Clinicopathological features of wild-type GISTs based on multiple-gene panel analysis

Date 25 November 2018
Event ESMO Asia 2018 Congress
Session Mini Oral - Melanoma and Sarcoma
Topics GIST
Pathology/Molecular Biology
Presenter Toshiro Nishida
Citation Annals of Oncology (2018) 29 (suppl_9): ix124-ix128. 10.1093/annonc/mdy443
Authors T. Nishida1, Y. Naito2, T. Takahashi3, Y. Honma4, T. Saito5, H. Ichikawa6, S. Hirota7
  • 1Department Of Surgery, National Cancer Center Hospital, 104-0045 - Tokyo/JP
  • 2Department Of Breast And Medical Oncology, National Cancer Center Hospital East, 277-8577 - Kashiwa/JP
  • 3Department Of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 595-0871 - Suita/JP
  • 4Department Of Gastrointestinal Medical Oncology, National Cancer Center Hospital, 104-0045 - Tokyo/JP
  • 5Department Of Surgery, Osaka Police Hospital, 543-0035 - Osaka/JP
  • 6Department Of Clinical Genomics, National Cancer Center Research Institute, 104-0045 - Tokyo/JP
  • 7Department Of Surgical Pathology, Hyogo College of Medicine, 663-8501 - Nishinomiya/JP

Abstract

Background

Clinicopathological features and prognosis of wild-type GIST defined as GIST lacking mutations in KIT and PDGFRA genes are unknown. We conducted the panel analysis of wild-type GIST.

Methods

Cohort 1: Total 255 pts with primary GISTs underwent surgery in 2 hospitals were consecutively registered between 2003 and 2014. Cohort 2: Total 515 pts with high-risk GISTs by Modified NIH classification diagnosed in 127 hospitals were prospectively registered between 2012 and 2015. Median follow-up periods of Cohort 1 and 2 were 3.4 and 4.2 years, respectively. Genotyping was performed using surgical specimens with conventional PCR/sequencing of KIT and PDGFRA, and, then, targeted sequencing with NCC Oncopanel ver. 5 for wild-type GIST.

Results

Wild-type GISTs found in Cohort 1 and 2 were 17 (6.7%) and 19 (3.7%), respectively. Compared with KIT-mutated GISTs, wild-type and PDGFRA-mutated GISTs showed lower mitotic counts (p = 0.009) and better recurrent-free survival (p = 0.004) in Cohort 1. Age at diagnosis was significantly younger in wild-type GIST than KIT- and PDGFRA-mutated GISTs. Frequency of high risk GISTs was similar among 3 mutation groups. Total 36 wild-type GISTs from two Cohorts located in the stomach (n = 16), small intestine (18), lower esophagus (1) or extra-GI (1). Panel analysis found mutations in NF1 (13), SDH complex (6; SDHA=3 and SDHB=3), BRAF (5), and no known GIST-associated mutation in 7 (the other 5 were not analytical due to poor or no DNA). BRAF-mutated (4 out of 5) and NF1-GISTs (10 of 13) mainly located in the small intestine, and SDH-mutated (5 of 6) located in the stomach. Multiple GISTs were recognized in 10 pts including 6 (46% of NF1) NF1- and 3 (50%) SDH-mutated GISTs. Among genotypes, there were no difference in tumor size and mitotic counts, but SDH-mutated GISTs were significantly younger than the other wild-type GISTs. Among 13 NF1-GIST pts, only 1 had family history and 5 pts met the diagnostic criteria of NF1. With a median follow-up of 3.4 years, new relpases were found in 10 pts with high risk GISTs. 15 out of 24 high risk wild-type GISTs received adjuvant therapy and 6 pts of 15 had relapses even under imatinib.

Conclusions

Wild-type GIST is a heterogeneous disease and relapse was associated with high-risk features despite imatinib-adjuvant.

Editorial acknowledgement

Clinical trial identification

UMIN000009531.

Legal entity responsible for the study

STAR Registry Goup.

Funding

The National Cancer Center Research and Development Fund.

Disclosure

All authors have declared no conflicts of interest.