DNA Repair Gene Alterations and PARP Inhibitor Response in Patients With Metastatic Castration-Resistant Prostate Cancer

Authors:
Eric Lu Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

Search for other papers by Eric Lu in
Current site
Google Scholar
PubMed
Close
 MD
,
George V. Thomas Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

Search for other papers by George V. Thomas in
Current site
Google Scholar
PubMed
Close
 MD
,
Yiyi Chen Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

Search for other papers by Yiyi Chen in
Current site
Google Scholar
PubMed
Close
 PhD
,
Alexander W. Wyatt Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

Search for other papers by Alexander W. Wyatt in
Current site
Google Scholar
PubMed
Close
 PhD
,
Paul Lloyd Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

Search for other papers by Paul Lloyd in
Current site
Google Scholar
PubMed
Close
 PhD
,
Jack Youngren Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

Search for other papers by Jack Youngren in
Current site
Google Scholar
PubMed
Close
 PhD
,
David Quigley Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

Search for other papers by David Quigley in
Current site
Google Scholar
PubMed
Close
 PhD
,
Raymond Bergan Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

Search for other papers by Raymond Bergan in
Current site
Google Scholar
PubMed
Close
 MD
,
Shawna Bailey Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

Search for other papers by Shawna Bailey in
Current site
Google Scholar
PubMed
Close
 MPH
,
Tomasz M. Beer Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

Search for other papers by Tomasz M. Beer in
Current site
Google Scholar
PubMed
Close
 MD
,
Felix Y. Feng Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

Search for other papers by Felix Y. Feng in
Current site
Google Scholar
PubMed
Close
 MD
,
Eric J. Small Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

Search for other papers by Eric J. Small in
Current site
Google Scholar
PubMed
Close
 MD
, and
Joshi J. Alumkal Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.
Department of Medicine, Oregon Health & Science University, Portland, Oregon; Department of Pathology & Laboratory Medicine, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Biostatistics Shared Resources, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon; Oregon Health & Science University – Portland State University School of Public Health, Portland, Oregon; Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada; and Helen Diller Family Comprehensive Cancer Center, Division of Hematology & Oncology, Department of Epidemiology and Biostatistics, and Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, California.

Search for other papers by Joshi J. Alumkal in
Current site
Google Scholar
PubMed
Close
 MD
Restricted access

Background: PARP inhibition is a promising therapeutic strategy for the treatment of men with metastatic castration-resistant prostate cancer whose tumors harbor homologous recombination DNA repair gene alterations. However, questions remain for many practicing clinicians about which patients are ideally suited for PARP inhibitor treatment. This report details our institutional experience using PARP inhibitor therapy in patients whose tumors harbored specific DNA repair gene alterations. Patients and Methods: We performed a retrospective chart review to identify patients at Oregon Health & Science University who were treated with PARP inhibition. We identified 8 patients and determined the impact of the specific DNA repair gene alterations on tumor response and time on treatment with PARP inhibition. Results: A number of DNA repair gene alterations were identified. Three patients had pathogenic BRCA2 mutations and one had a BRCA2 mutation of uncertain significance. Conversely, the 4 other patients' tumors harbored alterations in other DNA repair genes, none of which were clearly pathogenic. A statistically significant difference in benefit was seen between patients whose tumors harbored BRCA2 gene alterations and those whose tumors did not, as measured by >50% decline in prostate-specific antigen levels (100% vs 0%; P=.03) and duration on therapy (31.4 vs 6.4 weeks; P=.03). Conclusions: Our results demonstrate that not all DNA repair alterations are equally predictive of PARP inhibitor response. Importantly, all responding patients had tumors harboring BRCA2 DNA repair alterations, including one without a known pathogenic mutation. Conversely, among the 4 nonresponders, several DNA repair alterations in genes other than BRCA2 were identified that were not clearly pathogenic. This demonstrates the need to carefully examine the functional relevance of the DNA repair alterations identified, especially in genes other than BRCA2, when considering patients for PARP inhibitor treatment.

Correspondence: Joshi J. Alumkal, MD, Department of Medicine, Oregon Health & Science University, 3303 SW Bond Avenue, CH14R, Portland, OR 97239. Email: alumkalj@ohsu.edu

Supplementary Materials

    • Supplemental Material (PDF 105 KB)
  • Collapse
  • Expand