Rb loss and KRAS mutation are predictors of the response to platinum-based chemotherapy in pancreatic neuroendocrine neoplasm with grade 3: A Japanese multicenter pancreatic NEN-G3 study

Susumu Hijioka, Waki Hosoda, Keitaro Matsuo, Makoto Ueno, Masayuki Furukawa, Hideyuki Yoshitomi, Noritoshi Kobayashi, Masafumi Ikeda, Tetsuhide Ito, Shoji Nakamori, Hiroshi Ishii, Yuzo Kodama, Chigusa Morizane, Takuji Okusaka, Hiroaki Yanagimoto, Kenji Notohara, Hiroki Taguchi, Masayuki Kitano, Kei Yane, Hiroyuki MaguchiYoshiaki Tsuchiya, Izumi Komoto, Hiroki Tanaka, Akihito Tsuji, Syunpei Hashigo, Yoshiaki Kawaguchi, Tetsuya Mine, Atsushi Kanno, Go Murohisa, Katsuyuki Miyabe, Tadayuki Takagi, Nobutaka Matayoshi, Tsukasa Yoshida, Kazuo Hara, Masayuki Imamura, Junji Furuse, Yasushi Yatabe, Nobumasa Mizuno

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Abstract

Purpose: 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. Experimental Design: 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. Results: 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 KRAS (0%), whereas NEC-G3 showed higher Ki67-LI (median 80.0%), Rb loss (54.5%), and KRAS 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 (P < 0.001). When we stratified PanNEN-G3 with Rb and KRAS, PanNENs-G3 with Rb loss and those with mutated KRAS showed significantly higher RRs to platinum-based chemotherapy than those without (Rb loss, 80% vs. normal Rb, 24%, P = 0.006; mutated KRAS, 77% versus wild type, 23%, P = 0.023). Rb was a predictive marker of response to platinum-based chemotherapy even in NEC-G3 (P = 0.035). Conclusions: NET-G3 and NEC-G3 showed distinct clinicopathologic characteristics. Notably, NET-G3 does not respond to platinum-based chemotherapy. Rb and KRAS are promising predictors of response to platinum-based chemotherapy for PanNEN-G3, and Rb for NEC-G3.

Original languageEnglish
Pages (from-to)4625-4632
Number of pages8
JournalClinical Cancer Research
Volume23
Issue number16
DOIs
Publication statusPublished - 2017 Aug 15

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Hijioka, S., Hosoda, W., Matsuo, K., Ueno, M., Furukawa, M., Yoshitomi, H., Kobayashi, N., Ikeda, M., Ito, T., Nakamori, S., Ishii, H., Kodama, Y., Morizane, C., Okusaka, T., Yanagimoto, H., Notohara, K., Taguchi, H., Kitano, M., Yane, K., ... Mizuno, N. (2017). Rb loss and KRAS mutation are predictors of the response to platinum-based chemotherapy in pancreatic neuroendocrine neoplasm with grade 3: A Japanese multicenter pancreatic NEN-G3 study. Clinical Cancer Research, 23(16), 4625-4632. https://doi.org/10.1158/1078-0432.CCR-16-3135