Response to olaparib in a PALB2 germline mutated prostate cancer and genetic events associated with resistance
Standard
Response to olaparib in a PALB2 germline mutated prostate cancer and genetic events associated with resistance. / Horak, Peter; Weischenfeldt, Joachim; von Amsberg, Gunhild; Beyer, Burkhard; Schütte, Andreas; Uhrig, Sebastian; Gieldon, Laura; Klink, Barbara; Feuerbach, Lars; Hübschmann, Daniel; Kreutzfeldt, Simon; Heining, Christoph; Maier, Sebastian; Hutter, Barbara; Penzel, Roland; Schlesner, Matthias; Eils, Roland; Sauter, Guido; Stenzinger, Albrecht; Brors, Benedikt; Schröck, Evelin; Glimm, Hanno; Fröhling, Stefan; Schlomm, Thorsten.
in: CSH MOL CASE STUD, Jahrgang 5, Nr. 2, 04.2019.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Response to olaparib in a PALB2 germline mutated prostate cancer and genetic events associated with resistance
AU - Horak, Peter
AU - Weischenfeldt, Joachim
AU - von Amsberg, Gunhild
AU - Beyer, Burkhard
AU - Schütte, Andreas
AU - Uhrig, Sebastian
AU - Gieldon, Laura
AU - Klink, Barbara
AU - Feuerbach, Lars
AU - Hübschmann, Daniel
AU - Kreutzfeldt, Simon
AU - Heining, Christoph
AU - Maier, Sebastian
AU - Hutter, Barbara
AU - Penzel, Roland
AU - Schlesner, Matthias
AU - Eils, Roland
AU - Sauter, Guido
AU - Stenzinger, Albrecht
AU - Brors, Benedikt
AU - Schröck, Evelin
AU - Glimm, Hanno
AU - Fröhling, Stefan
AU - Schlomm, Thorsten
N1 - © 2019 Horak et al.; Published by Cold Spring Harbor Laboratory Press.
PY - 2019/4
Y1 - 2019/4
N2 - 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.
AB - 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.
U2 - 10.1101/mcs.a003657
DO - 10.1101/mcs.a003657
M3 - SCORING: Journal article
C2 - 30833416
VL - 5
JO - CSH MOL CASE STUD
JF - CSH MOL CASE STUD
SN - 2373-2873
IS - 2
ER -