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Clin Cancer Res. 2018 Jul 15;24(14):3282-3291. doi: 10.1158/1078-0432.CCR-17-1805. Epub 2018 Jan 19.

Exceptional Response to Pembrolizumab in a Metastatic, Chemotherapy/Radiation-Resistant Ovarian Cancer Patient Harboring a PD-L1-Genetic Rearrangement.

Author information

1
Department of Obstetrics and Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
2
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut.
3
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
4
Foundation Medicine, Cambridge, Massachusetts.
5
Department of Obstetrics and Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut. alessandro.santin@yale.edu.

Abstract

Purpose: Ovarian carcinoma no longer responsive to surgery and chemotherapy remains an incurable disease. Alternative therapeutic options remain desperately needed.Patients and Methods: We describe a heavily pretreated patient with ovarian cancer with recurrent disease experiencing a remarkable clinical response to treatment with the anti-PD1 immune checkpoint inhibitor pembrolizumab. The clinical, pathological, and genomic characteristics of this exceptional ovarian cancer responder were carefully investigated using immunohistochemistry (IHC), quantitative multiplex fluorescence methods (i.e., automated quantitative analysis, AQUA) and whole-exome sequencing (WES) techniques.Results: The patient harbored a recurrent/metastatic radiation and chemotherapy-resistant high-grade ovarian carcinoma with clear cell features. While progressing on any standard treatment modality, she demonstrated a remarkable complete response to the anti-PD1 immune checkpoint inhibitor pembrolizumab. WES results were notable for the presence a relative low number of mutations (tumor mutation load/Mb = 4.31, total mutations = 164) and a peculiar structural variant disrupting the 3' region of the PD-L1 gene causing aberrant PD-L1 surface expression as confirmed by IHC and AQUA technology. Heavy infiltration of the PD-L1-mutated and PD-L1-overexpressing tumor with T-cell lymphocytes (i.e., CD4+/CD8+ TIL), CD68+ macrophages, and CD20+ B cells was detected in the surgical specimen strongly suggesting immune evasion as a key mechanism of tumor growth and survival. Patient's complete clinical responses remain unchanged at the time of the writing of this report with no significant side effects reported to date.Conclusions: Anti-PD1 inhibitors may represent a novel treatment option for recurrent/metastatic human tumors refractory to salvage treatment harboring PD-L1 gene structural variations causing aberrant PD-L1 expression. Clin Cancer Res; 24(14); 3282-91. ©2018 AACRSee related commentary by Lheureux, p. 3233.

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