Accumulation of copy number alterations and clinical progression across advanced prostate cancer
Authors: Grist Emily , Friedrich Stefanie , Brawley Christopher , Mendes Larissa , Parry Marina , Ali Adnan , Haran Aine , Hoyle Alex , Gilson Claire , Lall Sharanpreet , Zakka Leila , Bautista Carla , Landless Alex , Nowakowska Karolina , Wingate Anna , Wetterskog Daniel , Hasan A. M. Mahedi , Akato Nafisah B. , Richmond Malissa , Ishaq Sofeya , Matthews Nik , Hamid Anis A. , Sweeney Christopher J. , Sydes Matthew R. , Berney Daniel M. , Lise Stefano ,   STAMPEDE investigators, Parmar Mahesh K. B. , Clarke Noel W. , James Nicholas D. , Cremaschi Paolo , Brown Louise C. , Attard Gerhardt 
Published: September 2022

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.