Accumulation of copy number alterations and clinical progression across advanced prostate cancer
Emily Grist, Stefanie Friedrich, Christopher Brawley, Larissa Mendes, Marina Parry, Adnan Ali, Aine Haran, Alex Hoyle, Claire Gilson, Sharanpreet Lall, Leila Zakka, Carla Bautista, Alex Landless, Karolina Nowakowska, Anna Wingate, Daniel Wetterskog, A M Mahedi Hasan, Nafisah B Akato, Malissa Richmond, Sofeya Ishaq, Nik Matthews, Anis A Hamid, Christopher J Sweeney, Matthew R Sydes, Daniel M Berney, Stefano Lise, STAMPEDE investigators, Mahesh K B Parmar, Noel W Clarke, Nicholas D James, Paolo Cremaschi, Louise C Brown, Gerhardt Attard, Emily Grist, Stefanie Friedrich, Christopher Brawley, Larissa Mendes, Marina Parry, Adnan Ali, Aine Haran, Alex Hoyle, Claire Gilson, Sharanpreet Lall, Leila Zakka, Carla Bautista, Alex Landless, Karolina Nowakowska, Anna Wingate, Daniel Wetterskog, A M Mahedi Hasan, Nafisah B Akato, Malissa Richmond, Sofeya Ishaq, Nik Matthews, Anis A Hamid, Christopher J Sweeney, Matthew R Sydes, Daniel M Berney, Stefano Lise, STAMPEDE investigators, Mahesh K B Parmar, Noel W Clarke, Nicholas D James, Paolo Cremaschi, Louise C Brown, Gerhardt Attard
Abstract
Background: Genomic copy number alterations commonly occur in prostate cancer and are one measure of genomic instability. The clinical implication of copy number change in advanced prostate cancer, which defines a wide spectrum of disease from high-risk localised to metastatic, is unknown.
Methods: We performed copy number profiling on 688 tumour regions from 300 patients, who presented with advanced prostate cancer prior to the start of long-term androgen deprivation therapy (ADT), in the control arm of the prospective randomised STAMPEDE trial. Patients were categorised into metastatic states as follows; high-risk non-metastatic with or without local lymph node involvement, or metastatic low/high volume. We followed up patients for a median of 7 years. Univariable and multivariable Cox survival models were fitted to estimate the association between the burden of copy number alteration as a continuous variable and the hazard of death or disease progression.
Results: The burden of copy number alterations positively associated with radiologically evident distant metastases at diagnosis (P=0.00006) and showed a non-linear relationship with clinical outcome on univariable and multivariable analysis, characterised by a sharp increase in the relative risk of progression (P=0.003) and death (P=0.045) for each unit increase, stabilising into more modest increases with higher copy number burdens. This association between copy number burden and outcome was similar in each metastatic state. Copy number loss occurred significantly more frequently than gain at the lowest copy number burden quartile (q=4.1 × 10-6). Loss of segments in chromosome 5q21-22 and gains at 8q21-24, respectively including CHD1 and cMYC occurred more frequently in cases with higher copy number alteration (for either region: Kolmogorov-Smirnov distance, 0.5; adjusted P<0.0001). Copy number alterations showed variability across tumour regions in the same prostate. This variance associated with increased risk of distant metastases (Kruskal-Wallis test P=0.037).
Conclusions: Copy number alteration in advanced prostate cancer associates with increased risk of metastases at diagnosis. Accumulation of a limited number of copy number alterations associates with most of the increased risk of disease progression and death. The increased likelihood of involvement of specific segments in high copy number alteration burden cancers may suggest an order underlying the accumulation of copy number changes.
Trial registration: ClinicalTrials.gov NCT00268476 , registered on December 22, 2005. EudraCT 2004-000193-31 , registered on October 4, 2004.
Keywords: Advanced prostate cancer; Copy number alteration; Genomic biomarkers; STAMPEDE trial.
Conflict of interest statement
MKBP and LCB report grants and non-financial support from Janssen, Astellas, Clovis Oncology, Novartis, Pfizer, and Sanofi. NWC reports personal fees from Janssen Pharmaceuticals, Astellas Pharma, and Bayer. NDJ reports grants and personal fees from Sanofi, Novartis, Janssen, Astellas, and Bayer.
GA certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (e.g., employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received or pending), are the following:
GA reports receiving commercial research grants from Janssen and Astra Zeneca; has received honoraria and/or travel support from the speakers’ bureaus of Janssen, Astellas, Pfizer, Ferring, Sanofi-Aventis and Roche/Ventana; and has served as a consultant for/advisory board member of Janssen, Bayer, Astellas, Pfizer, Novartis, Astra Zeneca, Orion, Essa. GA has an ownership interest (including patents) in The Institute of Cancer Research Rewards to Discoverers for abiraterone acetate.
MRS reports grants and non-financial support from Astellas, grants from Clovis, grants and non-financial support from Janssen, grants and non-financial support from Novartis, grants and non-financial support from Pfizer, grants and non-financial support from Sanofi, grants and non-financial support from Sanofi, all to support the underlying STAMPEDE trial. MRS also reports personal fees from Lilly Oncology, personal fees from Janssen, outside the submitted work. AAH reports a consulting/advisory role with AstraZeneca. CJS reports consulting or advisory roles with Sanofi, Janssen, Astellas Pharma, Bayer, Genentech, Pfizer, Lilly and reports research funding from Janssen Biotech, Astellas Pharma, Sanofi, Bayer, Sotio and Dendreon. CJS reports patents, royalties and other intellectual property for Patrhenolide (Indiana University); dimethylaminoparthenolide (Leuchemix); Exelixis: Abiraterone plus cabozantinib combination; FRAS1 SNP and tristetraprolin as biomarkers of lethal prostate cancer. CJS reports stock or other ownership for Leuchemix.
The remaining authors declare that they have no competing interests.
© 2022. The Author(s).
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