Rb Loss and <i>KRAS</i> Mutation Are Predictors of the Response to Platinum-Based Chemotherapy in Pancreatic Neuroendocrine Neoplasm with Grade 3: A Japanese Multicenter Pancreatic NEN-G3 Study

Abstract

<b>Purpose:</b> Patients with pancreatic neuroendocrine neoplasm grade-3 (PanNEN-G3) show variable responses to platinum-based chemotherapy. Recent studies indicated that PanNEN-G3 includes well-differentiated neuroendocrine tumor with G3 (NET-G3). Here, we examined the clinicopathologic and molecular features of PanNEN-G3 and assessed the responsiveness to chemotherapy and survival.<b>Experimental Design:</b> A total of 100 patients with PanNEN-G3 were collected from 31 institutions, and after central review characteristics of each histologic subtype [NET-G3 vs. pancreatic neuroendocrine carcinoma (NEC-G3)] were analyzed, including clinical, radiological, and molecular features. Factors that correlate with response to chemotherapy and survival were assessed.<b>Results:</b> Seventy patients analyzed included 21 NETs-G3 (30%) and 49 NECs-G3 (70%). NET-G3 showed lower Ki67-labeling index (LI; median 28.5%), no abnormal Rb expression (0%), and no mutated <i>KRAS</i> (0%), whereas NEC-G3 showed higher Ki67-LI (median 80.0%), Rb loss (54.5%), and <i>KRAS</i> mutations (48.7%). Chemotherapy response rate (RR), platinum-based chemotherapy RR, and prognosis differed significantly between NET-G3 and NEC-G3. Chemotherapeutic outcomes were worse in NET-G3 (<i>P</i> < 0.001). When we stratified PanNEN-G3 with Rb and <i>KRAS</i>, PanNENs-G3 with Rb loss and those with mutated <i>KRAS</i> showed significantly higher RRs to platinum-based chemotherapy than those without (Rb loss, 80% vs. normal Rb, 24%, <i>P</i> = 0.006; mutated <i>KRAS</i>, 77% versus wild type, 23%, <i>P</i> = 0.023). Rb was a predictive marker of response to platinum-based chemotherapy even in NEC-G3 (<i>P</i> = 0.035).<b>Conclusions:</b> NET-G3 and NEC-G3 showed distinct clinicopathologic characteristics. Notably, NET-G3 does not respond to platinum-based chemotherapy. Rb and <i>KRAS</i> are promising predictors of response to platinum-based chemotherapy for PanNEN-G3, and Rb for NEC-G3. <i>Clin Cancer Res; 23(16); 4625-32. ©2017 AACR</i>.