Abstract A01: Exploring phosphatase and tensin homolog (PTEN) loss as a potential predictive marker for response to everolimus in patients with pancreatic neuroendocrine tumors (PNETs)

• Published in: Molecular cancer therapeutics 2015-07, Vol.14 (7_Supplement), p.A01-A01
• Main Authors: Khushman, Moh'd, Slingerland, Joyce, Fan, Yao-Shan, Garcia-Buitrago, Monica, Bustinza, Ernesto, Restrepo, Maria, Sussman, Daniel, Rocha-Lima, Caio, Hosein, Peter
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1538-8514.PI3K14-A01

Introduction: Identification of patients with exquisite sensitivity and/or durable responses to targeted therapies may lead to improved patient selection and allow for more rational treatment designs. Loss of PTEN tumor suppressor gene function, usually due to deletion, leads to activation of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin (mTOR) signaling. The RADIANT-3 trial of everolimus in advanced PNETs demonstrated a significant prolongation of progression-free survival (PFS) from 4.6 months with placebo versus 11 months with everolimus. Despite the improvement in PFS, the response rate was only 5% among patients receiving everolimus. The index case for our study was an exceptional responder who had a significant radiological response as well as a PFS of 24 months, which were both better than expected from the literature. This led to the hypothesis that there may be mutational changes in genes affecting the mTOR pathway that could predict sensitivity to mTOR inhibitors. In this study, we specifically explored the role of PTEN loss as a potential predictive marker. Methods and Materials: Between 2010 and 2014, patients with well-differentiated unresectable and metastatic PNETs treated at the University of Miami/Sylvester Comprehensive Cancer Center and Jackson Memorial Hospital with everolimus were identified. Eight patients had pathology specimens available for testing. PTEN loss detected by Fluorescence In Situ Hybridization (FISH) was carried out using a commercially available probe for cytoband 10q23. Patients' response to everolimus was evaluated through June 2014. The primary outcome was PFS. PTEN expression by immunohistochemistry (IHC) will also be performed and the results will be compared to those obtained by FISH. Results: The median age was 60 years (range 45-78). 50% of the patients were females and 50% were males. Two patients had gastrinomas, 1 patient had an insulinoma, and five patients had non-functional PNETs. All patients had unresectable metastases to the liver. In addition to sandostatin LAR, the patients received everolimus starting at a dose of 10mg daily. Three patients were found to have deletion of PTEN. Of those, one patient did not tolerate everolimus and the PFS for the other two was 8 and 24 months respectively. Detection of PTEN loss by FISH yielded no results in 2 patients due to insufficient tumor left in the specimen. PFS in these 2 patients was 24 and 4 months respectively. Testing is ongoing in