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Cold Spring Harb Mol Case Stud. 2019 Apr 1;5(2). pii: a003657. doi: 10.1101/mcs.a003657. Print 2019 Apr.

Response to olaparib in a PALB2 germline mutated prostate cancer and genetic events associated with resistance.

Horak P1,2,3, Weischenfeldt J4,5, von Amsberg G6, Beyer B7, Schütte A8, Uhrig S3,9,10, Gieldon L11,12,13, Klink B11,12,13, Feuerbach L3,9, Hübschmann D14,15,16, Kreutzfeldt S1,3, Heining C12,13,17,18, Maier S19, Hutter B3,9, Penzel R3,20, Schlesner M21, Eils R22,23, Sauter G24, Stenzinger A3,20, Brors B3,9, Schröck E11,12,13, Glimm H12,13,17,18, Fröhling S1,2,3, Schlomm T5.

Author information

1
Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
2
DKFZ-Heidelberg Center for Personalized Oncology (HIPO), 69120 Heidelberg, Germany.
3
German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
4
Biotech Research & Innovation Centre (BRIC) and Finsen Laboratory, University of Copenhagen and Rigshospitalet, 2200 Copenhagen, Denmark.
5
Department of Urology, Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany.
6
Hubertus Wald Tumorzentrum, University Cancer Center Hamburg (UCCH), 20251 Hamburg, Germany.
7
Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
8
Department of Urology, St. Antonius-Hospital, 48599 Gronau, Germany.
9
Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, 69120 Heidelberg, Germany.
10
Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany.
11
Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
12
NCT Dresden, 01307 Dresden, Germany.
13
German Cancer Consortium (DKTK) Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
14
Division of Theoretical Bioinformatics, DKFZ, 69120 Heidelberg, Germany.
15
Department of Pediatric Immunology, Hematology and Oncology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
16
Division of Stem Cells and Cancer, DKFZ, Heidelberg, Germany and Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany.
17
Department of Translational Medical Oncology, NCT Dresden, 01307 Dresden, Germany.
18
University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
19
Progether Prostate Cancer Network, 0349 Oslo, Norway.
20
Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
21
Bioinformatics and Omics Data Analytics, DKFZ, 69120 Heidelberg, Germany.
22
Health Data Science Unit, Bioquant, Medical Faculty, University of Heidelberg, 69120 Heidelberg, Germany.
23
Center for Digital Health, Berlin Institute of Health and Charité Universitätsmedizin Berlin, 10178 Berlin, Germany.
24
Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

Abstract

Prostate cancers harboring DNA repair gene alterations are particularly sensitive to PARP inhibitor treatment. We report a case of an advanced prostate cancer patient profiled within the NCT-MASTER (Molecularly Aided Stratification for Tumor Eradication Research) precision oncology program using next-generation sequencing. Comprehensive genomic and transcriptomic analysis identified a pathogenic germline PALB2 variant as well as a mutational signature associated with disturbed homologous recombination together with structural genomic rearrangements. A molecular tumor board identified a potential benefit of targeted therapy and recommended PARP inhibition and platinum-based chemotherapy. Single-agent treatment with the PARP inhibitor olaparib as well as subsequent combination with platinum-based chemotherapy resulted in disease stabilization and substantial improvement of clinical symptoms. Upon progression, we performed whole-exome and RNA sequencing of a liver metastasis, which demonstrated up-regulation of several genes characteristic for the neuroendocrine prostate cancer phenotype as well as a novel translocation resulting in an in-frame, loss-of-function fusion of RB1. We suggest that multidimensional genomic characterization of prostate cancer patients undergoing PARP inhibitor therapy will be necessary to capture and understand predictive biomarkers of PARP inhibitor sensitivity and resistance.

KEYWORDS:

prostate cancer

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