Impact of KRAS and BRAF mutations on treatment efficacy and survival in high-grade gastroenteropancreatic neuroendocrine neoplasms
Elvebakken, Hege; Hjortland, Geir Olav; Garresori, Herish; Andresen, Per Arne; Janssen, Emiel; Vintermyr, Olav Karsten; Lothe, Inger Marie Bowitz; Sorbye, Halfdan
Peer reviewed, Journal article
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Date
2023Metadata
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Elvebakken, H., Hjortland, G. O., Garresori, H., Andresen, P. A., Janssen, E. A., Vintermyr, O. K., ... & Sorbye, H. (2023). Impact of KRAS and BRAF mutations on treatment efficacy and survival in high‐grade gastroenteropancreatic neuroendocrine neoplasms. Journal of Neuroendocrinology, 35(4), e13256. 10.1111/jne.13256Abstract
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 associatedwith inferior overall survival for the wholeNEC 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.