Prostate cancer liver metastases: Genomic profiling and clinical outcomes.
Authors: Roberts Hayley Nicole , Liao Yi Jou Ruby , Herberts Cameron , Tolmeijer Sofie H. , Wang Catherine , Riminchan Anna , Sartori-Muller Elsa , Kwan Edmond Michael , Annala Matti , Fonseca Nicolette M. , Vergidis Joanna , Noonan Krista , Finch Daygen L. , Zulfiqar Muhammad , Stacy Miller , Vandekerkhove Gillian , Wyatt Alexander William , Maurice-Dror Corinne , Chi Kim N. 
Published: February 2025

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Background:
Patients (pts) with metastatic prostate cancer and liver metastases have poor prognosis, but clinicogenomic analyses are limited. We examined the clinical and genomic features of a cohort with prostate cancer liver metastases (PCLM).
Methods:
Pts were identified from a prospective population-based biobank in British Columbia, Canada. Eligible pts had PCLM identified on imaging prior to any line of treatment. We collated clinical outcomes with cell-free DNA (cfDNA) sequencing results including circulating tumor DNA fraction (ctDNA%) and genomic alterations.
Results:
2048 metastatic prostate cancer pts were enrolled from October 2016 to July 2024, of whom 1258 had sufficient clinical annotation to evaluate PCLM status. Of these, 167 (13%) were diagnosed with PCLM: 36 (22%) with castration-sensitive prostate cancer (mCSPC), 48 (29%) prior to first-line castration-resistant prostate cancer treatment (1L mCRPC), 30 (18%) prior to 2L mCRPC, and 53 (32%) prior to ≥3L mCRPC. Median follow-up was 60.3 months. Median age at metastatic diagnosis was 68.7 (IQR 61.8-74.7) years, 93 (56%) had
de novo
metastatic disease, 20 (12%) had histologically proven small cell carcinoma, 27 (16%) had low PSA (<5ng/mL) at baseline, and 111 (66%) had ≥3 liver metastases. For mCSPC pts, 27 (75%) received treatment intensification beyond ADT alone, including 5 (14%) with platinum chemotherapy. Median overall survival (mOS) for mCSPC pts was 15.5 months (95% CI 11.7-28.1), and median time to castration resistance was 8.1 months (95% CI 5.7-10.7). For mCRPC pts, 94 (72%) had prior exposure to ARPI, 56 (43%) to taxane, and 8 (6%) to platinum. mOS for 1L mCRPC pts was 9.4 months (95% CI 6.7-12.6), for 2L mCRPC 4.9 months (95% CI 3.5-9.7) and for ≥3L mCRPC 5.6 months (95% CI 4.1-8.4). For 134 pts with cfDNA results the median ctDNA% was 24.7 (IQR 4.6-53.9). Alterations were found in
TP53
(47%),
PTEN
(26%),
RB1
(19%), with 82 pts (61%) having alterations in at least one tumor suppressor gene (TSG) and 34 (25%) in more than one TSG. 14 pts (10%) had a
BRCA2
alteration. ctDNA% and detectable TSG alterations were associated with survival of pts with PCLM (Table). Of 17 long survivors (pts who lived >24 months from start of next line treatment), 12 had cfDNA results available, median ctDNA% was 13.6%, and only 1 had TSG loss detected (
PTEN
).
Conclusions:
Pts with PCLM exhibit poor clinical outcomes; both elevated ctDNA% and TSG loss correlate with reduced overall survival.

mCSPCmOS (months)N = 24 pts with cfDNA
1L mCRPCmOS (months) N = 35 pts with cfDNA
2L mCRPCmOS (months)N = 25 pts with cfDNA

TSG status
No alteration detected
57
23.6
8

Alteration detected
11.7
6.8
4.3

Univariable HR (95% CI)
9.3 (2.0-42.7)p<0.01
5.6 (2.1-15.5)p<0.01
1.4 (0.6-3.2)p=0.4

ctDNA%
≤ median ctDNA% (24.7%)
57
18.1
9

> median ctDNA% (24.7%)
14.7
5.8
12

Univariable HR (95% CI)
2.4 (1.0-5.4)p<0.05
2.7 (1.5-5.0)p<0.01
1.1 (0.6-2.0)p=0.8