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

in Endocrine-Related Cancer
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Pauline Bourdeleau Université Paris-Cité, Department of Pancreatology and Digestive Oncology, Beaujon Hospital (APHP.Nord), Clichy, France

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Johanna Pokossy-Epée Université Paris-Cité, Department of Pancreatology and Digestive Oncology, Beaujon Hospital (APHP.Nord), Clichy, France
Center of Research on Inflammation, INSERM UMR1149, Paris, France

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Olivia Hentic Université Paris-Cité, Department of Pancreatology and Digestive Oncology, Beaujon Hospital (APHP.Nord), Clichy, France

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Matthieu Tihy Université Paris-Cité, Department of Pathology, Bichat Hospital (APHP.Nord), Clichy, France

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https://orcid.org/0000-0002-9314-4657
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Zaima Afzal Awan Center of Research on Inflammation, INSERM UMR1149, Paris, France

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Anne Couvelard Center of Research on Inflammation, INSERM UMR1149, Paris, France
Université Paris-Cité, Department of Pathology, Bichat Hospital (APHP.Nord), Clichy, France

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Maxime Ronot Center of Research on Inflammation, INSERM UMR1149, Paris, France
Université Paris-Cité, Department of Radiology, Beaujon Hospital (APHP.Nord), Clichy, France

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Vinciane Rebours Université Paris-Cité, Department of Pancreatology and Digestive Oncology, Beaujon Hospital (APHP.Nord), Clichy, France
Center of Research on Inflammation, INSERM UMR1149, Paris, France

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Philippe Ruszniewski Université Paris-Cité, Department of Pancreatology and Digestive Oncology, Beaujon Hospital (APHP.Nord), Clichy, France
Center of Research on Inflammation, INSERM UMR1149, Paris, France

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Jérôme Cros Center of Research on Inflammation, INSERM UMR1149, Paris, France
Université Paris-Cité, Department of Pathology, Beaujon Hospital (APHP.Nord), Clichy, France

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https://orcid.org/0000-0002-4935-3865
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Louis de Mestier Université Paris-Cité, Department of Pancreatology and Digestive Oncology, Beaujon Hospital (APHP.Nord), Clichy, France
Center of Research on Inflammation, INSERM UMR1149, Paris, France

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Correspondence should be addressed to L de Mestier: louis.demestier@aphp.fr
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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.

Supplementary Materials

 

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