Impact of KRAS and BRAF mutations on treatment efficacy and survival in high‐grade gastroenteropancreatic neuroendocrine neoplasms

• Published in: Journal of neuroendocrinology 2023-04, Vol.35 (4), p.e13256-n/a
• Main Authors: Elvebakken, Hege, Hjortland, Geir Olav, Garresori, Herish, Andresen, Per Arne, Janssen, Emiel A. M., Vintermyr, Olav Karsten, Lothe, Inger M. B., Sorbye, Halfdan
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; BRAF; Carcinoma; Carcinoma, Neuroendocrine - drug therapy; Chemotherapy; Colon; Disease Progression; Etoposide; gastroenteropancreatic; Humans; KRAS; Medical prognosis; Metastases; Metastasis; Microsatellite instability; Mutation; neuroendocrine carcinoma; neuroendocrine neoplasms; Neuroendocrine tumors; Neuroendocrine Tumors - drug therapy; Neuroendocrine Tumors - genetics; Neuroendocrine Tumors - pathology; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Patients; Prognosis; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - therapeutic use; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - therapeutic use; Survival; Treatment Outcome; Tumors
• ISSN: 0953-8194; 1365-2826
• DOI: 10.1111/jne.13256

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. In this study, we assessed 88 high grade gastroenteropancreatic neoplasms for correlations between KRAS and BRAF mutations and outcome of first‐line palliative chemotherapy. BRAF mutations predicted limited effect of cis/carboplatin and etoposide without affecting PFS or OS. The benefit of chemotherapy was particularly low for BRAF mutated colon NEC. Wefound no significant correlation wit