Cancers (Feb 2021)

Biomarkers of Response to Etoposide-Platinum Chemotherapy in Patients with Grade 3 Neuroendocrine Neoplasms

  • Caroline Lacombe,
  • Ophélie De Rycke,
  • Anne Couvelard,
  • Anthony Turpin,
  • Aurélie Cazes,
  • Olivia Hentic,
  • Valérie Gounant,
  • Gérard Zalcman,
  • Philippe Ruszniewski,
  • Jérôme Cros,
  • Louis de Mestier

DOI
https://doi.org/10.3390/cancers13040643
Journal volume & issue
Vol. 13, no. 4
p. 643

Abstract

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Etoposide-platinum (EP) chemotherapy has long been the reference treatment for grade 3 neuroendocrine neoplasms (G3 NEN). However, G3 NEN are heterogeneous, including well-differentiated tumors (NET) and poorly differentiated large (LCNEC) or small (SCNEC) cell carcinomas, whose response to EP chemotherapy varies considerably. Our aim was to evaluate predictive biomarkers for the response to EP chemotherapy in G3 NEN. We retrospectively studied 89 patients with lung (42%) and digestive (58%) G3 NEN treated by EP chemotherapy between 2006 and 2020. All cases were centrally reviewed for cytomorphology/Ki-67 and immunohistochemistry of retinoblastoma protein (Rb)/p53/p16, analyzed using a semi-quantitative score. The absence of Rb staining (Rbinap) or the absence of very intense p53 staining (p53inap) were considered inappropriate. Rb staining was also studied as a quantitative marker, the best threshold being determined by ROC curve. Intense p16 staining (p16high) also suggested cell cycle dysregulation. Our primary endpoint was the objective response rate (ORR). We included 10 G3 NET, 31 LCNEC and 48 SCNEC, which showed ORR of 20%, 32% and 75%, respectively (NET vs. NEC, p = 0.040; LCNEC vs. SCNEC, p inap (63% vs. 42%, p = 0.025) and p16high (66% vs. 35%, p = 0.006). Rb p p = 0.005). On multivariate analysis, only Rb p = 0.034). We confirm the heterogeneity of the response to EP treatment in G3 NEN. Rb < 150 was the best predictive biomarker for the response to EP, and p53 immunostaining had no additional value.

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