Temporal increase in Ki-67 index in patients with pancreatic neuroendocrine tumours

Pancreatic neuroendocrine tumours (PanNETs) have intra-tumour heterogeneity, notably regarding the Ki-67 index, which is a major prognostic factor. The temporal evolution of PanNET biology is poorly known. We aimed to study the prognostic impact of the temporal evolution of Ki-67 and other molecular markers (MEN1, ATRX/DAXX and PDX1/ARX) in PanNETs. We retrospectively studied 109 patients with sporadic PanNETs and serial tumour samples (n = 286), in which we measured the Ki-67 index and the expression of the other markers. Variables associated with shorter overall survival (OS) and Ki-67 increase over time were explored using multivariable analyses. The median time between the initial and last samples was 49.4 months, with a median variation in Ki-67 of +4% (interquartile range (IQR): -1 to +15%; P < 0.001) and +0.5%/year (IQR: -0.2 to +3.3%). Tumour grade increased in 36% of cases. At multivariable analysis, an increase in Ki-67 ≥ 2%/year was associated with shorter OS (HR 1.96, 95% CI [1.02-3.73], P = 0.041). This variation was more common in patients who received alkylating agents (OR 4.47, 95% CI [1.48-15.38], P = 0.011) and was less common in those who achieved tumour control with somatostatin analogues (OR 0.27, 95% CI [0.08-0.82], P = 0.027). MEN1 and ATRX/DAXX expressions were stable over time, while the proportion of alpha-like signatures (PDX1-/ARX+) decreased (P = 0.016); none was associated with Ki-67 nor influenced prognosis. Overall, an increase in PanNET grade and Ki-67 index is frequent over time, indicates a poorer prognosis and is promoted by alkylating agents. Rebiopsy during PanNET evolution seems relevant to adjust prognosis evaluation and therapeutic strategy.