. We correlated expression levels with clinical outcomes, after adjusting for other prognostic variables. RESULTS: We observed anticipated correlations between expression of upstream components of the MTOR pathway and their downstream targets. Expression of PIK3CA, MTOR, or p-EIF4EBP1 was associated with high MKI67 (Ki-67) labeling index. We failed to identify clinical correlations associated with expression of the upstream regulators TSC1, TSC2, AKT, p-AKT, PDPK1, PTEN, PIK3R1, or PIK3CA. In contrast, high expression of MTOR or its activated downstream targets p-RPS6KB1, p-RPS6, or p-EIF4EBP1 was associated with adverse clinical outcomes. CONCLUSION: Our observations suggest that expression of MTOR or its downstream targets may be adverse prognostic factors in neuroendocrine tumors.

Clinical presentation, recurrence, and survival in patients with neuroendocrine tumors: results from a prospective institutional database.

The rarity of neuroendocrine tumors (NET) has contributed to a paucity of large epidemiologic studies of patients with this condition. We characterized presenting symptoms and clinical outcomes in a prospective database of over 900 patients with NET. We used data from patient questionnaires and the medical record to characterize presenting symptoms, disease-free survival (DFS), and overall survival (OS). The majority of patients in this database had gastroenteropancreatic NET. The median duration of patient-reported symptoms before diagnosis was 3.4 months; 19.5% reported durations from 1 to 5 years, 2.5% from 5 to 10 years, and 2% >10 years. The median DFS among patients with resected small bowel NET or pancreatic NET (panNET) was 5.8 and 4.1 years respectively. After correcting for left truncation bias, the median OS was 7.9 years for advanced small bowel NET and 3.9 years for advanced panNET. Chromogranin A (CGA) above twice the upper limit of normal was associated with shorter survival times (hazard ratios 2.8 (1.9, 4.0) P<0.001) in patients with metastatic disease, regardless of tumor subtype. Our data suggest that while most NET patients are diagnosed soon after symptom onset, prolonged symptom duration before diagnosis is a prominent feature of this disease. Though limited to observations from a large referral center, our observations confirm the prognostic value of CGA and suggest that median survival durations may be shorter than that reported in other institutional databases.