Abstract
BACKGROUND: Hyperactivation of mTOR pathway and angiogenesis have been implicated in the pathogenesis of neuroendocrine tumors (NETs). Everolimus, an oral inhibitor of mTOR, and sunitinib, an antiangiogenic drug, are effective targeted therapies approved to treat locally advanced/metastatic pancreatic neuroendocrine tumors (pNETs). Most pNETs are sporadic and mutations in genes involved directly or indirectly in mTOR pathway regulation have been implicated, including somatic mutation in MEN1 in 44% of cases. About 10% of pNETs can be part of hereditary syndromes, e.g., multiple endocrine neoplasia type 1 (MEN1) and Von-Hippel Lindau (VHL), and these patients are underrepresented in pivotal phase III trials. We hypothesized that everolimus would be particularly effective in patients with MEN1-associated pNETs. Likewise, we inferred that sunitinib would also be beneficial to patients with VHL-associated pNETs. METHODS: We conducted a multicenter retrospective and comparative study to assess the efficacy of everolimus and/or sunitinib in a cohort of patients with advanced pNETs with or without known MEN1 or VHL syndrome. The evaluation of the germline mutational status of VHL and MEN1 genes was retrospectively collected from the medical records. The primary endpoints were progression free survival (PFS) and time to treatment failure (TTF) of patients who received at least one month of sunitinib or everolimus in monotherapy. RESULTS: Thirty-three patients were identified from September 2009 to April 2018. Most were male 60.6%. Median Ki67 was 9%, liver metastases were present in 97%. The majority of tumors were non-functioning. Thirty-one patients received everolimus, of them 8 patients had germline mutations (6 in MEN1 and 2 in VHL genes). Nine patients received sunitinib, of them 3 had germline mutation (2 in MEN1 and 1 in VHL genes). In a median follow up of 26 months, among everolimus-treated patients, mTTF and mPFS were numerically superior in patients with germline mutations compared with those with sporadic pNETs (mTTF: 16.1 vs. 9.9 months, P=0.888; mPFS: 33.1 vs. 12.3 months, P=0.383). The disease control rate with everolimus was numerically higher in favor of germline mutated tumors compared to sporadic ones (87.5% vs. 68.4%). Sunitinib was used by 1 patient with VHL syndrome, achieving a PFS of 17.6 months. In the subgroup of sporadic pNETs, sunitinib was used by 6 patients reaching a mPFS of 18 months (range, 5-25 months), predominantly in second line. CONCLUSIONS: Our study suggests that everolimus may offer a prolonged tumor control in pNETS with germline mutations (MEN1 or VHL) compared to sporadic ones. The small number of patients and the retrospective nature of this study precludes any definitive conclusions.