123264-143

Profiling of a global cohort of 1,250 neuroendocrine tumors to identify multiple potential drug targets.

Subcategory: 
Category: 
Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract
Session Type and Session Title: 
General Poster Session B: Cancers of the Pancreas, Small Bowel, and Hepatobiliary Tract
Abstract Number: 
214
Citation: 
J Clin Oncol 32, 2014 (suppl 3; abstr 214)
Author(s): 
Igor A. Astsaturov, Steven J. Cohen, Paul F. Engstrom, Zoran Gatalica, Ryan P. Bender, Gargi Dan Basu, Sherri Z. Millis; Fox Chase Cancer Center, Philadelphia, PA; Caris Life Sciences, Phoenix, AZ

Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).

Abstract Disclosures

Abstract: 

Background: Identification of new drug targets may extend treatment options for NET, regardless of histologic classification or primary organ site. Methods: 1,250 cases of infradiaphragmatic neuroendocrine tumors (all grades and sites) were identified among >50,000 cases profiled in a CLIA certified laboratory. Biomarker profiling utilized multiple platforms: gene sequencing (next generation sequencing, Sanger or pyrosequencing), gene copy number by in-situ hybridization, and protein expression by immunohistochemistry. The results are shown relative to the total number of tests performed. Results: Overall, drug therapy-relevant alterations were identified in 1,130 of 1,250 (90%) of cases. Low or absent (0 or 1+ by IHC) MGMT, a biomarker of sensitivity to alkylating agents, was found in 130/219 pancreatic cases (59%), and in 450/991 (45%) of non-pancreatic NET. Low or absent (0 or 1+ by IHC) expression of RRM1, a biomarker of gemcitabine sensitivity, was found in 813/1,100 of NET (74%) and low or absent thymidine synthase, TS, a biomarker of fluoropyrimidine sensitivity, was shown for 793/1,096 (72%) of NET by IHC. Sequencing of tumors showed oncogenic mutations in BRAF (4/369 (V600E in 3 and G596R in 1), CTNNB1 (2/150), KIT (3/281), EGFR (1/178), FGFR2 (1/150), GNAS (1/150), HRAS (2/150), PIK3CA (6/343), RB (2/150) VHL (1/150), KRAS (10/125), NRAS (2/274), and APC (2/150) and amplifications of EGFR (46/686) and MET (4/236). Ki67 status and correlation between the site of origin and biomarkers will be presented. Therapies guided by mechanism-based biomarkers produced durable responses in documented cases: partial response (PR) >1 year to imatinib in a patient with KIT-mutant metastatic NET, and in cases of MGMTlow/TSlowtreated with streptozocine or temizolomide plus fluoropyrimidine chemotherapy, thus supporting the clinical relevance of target profiling in NET. Conclusions: Comprehensive multiplatform profiling of a large series (n=1,250) of NET, despite low frequency of individual biomarkers, identified clinically relevant targets in the majority of patients. Our results provide the basis for future clinical trials to assess the efficacy of biomarker-based therapy for NET.