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Poster display session

3095 - Comprehensive characterization of BRCA1 and BRCA2 alterations in circulating tumor DNA and tumor tissue in men with prostate cancer: implications for clinical care

Date

10 Sep 2017

Session

Poster display session

Topics

Translational Research;  Prostate Cancer

Presenters

Primo Lara

Citation

Annals of Oncology (2017) 28 (suppl_5): v269-v294. 10.1093/annonc/mdx370

Authors

P. Lara1, J. McPherson2, W. Heyer3, R. Hartmaier4, R. Devere White5, J. Chung6, S.M. Ali7, M. Dall'Era5

Author affiliations

  • 1 Internal Medicine/hematology-oncology, University of California Davis Comprehensive Cancer Center, 95817 - Sacramento/US
  • 2 Biochemistry/molecular Medicine, University of California Davis Comprehensive Cancer Center, 95817 - Sacramento/US
  • 3 College Of Biological Sciences, University of California Davis Comprehensive Cancer Center, 95817 - Sacramento/US
  • 4 Foundation One, Foundation Medicine, 02141 - Cambridge/US
  • 5 Urology, University of California Davis Comprehensive Cancer Center, 95817 - Sacramento/US
  • 6 Pathology, Foundation Medicine, 02141 - Cambridge/US
  • 7 R & D, Foundation Medicine, 02141 - Cambridge/US
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Resources

Abstract 3095

Background

Alterations in genes encoding for DNA damage repair (DDR) such as BRCA1 or 2 – as detected by next generation sequencing (NGS) – can predict for sensitivity to PARP inhibitors or platinum-based chemotherapy in advanced prostate cancer (PC). Detection of these alterations either in tumor tissue or in circulating tumor DNA (ctDNA) in men with advanced PC is clinically actionable in certain clinical contexts. Previously, we reported the comprehensive molecular characterization of DNA DDR genes in 936 unique primary & metastatic PC specimens (Dall’era, ASCO GU 2017) where 24.4% had at least 1 mutation in a DNA repair gene. We also reported that DNA DDR alterations were more common in metastatic vs. localized disease. We sought to expand this work by employing NGS in ctDNA as part of clinical care to ascertain the mutational status of BRCA1 and 2 in men with PC.

Methods

The nature and prevalence of BRCA1 and 2 alterations in ctDNA were determined from 207 men with PC through the Foundation ACT NGS assay. Mean depth of coverage was 6963x. Similarly, BRCA1/2 alterations in 936 unique PC specimens were assessed as part of the Foundation One NGS assay. Mean depth of coverage was >500X.

Results

In ctDNA specimens from 207 patients, 15 (7.2%) arboured known or likely deleterious BRCA1 (n = 4) and/or BRCA2 (n = 12) alterations consisting of 19 short variants and 2 rearrangements. One case had 4 variants in BRCA2 while 3 cases had 3 variants, of which 1 case had both BRCA1 and 2 variants. An additional 17 ctDNA cases (8.2%) arboured BRCA1/2 alterations categorized as variants of unknown significance (VUS). In the 936 tumor specimens, 118 (12%) had known or likely deleterious BRCA1 (n = 11) or BRCA2 (n = 107) alterations consisting of 4 rearrangements, 89 short variants, and 30 copy number variants. VUS were not available for tumor specimens.

Conclusions

Potentially actionable BRCA1 and/or BRCA2 alterations are detectable in ctDNA or tumor tissue in up to 15% of men with PC in this large dataset of specimens obtained in the course of clinical care. Employing plasma-based ctDNA NGS provides a clinically convenient means for assessing the status of DNA gene repair alterations comparable to that of tumor tissue.

Clinical trial identification

Legal entity responsible for the study

University of California Davis Comprehensive Cancer Center and Foundation Medicine

Funding

None

Disclosure

R. Hartmaier, S.M. Ali: Employee of Foundation Medicine. All other authors have declared no conflicts of interest.

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