Homologous recombination deficiency signature (HRDsig+) and the genomic landscape of clinically advanced prostate carcinoma (CAPC).
Authors: Mercinelli Chiara , Spiess Philippe E. , Li Roger , Kamat Ashish M. , Grivas Petros , Gupta Shilpa , Agarwal Neeraj , Cheng Liang , Pavlick Dean , Sokol Ethan , Graf Ryon P , Ross Jeffrey S. , Schrock Alexa Betzig , Quintanilha Julia , Li Gerald , Lin Douglas I , Jacob Joseph M , Bratslavsky Gennady , Basnet Alina , Necchi Andrea 
Published: February 2025

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Background:
CAPC is very challenging with significant need for improvement in systemic therapy, including for patients (pts) with incurable disease. Recently a novel HRDsig biomarker has been linked to clinical outcomes after PARP inhibitor-based treatments. We aimed to explore HRD sig status and related biomarkers, including other GA, to generate hypothesis and inform clinical trial designs for pts with CAPC.
Methods:
22,061 cases of CAPC 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 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 (TPS) system. Results were compared using the Fisher exact system with the Benjamini-Hochberg adjustment to correct for false discovery.
Results:
Overall, 2,244 (10.2%) of CAPC cases were HRDsig+. There were slightly more MSI-high cases in the HRDsig- vs HRDsig+ CAPC (3.1% vs 0.5%; P<.0001). Both TMB and PD-L1 levels were low and varied in both groups. HRD associated GA included
BRCA2
and
RAD21
were more frequent in the CAPC HRDsig+ cases.
BRCA1
GA were extremely rare in both groups. In the HRDsig- group, 90%/49% of
BRCA1
/
BRCA2
mutated CAPC were mono-allelic, likely non-driver GA, respectively Higher frequencies of GA in
CDK12
and
SPOP
(11.1% vs 5.9%; P<.0001) were found in HRDsig- cases and a higher frequency of
AR
GA in HRDsig+ cases. MTOR pathway related GA in
PTEN
were similar, although homozygous deletions of
PTEN
were more frequent in the HRDsig- cases (22.2% vs 19.2%; P=.0009; Table).
Conclusions:
With a 10.2% frequency, HRDsig+ status is a relatively common biomarker in CAPC. HRDsig+ status was associated with a higher frequency of
BRCA2
GA, including homozygous deletions in >20% of these pts, which has been associated with prolonged benefit from PARPi in selected pts. Given that likely non-driver mono-allelic BRCA1/2 GA are frequently identified in HRDsig- CAPC, mono-allelic GA may not be associated with HRDsig status and might not yield similar clinical benefit from PARPi. Limitations include the retrospective nature, potential selection bias and lack of clinical outcomes annotation.

Main differences in GA classes between HRDSig- and HRDSig+.

HRDSig-
HRDSig+
P value

Age (yrs)
68
70
<.0001

AFR ancestry
15.4%
13.1%
0.0110

AR

10.8%
17.3%
<.0001

BRCA2
mutation

3.3%
52.3%
<.0001

BRCA2
homozygous deletion

0.6%
21.4%
<.0001

CDK12

5.5%
1.2%
<.0001

RAD21

7.2%
16.3%
<.0001

MMR sig
4.0%
2.0%
<.0001

TMB≥10 mut/Mb
4.4%
3.7%
NS