PMID- 37017614
OWN - NLM
STAT- MEDLINE
DCOM- 20230428
LR  - 20230620
IS  - 1365-2826 (Electronic)
IS  - 0953-8194 (Linking)
VI  - 35
IP  - 4
DP  - 2023 Apr
TI  - Impact of KRAS and BRAF mutations on treatment efficacy and survival in 
      high-grade gastroenteropancreatic neuroendocrine neoplasms.
PG  - e13256
LID - 10.1111/jne.13256 [doi]
AB  - High-grade gastroenteropancreatic neuroendocrine neoplasms (HG GEP-NEN) typically 
      disseminate early. Treatment of metastatic disease has limited benefit and 
      prognosis is generally discouraging. Data on the clinical impact of mutations in 
      HG GEP-NEN are scarce. There is an unmet need for reliable biomarkers to predict 
      treatment outcome and prognosis in metastatic HG GEP-NEN. Patients with 
      metastatic HG GEP-NEN diagnosed at three centres were selected for KRAS-, BRAF 
      mutation and microsatellite instability (MSI) analyses. Results were linked to 
      treatment outcome and overall survival. After pathological re-evaluation, 83 
      patients met inclusion criteria: 77 (93%) GEP neuroendocrine carcinomas (NEC) and 
      six (7%) GEP neuroendocrine tumours (NET) G3. NEC harboured higher frequency of 
      mutations than NET G3. Colon NEC harboured a particular high frequency of BRAF 
      mutations (63%). Immediate disease progression on first-line chemotherapy was 
      significantly higher for NEC with BRAF mutation (73%) versus wild-type (27%) 
      (p = .016) and for colonic primary (65%) versus other NEC (28%) (p = .011). Colon 
      NEC had a significant shorter PFS compared to other primary sites, a finding 
      independent of BRAF status. Immediate disease progression was particularly 
      frequent for BRAF mutated colon NEC (OR 10.2, p = .007). Surprisingly, BRAF 
      mutation did not influence overall survival. KRAS mutation was associated with 
      inferior overall survival for the whole NEC population (HR 2.02, p = .015), but 
      not for those given first-line chemotherapy. All long-term survivors (>24 m) were 
      double wild-type. Three NEC cases (4.8%) were MSI. Colon NEC with BRAF mutation 
      predicted immediate disease progression on first-line chemotherapy, but did not 
      affect PFS or OS. Benefit of first-line platinum/etoposide treatment seems 
      limited for colon NEC, especially for BRAF mutated cases. KRAS mutations did not 
      influence treatment efficacy nor survival for patients receiving first-line 
      chemotherapy. Both frequency and clinical impact of KRAS/BRAF mutations in 
      digestive NEC differ from prior results on digestive adenocarcinoma.
CI  - (c) 2023 British Society for Neuroendocrinology.
FAU - Elvebakken, Hege
AU  - Elvebakken H
AUID- ORCID: 0000-0001-7458-4836
AD  - Department of Oncology, Alesund Hospital, More og Romsdal Hospital Trust, 
      Alesund, Norway.
AD  - Department of Clinical and Molecular Medicine, Faculty of Medicine and Health 
      Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
FAU - Hjortland, Geir Olav
AU  - Hjortland GO
AD  - Department of Oncology, Oslo University Hospital, Oslo, Norway.
FAU - Garresori, Herish
AU  - Garresori H
AD  - Department of Haematology and Oncology, Stavanger University Hospital, Stavanger, 
      Norway.
FAU - Andresen, Per Arne
AU  - Andresen PA
AD  - Department of Pathology, Oslo University Hospital, Oslo, Norway.
FAU - Janssen, Emiel A M
AU  - Janssen EAM
AD  - Department of Pathology, Stavanger University Hospital, Stavanger, Norway.
AD  - Department of Chemistry, Bioscience and Environmental Engineering, Stavanger 
      University, Stavanger, Norway.
FAU - Vintermyr, Olav Karsten
AU  - Vintermyr OK
AD  - Department of Pathology, Haukeland University Hospital, Bergen, Norway.
FAU - Lothe, Inger M B
AU  - Lothe IMB
AD  - Department of Pathology, Oslo University Hospital, Oslo, Norway.
FAU - Sorbye, Halfdan
AU  - Sorbye H
AUID- ORCID: 0000-0002-7132-6214
AD  - Department of Oncology, Haukeland University Hospital, Bergen, Norway.
AD  - Department of Clinical Science, University of Bergen, Bergen, Norway.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230405
PL  - United States
TA  - J Neuroendocrinol
JT  - Journal of neuroendocrinology
JID - 8913461
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - 0 (KRAS protein, human)
RN  - EC 2.7.11.1 (BRAF protein, human)
SB  - IM
MH  - Humans
MH  - Proto-Oncogene Proteins B-raf/genetics/therapeutic use
MH  - Proto-Oncogene Proteins p21(ras)/genetics/therapeutic use
MH  - *Pancreatic Neoplasms/drug therapy/genetics/pathology
MH  - *Neuroendocrine Tumors/drug therapy/genetics/pathology
MH  - Treatment Outcome
MH  - *Carcinoma, Neuroendocrine/drug therapy
MH  - Prognosis
MH  - Mutation
MH  - Disease Progression
OTO - NOTNLM
OT  - BRAF
OT  - KRAS
OT  - gastroenteropancreatic
OT  - neuroendocrine carcinoma
OT  - neuroendocrine neoplasms
EDAT- 2023/04/06 06:00
MHDA- 2023/04/28 06:41
CRDT- 2023/04/05 10:43
PHST- 2023/03/01 00:00 [revised]
PHST- 2022/11/14 00:00 [received]
PHST- 2023/03/08 00:00 [accepted]
PHST- 2023/04/28 06:41 [medline]
PHST- 2023/04/06 06:00 [pubmed]
PHST- 2023/04/05 10:43 [entrez]
AID - 10.1111/jne.13256 [doi]
PST - ppublish
SO  - J Neuroendocrinol. 2023 Apr;35(4):e13256. doi: 10.1111/jne.13256. Epub 2023 Apr 
      5.