Clinically advanced prostate cancer (CAPC) in extremely young men: A genomic landscape study.
Authors: Sager Rebecca A , Necchi Andrea , Li Roger , Spiess Philippe E. , Kamat Ashish M. , Grivas Petros , Gupta Shilpa , Agarwal Neeraj , Cheng Liang , Pavlick Dean , Sokol Ethan , Lin Douglas I , Gjoerup Ole , Ross Jeffrey S. , Jacob Joseph M , Basnet Alina , Bratslavsky Gennady 
Published: February 2025

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Background:
CAPC arising in young patients is a challenging disease with significant need for improvements in systemic therapies, especially for patients with surgically incurable disease. Here we sought to explore the genomic landscape to generate hypotheses and inform clinic trial design.
Methods:
13 cases of CAPC in men under the age of 39 years (CAPC <39) and 23,364 cases of CAPC in men 50 or older (CAPC >50) underwent comprehensive genomic profiling (CGP) to examine all classes of genomic alterations (GA). MSI high status, tumor mutation burden (TMB) levels, genomic ancestry and trinucleotide mutational signatures were determined from the sequencing data. HRDsig status was calculated using a broad set of genome-wide copy number features. PD-L1 was determined by IHC using the Dako 22C3 tumor proportional score system. Results were compared using the Fisher exact system with the Benjamini-Hochberg adjustment to correct for false discovery.
Results:
The GA rates were similar in the very young and more senior patient cohorts (3 GA/tumor for both groups). Genomic ancestry distribution revealed more African ancestry cases in the CAPC <39 group (30.8% vs 15.1%; NS) and more European ancestry in the CAPC >50 group (75.1% vs 53.9%; NS). MSI high status was trending more common in the CAPC <39 group (7.7% vs 3.0%; NS) as was a positive HRD signature (15.4% vs 10.2%; NS). The median TMB levels were low and similar in both groups (range 1.3 to 2.4 mut/Mb) as was the frequency of TMB > 10 mut/Mb (range 4.3% to 7.7%). Defined trinucleotide signatures were rare and similar in both groups. PD-L1 expression was available for a subset of the of the cases and showed no distinct differences. GA in genes associated with HRD were trending more frequent in the younger cohort including
BRCA1
(7.7% vs 1.1%; NS),
BRCA2
(15.4% vs 8.0%; NS),
ATM
(7.7% vs 5.7%; NS) and
PALB2
(7.7% vs 0.7%; NS). Other GA more frequent in the CAPC <39 group included
BRAF
(15.4% vs 4.0%; NS),
CDK12
(7.7% vs 4.9%; NS),
CDKN2A
(15.4% vs 2.5%; NS),
CDKN2B
(7.7% vs 1.5%; NS),
MTAP
(7.7% vs 1.4%; NS),
PTEN
(46.2% vs 31.2%; NS),
RB1
(7.7% vs 4.8%; NS),
TP53
(53.8% vs 37.9%; NS) and
TMPRSS2
-
ERG
fusions (38.5% vs 31.7%; NS). GA in
AR
(11.3% vs 7.7%; NS),
SPOP
(10.9% vs 0%; NS) and
PIK3CA
(6.4% vs 0%; NS) were more frequent in the CAPC >50 group.
Conclusions:
In contrast with CAPC arising in men >50, CAPC arising in extremely young men under 39 featured relatively different frequencies of biomarker and GA distribution, without reaching statistical significance. Our results are hypothesis-generating; limitations include the small sample size of patients < 39, retrospective nature, potential selection bias, and lack of clinical outcomes annotation.

<39 years
>50 years
P value

AFR Ancestry
30.8%
15.1%
NS

EUR Ancestry
53.9%
75.1%
NS

BRAF

15.4%
4.0%
NS

BRCA2

15.4%
8.0%
NS

CDK12

7.7%
4.9%
NS

PTEN

46.2%
31.2%
NS

SPOP

0.0%
10.9%
NS

MSI High
7.7%
3.0%
NS

TMB > 10 mut/Mb
7.7%
4.3%
NS