Supplementary Material for: Prognostic Factors Across Poorly Differentiated Neuroendocrine Neoplasms: a Pooled Analysis

Introduction: Poorly differentiated neuroendocrine carcinomas (NECs) are characterized by aggressive clinical course and poor prognosis. No reliable prognostic markers have been validated to date; thus, the definition of a specific NEC prognostic algorithm represents a clinical need. This study aimed to analyze a large NEC case series to validate the specific prognostic factors identified in previous studies on gastro-entero-pancreatic (GEP) and lung NECs and to assess if further prognostic parameters can be isolated. Methods: A pooled analysis of four NEC retrospective studies was performed to evaluate: the prognostic role of Ki-67 cut-off, the OS according to primary cancer site, and further prognostic parameters using multivariable Cox proportional hazards model and machine-learning random survival forest (RSF). Results: 422 NECs were analyzed. The most represented tumor site was the colorectum (n=156, 37%), followed by the lungs (n=111, 26%), gastroesophageal site (n=83, 20%; 66 gastric, 79%). The Ki-67 index was the most relevant predictor, followed by morphology (pure or mixed/combined NECs), stage, and site. The predicted RSF response for survival at 1, 2, or 3 years showed decreasing survival with increasing Ki-67, pure NEC morphology, stage III–IV, and colorectal NEC disease. Patients with Ki-67