Abstract There is limited data regarding the rare and aggressive colorectal neuroendocrine carcinoma (CR‐NEC). In this large prospective study, molecular–clinical characteristics and treatment outcomes following palliative chemotherapy are reported for 163 metastatic CR‐NEC patients, with a comparison to a population‐based prospective cohort of 263 metastatic colorectal adenocarcinoma (CR‐AC) patients. Eighty‐three percent of CR‐NEC received first‐line platinum‐etoposide, while 98% of CR‐AC patients received first‐line fluorouracil‐based chemotherapy. Disease control rate across all first‐line regimens in CR‐NEC and CR‐AC was 43% vs. 74%, immediate progressive disease 46% vs. 15%, progression‐free survival 2.4 months (m) (95% CI 2.1–3.3) vs. 7.7 m (95% CI 6.9–8.5), and overall survival 6.7 m (95% CI 5.6–8.8) vs. 16.8 m (95% CI 13.7–20.3), all, p < .001. CR‐NEC more often had synchronous metastases, worse performance status, and symptom burden at treatment initiation than CR‐AC (all, p < .001). Two‐year survival was 9% vs. 37% in CR‐NEC and CR‐AC ( p < .001). BRAF mutations were frequent in CR‐NEC and CR‐AC (26% vs. 20%, p = .153) and associated with shorter OS in CR‐NEC and CR‐AC ( p = .025 and p = .003). KRAS mutations were less frequent in CR‐NEC than CR‐AC (34% vs. 45%, p = .041), but only associated with shorter OS in rectal NEC ( p = .04). The frequencies of APC and TP53 mutations were similar between the cohorts and did not impact survival. Metastatic CR‐NEC and CR‐AC are clinically distinct, with NEC demonstrating more aggressive features, limited treatment effect, and worse prognosis. Although they share important driver mutations, the underlying reason for their marked clinical differences remains unclear.
Morken et al. (2026) studied this question.