Whole-genome sequencing identifies homozygous BRCA2 deletion guiding treatment in dedifferentiated prostate cancer.

Andrew Protheroe,Zoe Traill,Karin Purshouse,Pavlos Antoniou,Sam Knight,Helene Dreau,Mark Tuthill,Benjamin P. Fairfax,Ian Roberts,Anna Schuh,David Kerr,Jenny C. Taylor,Lisa Browning,Clare Verrill,Niko Popitsch,Kevin Gatter

doi:10.1101/mcs.a001362

Abstract

Whole-genome sequencing (WGS) has transformed the understanding of the genetic drivers of cancer and is increasingly being used in cancer medicine to identify personalized therapies. Here we describe a case in which the application of WGS identified a tumoral BRCA2 deletion in a patient with aggressive dedifferentiated prostate cancer that was repeat-biopsied after disease progression. This would not have been detected by standard BRCA testing, and it led to additional treatment with a maintenance poly ADP ribose polymerase (PARP) inhibitor following platinum-based chemotherapy. This case demonstrates that repeat biopsy upon disease progression and application of WGS to tumor samples has meaningful clinical utility and the potential to transform outcomes in patients with cancer.

Highlights

The role of whole-genome sequencing (WGS) in identifying targetable mutations in cancer remains one of the greatest hopes in achieving personalized cancer therapy
A prostate biopsy confirmed adenocarcinoma with a Gleason score of 8 (4 + 4) (Fig. 2A,B). He was referred to oncology and started androgen-deprivation therapy (ADT) with bicalutamide and goserelin (Zoladex) injections
The patient continues on rucaparib with clinical benefit at the time of submission (13 mo). This case highlights the potential value of rebiopsy and utility of WGS in personalized treatment of prostate cancer

Summary

Introduction

The role of whole-genome sequencing (WGS) in identifying targetable mutations in cancer remains one of the greatest hopes in achieving personalized cancer therapy. Its role in patients with advanced treatment-resistant cancer by rebiopsying patients at the point of progression has not been fully explored. Most prostate cancers are adenocarcinomas, which are sensitive to androgen-deprivation therapy. Rebiopsy and WGS in personalized cancer care are few in number and normally lie quiescent, can flourish because of a cascade of molecular events, resulting in neuroendocrine dedifferentiation and androgen therapy–resistant prostate cancer (Li et al 2013, 2016). The increased prevalence of prostate cancer in patients with germline BRCA1 and BRCA2 mutations has prompted consideration of prostate cancer screening in such patients by the IMPACT screening study (Bancroft et al 2014)

Methods

Results

Conclusion