ASCO 2017: Clinical Implications of Genomic Sequencing in Prostate Cancer

Chicago, IL ( Dr. Heather Cheng gave a short introduction before giving an excellent summary of abstracts 5009, 5010 and 5011. Nowadays there are many life prolonging treatments for metastatic castrate resistant prostate cancer (mCRPC), and more in development. Genomic sequencing is advancing in tremendous steps but is still not a standard in prostate cancer. It is however known, that mCRPC has >20% defects in DNA repair genes (BRCA1-2, ATM and more) and >10% of DNA repair defects are germline (heritable). Lastly, treatment with androgen receptor (AR) targeted agents can select for more aggressive variants. 

Dr. Cheng continued with the summary of abstract 5009 – Need for re-evaluation of current guidelines based on results from germline genetic testing in prostate cancer (PC), presented by Dr. Piper Nicholsi. A study published in the New England Journal of Medicine in 2016 of 692 men with metastatic prostate cancer demonstrated that 11.8% had germline DNA mutations.1 The mutations were associated with autosomal dominant cancer predisposition in men unselected for family history of age of onset of disease. Unfortunately, existing guidelines for genetic testing rely on family history of cancer. Abstract 5009 analyzed 1158 patients with PC and all had germline genetic testing for 80 genes associated with cancer (with 14 being specific for PC). The authors also analyzed whether the current genetic guidelines would have prompted a genetic testing for all relevant patients. Key findings of this study included 17% having one of these genetic mutations, out of which 34% were in BRCA1 or BRCA2 and 43% in one of the other 12 prostate specific genes. Unfortunately, 40% of high risk men did not meet current guidelines criteria for genetic testing. Therefore, new guidelines are urgently needed for genetic testing.

Dr. Cheng moved on to abstract 5010 – Next generation sequencing (NGS) of tissue and cell free DNA to identify somatic and germline alterations in advanced prostate cancer, presented by Dr. Michael Cheng. It is known that over 20% of mCRPC men have homologous recombination DNA repair defects – enabling them to potentially benefit from PARP inhibitors and platinum chemotherapy. Furthermore, 5-10% of mCRPC have evidence of microsatellite instability/hyperstimulation, potentially making them candidates for immune checkpoint inhibitors. In the study presented in abstract 5010, 1038 tumor/normal DNA pairs were prospectively analyzed from 896 PC patients using the MSK-IMPACT NGS assay. The authors found that 29% had DNA damage response (DDR) mutations detected when somatic and germline analysis was done, compared to 11% with somatic only analysis. Therefore, combination of somatic and germline sequencing identified more patients with potentially actionable DDR alterations.

The final abstract Dr. Cheng summarized was abstract 5011 – Whole exome sequencing (WES) of circulating tumor DNA in patients with neuroendocrine prostate cancer (NPEC) informs tumor heterogeneity, presented by Dr. Himisha Beltran. NPEC is a distinctly aggressive clinical entity, diagnosed with specific clinical features and treated with different chemotherapy regimens. In this study the authors enrolled 64 CRPC patients to characterize heterogeneity (CRPC-adenocarcinoma patients vs. CRPC-NPEC patients). Additionally, they did WES of circulating tumor DNA (ctDNA). Key findings included 80% concordance between mutations in plasma DNA versus metastasis, ctDNA identifying relevant alterations not found in a single site biopsy, and greater similarity in ctDNA and tumor in CRPC-NPEC than in CRPC-adenocarcinoma. In summary, if the results of this study are validated in the future, ctDNA may aid in early diagnosis, tumor taxonomy, and directing patients to research and treatment opportunities. 

Dr. Cheng concluded her presentation by stating that genomic biomarkers to guide treatment will soon be standard for prostate cancer. In order to continue on the right path, there is need for reproducibility, measures of sensitivity and specificity, a requirement to pair genomic data with clinical outcomes, caution and discipline in interpretation of various associations, and lastly, we need to exercise care in setting appropriate expectations for patients.

Presented By: Heather H. Cheng, MD, PhD, University of Washington, Seattle, WA

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
Twitter: @GoldbergHanan

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA

1. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. The New England journal of medicine 2016; 375(5): 443-53.