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

Abstract

AbstractHigh‐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.