HRAS expression predicts Lenvatinib responsiveness in human primary gastroenteropancreatic neuroendocrine tumor cells.

Abstract

e16211 Background: Neuroendocrine neoplasms (NENs) are a rare group of heterogeneous tumors, with clinical presentation ranging from indolent and small lesions to very aggressive, metastatic and therapy refractory forms. Despite a high number of trials, few drugs have been introduced in the clinical practice and therapeutic options for systemic intervention are limited. The recent TALENT trial demonstrated the efficacy of Lenvatinib, a multi-tyrosine kinase inhibitor (MKI), in the treatment of patients with advanced well differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing from targeted therapies or somatostatin analogues with no other treatment indication. Lenvatinib might represent a novel therapeutic opportunity for these rare tumor patients. However, the treatment approach with MKI lacks clinically validated tissue or blood biomarkers to guide patient selection and improve efficacy. Methods: Here we established 11 human primary cultures from patients with GEP-NEN of different grades and sites of origin and assessed the antitumor activity of Lenvatinib compared with standard treatment agents. All primary cultures were molecularly characterized to identify possible predictors of response. Results: Lenvatinib exerted a significant inhibition of cell growth in primary GEP-NET cells, with median survival inhibitions similar or higher than those of standard treatments. Of the 11 primary cultures analyzed in our case series, 6 were classified as responder with survival inhibition higher than 15%, and 5 as non-responder with survival inhibition lower than 15%. A high expression of HRAS in the tumor tissues compared to the matched healthy tissues significantly correlated with responsiveness of primary cells to Lenvatinib. All 5 non-responder patients showed low expression of HRAS, while of the 6 responder patients, 5 showed a high HRAS expression and only 1 low. None of the other evaluated clinical variables (grade, Ki67, site of origin and syndromic disease) correlated with response. Conclusions: In conclusion, we believe that the evaluation of HRAS expression and mutation might be of great interest in GEP-NET patients receiving Lenvatinib to improve patient selection.