TY - JOUR
T1 - Treatment strategies for DNA repair-deficient prostate cancer
AU - Teply, Benjamin A.
AU - Antonarakis, Emmanuel S.
N1 - Funding Information:
This work was partially supported by NIH grants R01 CA185297 and P30 CA006973 (ES Antonarakis).
Publisher Copyright:
© 2017 Informa UK Limited, trading as Taylor & Francis Group.
PY - 2017/8/3
Y1 - 2017/8/3
N2 - Introduction: Common recurrent genetic alterations have been identified in prostate cancer through comprehensive sequencing efforts, and the prevalence of mutations in DNA repair pathway genes in patients with advanced and metastatic disease approaches 20–25%. Identification of these underlying DNA repair defects may present unique treatment opportunities for patients, both in terms of standard-of-care treatments and selected investigational agents. Areas covered: We review our current understanding of the genomic landscape of prostate cancer, with special attention to alterations in DNA repair pathway genes in metastatic castration-resistant disease. For patients with tumors deficient in homologous recombination repair, potential opportunities for treatment include platinum chemotherapy, poly(ADP) ribose polymerase (PARP) inhibitors, bipolar androgen therapy, and maybe immune checkpoint blockade therapy. In addition, tumors with mismatch repair defects (i.e. microsatellite instability) may be particularly susceptible to checkpoint blockade immunotherapy. Expert commentary: We anticipate that genomic profiling of tumors will become necessary to guide treatment of advanced prostate cancer in the coming years. Work is needed to define the optimal tissue to test, and to define the natural history of tumors with specific genetic defects. The prognostic and therapeutic importance of germline vs somatic DNA repair alterations, and mono-allelic vs bi-allelic inactivation, also remains unclear. Finally, optimal strategies to sequence or combine targeted agents for these patients with ‘actionable’ mutations are now needed.
AB - Introduction: Common recurrent genetic alterations have been identified in prostate cancer through comprehensive sequencing efforts, and the prevalence of mutations in DNA repair pathway genes in patients with advanced and metastatic disease approaches 20–25%. Identification of these underlying DNA repair defects may present unique treatment opportunities for patients, both in terms of standard-of-care treatments and selected investigational agents. Areas covered: We review our current understanding of the genomic landscape of prostate cancer, with special attention to alterations in DNA repair pathway genes in metastatic castration-resistant disease. For patients with tumors deficient in homologous recombination repair, potential opportunities for treatment include platinum chemotherapy, poly(ADP) ribose polymerase (PARP) inhibitors, bipolar androgen therapy, and maybe immune checkpoint blockade therapy. In addition, tumors with mismatch repair defects (i.e. microsatellite instability) may be particularly susceptible to checkpoint blockade immunotherapy. Expert commentary: We anticipate that genomic profiling of tumors will become necessary to guide treatment of advanced prostate cancer in the coming years. Work is needed to define the optimal tissue to test, and to define the natural history of tumors with specific genetic defects. The prognostic and therapeutic importance of germline vs somatic DNA repair alterations, and mono-allelic vs bi-allelic inactivation, also remains unclear. Finally, optimal strategies to sequence or combine targeted agents for these patients with ‘actionable’ mutations are now needed.
KW - PARP inhibition
KW - Prostate cancer
KW - homologous recombination deficiency
KW - immunotherapy
KW - microsatellite instability
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U2 - 10.1080/17512433.2017.1338138
DO - 10.1080/17512433.2017.1338138
M3 - Review article
C2 - 28573914
AN - SCOPUS:85025094097
SN - 1751-2433
VL - 10
SP - 889
EP - 898
JO - Expert Review of Clinical Pharmacology
JF - Expert Review of Clinical Pharmacology
IS - 8
ER -