The Impact of Whole Genome Data on Therapeutic Decision-Making in Metastatic Prostate Cancer: A Retrospective Analysis

Megan Crumbaker; Eva K F Chan; Tingting Gong; Niall Corcoran; Weerachai Jaratlerdsiri; Ruth J Lyons; Anne-Maree Haynes; Anna A Kulidjian; Anton M F Kalsbeek; Desiree C Petersen; Phillip D Stricker; Christina A M Jamieson; Peter I Croucher; Christopher M Hovens; Anthony M Joshua; Vanessa M Hayes

doi:10.3390/cancers12051178

The Impact of Whole Genome Data on Therapeutic Decision-Making in Metastatic Prostate Cancer: A Retrospective Analysis

Cancers (Basel). 2020 May 7;12(5):1178. doi: 10.3390/cancers12051178.

Authors

Megan Crumbaker^{1

2

3}, Eva K F Chan^{1

2}, Tingting Gong^{1

4}, Niall Corcoran^{5

6

7}, Weerachai Jaratlerdsiri¹, Ruth J Lyons¹, Anne-Maree Haynes¹, Anna A Kulidjian^{8

9}, Anton M F Kalsbeek¹, Desiree C Petersen¹⁰, Phillip D Stricker¹¹, Christina A M Jamieson¹², Peter I Croucher^{1

13}, Christopher M Hovens^{5

6}, Anthony M Joshua^{1

2

3}, Vanessa M Hayes^{1

2

4}

Affiliations

¹ Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
² St. Vincent's Clinical School, University of New South Wales, Sydney, Randwick NSW 2031, Australia.
³ Kinghorn Cancer Centre, Department of Medical Oncology, St. Vincent's Hospital, Darlinghurst NSW 2010, Australia.
⁴ Central Clinical School, University of Sydney, Sydney, Camperdown NSW 2050, Australia.
⁵ Australian Prostate Cancer Research Centre Epworth, Richmond VIC 3121, Australia.
⁶ Department of Surgery, University of Melbourne, Melbourne VIC 3010, Australia.
⁷ Division of Urology, Royal Melbourne Hospital, Melbourne VIC 3050, Australia.
⁸ Department of Orthopedic Surgery, Scripps Clinic, La Jolla, CA 92037, USA..
⁹ Orthopedic Oncology Program, Scripps MD Anderson Cancer Center, La Jolla CA 92037, USA.
¹⁰ The Centre for Proteomic and Genomic Research, Cape Town 7925, South Africa.
¹¹ Department of Urology, St. Vincent's Hospital, Darlinghurst NSW 2010, Australia.
¹² Department of Urology, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92037, USA.
¹³ School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Randwick, NSW 2031, Australia.

Abstract

Background: While critical insights have been gained from evaluating the genomic landscape of metastatic prostate cancer, utilizing this information to inform personalized treatment is in its infancy. We performed a retrospective pilot study to assess the current impact of precision medicine for locally advanced and metastatic prostate adenocarcinoma and evaluate how genomic data could be harnessed to individualize treatment.

Methods: Deep whole genome-sequencing was performed on 16 tumour-blood pairs from 13 prostate cancer patients; whole genome optical mapping was performed in a subset of 9 patients to further identify large structural variants. Tumour samples were derived from prostate, lymph nodes, bone and brain.

Results: Most samples had acquired genomic alterations in multiple therapeutically relevant pathways, including DNA damage response (11/13 cases), PI3K (7/13), MAPK (10/13) and Wnt (9/13). Five patients had somatic copy number losses in genes that may indicate sensitivity to immunotherapy (LRP1B, CDK12, MLH1) and one patient had germline and somatic BRCA2 alterations.

Conclusions: Most cases, whether primary or metastatic, harboured therapeutically relevant alterations, including those associated with PARP inhibitor sensitivity, immunotherapy sensitivity and resistance to androgen pathway targeting agents. The observed intra-patient heterogeneity and presence of genomic alterations in multiple growth pathways in individual cases suggests that a precision medicine model in prostate cancer needs to simultaneously incorporate multiple pathway-targeting agents. Our whole genome approach allowed for structural variant assessment in addition to the ability to rapidly reassess an individual's molecular landscape as knowledge of relevant biomarkers evolve. This retrospective oncological assessment highlights the genomic complexity of prostate cancer and the potential impact of assessing genomic data for an individual at any stage of the disease.

Keywords: optical mapping; precision medicine; prostate cancer; therapy; whole genome sequencing.