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

被引：31

作者：

Horak, Peter ^{[1
,2
,3
,4
]}

Weischenfeldt, Joachim ^{[5
,6
,7
,30
]}

von Amsberg, Gunhild ^{[8
]}

Beyer, Burkhard ^{[9
]}

Schuette, Andreas ^{[10
]}

Uhrig, Sebastian ^{[4
,11
,12
,13
]}

Gieldon, Laura ^{[2
,14
,15
,16
]}

Klink, Barbara ^{[2
,14
,15
,16
]}

Feuerbach, Lars ^{[4
,11
,12
]}

Huebschmann, Daniel ^{[17
,18
,19
,20
]}

Kreutzfeldt, Simon ^{[1
,2
,4
]}

Heining, Christoph ^{[2
,15
,16
,21
,22
]}

Maier, Sebastian ^{[23
]}

Hutter, Barbara ^{[4
,11
,12
]}

Penzel, Roland ^{[4
,24
]}

Schlesner, Matthias ^{[25
]}

Eils, Roland ^{[26
,27
,28
]}

Sauter, Guido ^{[29
]}

Stenzinger, Albrecht ^{[4
,24
]}

Brors, Benedikt ^{[4
,11
,12
]}

Schroeck, Evelin ^{[2
,14
,15
,16
]}

Glimm, Hanno ^{[2
,15
,16
,21
,22
]}

Froehling, Stefan ^{[1
,2
,3
,4
]}

Schlomm, Thorsten ^{[30
]}

机构：

[1] Natl Ctr Tumor Dis NCT Heidelberg, Dept Translat Med Oncol, D-69120 Heidelberg, Germany

[2] German Canc Res Ctr, D-69120 Heidelberg, Germany

[3] DKFZ Heidelberg Ctr Personalized Oncol HIPO, D-69120 Heidelberg, Germany

[4] German Canc Consortium DKTK, D-69120 Heidelberg, Germany

[5] Univ Copenhagen, Biotech Res & Innovat Ctr, DK-2200 Copenhagen, Denmark

[6] Univ Copenhagen, Finsen Lab, DK-2200 Copenhagen, Denmark

[7] Rigshosp, DK-2200 Copenhagen, Denmark

[8] Univ Canc Ctr Hamburg, Hubertus Wald Tumorzentrum, D-20251 Hamburg, Germany

[9] Univ Med Ctr Hamburg Eppendorf, Prostate Canc Ctr, Martini Clin, D-20246 Hamburg, Germany

[10] St Antonius Hosp, Dept Urol, D-48599 Gronau, Germany

[11] DKFZ, Div Appl Bioinformat, D-69120 Heidelberg, Germany

[12] NCT Heidelberg, D-69120 Heidelberg, Germany

[13] Heidelberg Univ, Fac Biosci, D-69120 Heidelberg, Germany

[14] Tech Univ Dresden, Fac Med Carl Gustav Carus, Inst Clin Genet, D-01307 Dresden, Germany

[15] NCT Dresden, D-01307 Dresden, Germany

[16] German Canc Consortium DKTK Dresden, D-69120 Heidelberg, Germany

[17] DKFZ, Div Theoret Bioinformat, D-69120 Heidelberg, Germany

[18] Heidelberg Univ Hosp, Dept Pediat Immunol Hematol & Oncol, D-69120 Heidelberg, Germany

[19] DKFZ, Div Stem Cells & Canc, Heidelberg, Germany

[20] Heidelberg Inst Stem Cell Technol & Expt Med HI S, D-69120 Heidelberg, Germany

[21] NCT Dresden, Dept Translat Med Oncol, D-01307 Dresden, Germany

[22] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, D-01307 Dresden, Germany

[23] Progether Prostate Canc Network, N-0349 Oslo, Norway

[24] Heidelberg Univ Hosp, Inst Pathol, D-69120 Heidelberg, Germany

[25] DKFZ, Bioinformat & Omics Data Analyt, D-69120 Heidelberg, Germany

[26] Heidelberg Univ, Med Fac, Hlth Data Sci Unit, Bioquant, D-69120 Heidelberg, Germany

[27] Berlin Inst Hlth, Ctr Digital Hlth, D-10178 Berlin, Germany

[28] Charite Univ Med Berlin, D-10178 Berlin, Germany

[29] Univ Med Ctr Hamburg Eppendorf, Inst Pathol, D-20251 Hamburg, Germany

[30] Charite Univ Med Berlin, Dept Urol, D-10117 Berlin, Germany

来源：

COLD SPRING HARBOR MOLECULAR CASE STUDIES | 2019年 / 5卷 / 02期

关键词：

FANCONI-ANEMIA; AMPLIFICATION; MUTATIONS; PARTNER;

D O I：

10.1101/mcs.a003657

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 multi-dimensional 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.

引用

页数：9

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