Exceptional Response to Pembrolizumab in a Metastatic, Chemotherapy/Radiation-Resistant Ovarian Cancer Patient Harboring a PD-L1-Genetic Rearrangement - PubMed (original) (raw)

Case Reports

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

Stefania Bellone et al. Clin Cancer Res. 2018.

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 AACR See related commentary by Lheureux, p. 3233.

©2018 American Association for Cancer Research.

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Conflict of interest statement

Conflicts of interest: None

Figures

Figure 1

Figure 1

Representative CAT scans demonstrating activity (ie, complete response) to pembrolizumab. Left upper panel: Pretreatment images with baseline measurement of the representative metastatic tumor deposit (ie, pelvic/vaginal mass). Right upper Panel; stability of the lesion after 3 pembrolizumab infusions. Left and Right Lower panels: Complete regression of the metastatic tumor deposits after 16 and 24 weeks from treatment initiation with pembrolizumab.

Figure 2

Figure 2

Whole exome sequencing results. (A) Quality assessment and quality control of sequencing data for tumor and matched normal samples. (B) Somatic mutation classification. (C) The distribution of six different substitution subtypes. (D) Potential neoantigen classification. Strong: IC50 ≤ 50 nM, Intermediate: 50 nM < IC50 ≤ 150 nM, Weak: 150 nM < IC50 ≤ 500 nM. (E) Integrative Genomics Viewer (IGV) plots showing genomic rearrangement involving the PD-L1 gene. The event consists in a translocation/insertion of a 5′ 32 nucleotide fragment from the exon 5 of the PLGRKT gene, in the 5′ end of the PD-L1 gene, resulting in a breakpoint in exon 7 (3′ UTR). Green reads indicate the tandem duplication. Grey reads display normal sequencing reads.

Figure 3

Figure 3

Whole exome sequencing results. Somatic mutations (SNV), in cancer or immune-related genes and copy number variations (CNV) in cancer and immune related genes.

Figure 4

Figure 4

High grade ovarian carcinoma with marked peritumoral inflammatory cell infiltrate (A). The tumor cells and peritumoral inflammatory cells show moderately to intense membranous staining with PD-L1 immunohistochemistry (B). T-lymphocytes represent the predominant component among the immune cells, highlighted by CD4 (C) and CD8 (D) immunostains. B-lymphocytes (E: CD20 immunostain) and macrophages (F: CD68 immunostain) are present in a smaller proportion. CD56 and TIA immunostains were negative for NK-cells (image not shown). (A: hematoxylin-eosin stain, B: PD-L1 immunostain, C: CD4 immunostain, D: CD8 immunostain, E: CD20 immunostain, F: CD68 immunostain; all images at 200x original magnification).

Figure 5

Figure 5

Detection of PD-L1 protein expression in tumor cells using immunofluorescence multiplexing panel. A–F, Multiplex IF panel of PD-L1 (red)/Cytokeratin (green)/DAPI (blue)/CD68 (magenta) of the same region. A–D, Representative images of single channels (DAPI, CK, PD-L1, CD68) of the multiplex IF panel. E, Representative fluorescence image showing the colocalization of PD-L1 and cytokeratin. CD68+ macrophages do not express PD-L1. F, H&E staining. G–L, Multiplex IF panel of PD-L1 (red)/cytokeratin (green)/DAPI (blue)/CD8 (magenta) of the same region. G–J, Representative images of single channels (DAPI, CK, PD-L1, CD8) of the multiplex IF panel. K, Representative fluorescence image showing the colocalization of PD-L1 (red) and cytokeratin (green). CD8 (magenta)+ T cells do not express PD-L1. L, H&E staining.

Figure 6

Figure 6

PD-L1 expression by immunohistochemistry in representative high grade ovarian serous carcinomas from the TMA. A: Focal PD-L1 expression (between 1–50%) in tumor cells. C, D, E: No PD-L1 expression is identified in tumor cells. (All images at 200x original magnification).

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