The MTOR serine/threonine kinase pathway is implicated in regulation of neuroendocrine tumor growth. In a study reported in the Journal of Clinical Oncology, Qian and colleagues investigated the potential prognostic significance of MTOR pathway component expression in patients with neuroendocrine tumors.
Immunohistochemical expression of MTOR and phospho (p)–MTOR, its downstream targets RPS6KB1, RPS6, and EIF4EBP1, and its upstream regulators was examined in a cohort of 195 archived neuroendocrine tumors. The association of expression levels with clinical outcomes was evaluated with adjustment for other prognostic variables.
Anticipated correlations between expression of upstream components of the MTOR pathway and their downstream targets were observed. Expression of PIK3CA, MTOR, or p-EIF4EBP1 was associated with a high MKI67 (Ki-67) labeling index. No clinical correlations with expression of the upstream regulators TSC1, TSC2, AKT, p-AKT, PDPK1, PTEN, PIK3R1, or PIK3CA were observed. However, high expression levels of MTOR or its activated downstream targets p-RPS6KB1, p-RPS6, and p-EIF4EBP1 were associated with adverse clinical outcomes.
In particular, in a multivariate analysis among patients with primary tissue tumor available, p-RPS6KB1 expression (hazard ratio [HR] = 3.13, P = .002) and p-RPS6 expression (HR = 2.62, P = .019) were associated with significantly shorter overall survival. Among patients with small intestinal neuroendocrine tumors, MTOR expression (HR = 5.15, P = .01) was associated with significantly shorter disease-free survival. In patients with metastatic disease, expression levels of MTOR (HR = 2.94, P = .011), p-RPS6KB1 (HR = 3.28, P = .015), p-RPS6 (HR = 2.69, P = .043), and p-EIF4EBP1 (HR = 3.15, P = .009) were associated with significantly shorter overall survival.
The investigators concluded, “[W] e found expression of MTOR and its downstream effectors to be associated with adverse clinical outcomes in a large cohort of patients with neuroendocrine tumors. Confirmatory studies, as well as studies evaluating the potential predictive value of these markers in patients receiving everolimus [Afinitor] or other MTOR inhibitors, are warranted.” ■