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Updated: Aug 15, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
How Often are druggable mutations detectable in Metastatic Castration Resistant Prostate Cancer?
Objectives:
To analyze the type and frequency druggable mutations in patients with progressive metastatic castration-resistant prostate cancer (mCRPC).
Patients And Methods:
From 2018 to 2023, 311 patients with mCRPC underwent molecular panel analysis of archived prostatectomy samples (n=96) or CT-guided biopsies of progressive metastases (n=215).Mutation analysis was performed using NGS with an 18 multiplex PCR amplicon (AR, ATM, AURKA/MYC, BRCA1/2, CDK12, CTNNB1, DLL3, ETS family, FOXA1, FOXO1, MED12, PIK3CA, PTEN, RAD51C, TP53, Wnt-Pathway). Since 2023, we applied the TSO500 panel in selected cases. The HRD score was calculated by combining BRCA1 and BRCA2 mutations (Genomic ScarScore GSS) using the HANDLE HRD Focus Panel. The data were evaluated using the following thresholds: tumor cell content ≥ 30%, GScore positive at ≥ 50, HRD positive: GScore at ≥ 50 or BRCA1/2 category 4/5 mutation. MSI-high and mutations of MSH2, MSH6, PMS2, and MLH1 were analysed. The following databases were reviewed to identify druggable mutations: OncoKB, ClinVar, JAX-CKB, COSMIC, and My Cancer Genome.
Results:
299/311 (96%) biopsies had sufficient DNA content for NGS. NGS was performed from prostate (31%), lymph node (30%), visceral (15%), and bone (24%) metastases with informative DNA retrival in 95%, 95%, 92%, and 85%, respectively. 157 patients (50.5%) had no or non druggable mutations, while 154 patients (49.5%) exhibited druggable mutations. HRD gene mutations and inactivating p53 mutations were observed in 66 patients (22%). 3 patients had p53 mutations with gain-of-function resulting in ATM inactivation. 50% of HRD gene mutations iwere pathogen and treated with PARPi resulting in a progression-free survival of 3-28 months. Activating AR mutations and inactivating PTEN/activating PIC3Ca mutations were found in 42 (14%) and 24 (8%) patients, respectively. Switch of treatment for AR mutation resulted in PFS of 6-9 months. Mismatch repair deficiency/MSI high mutations were identified in 3 cases who received pembrolizumab with a PFS of 4-8 months.
Conclusions:
NGS analysis in mCRPC reveals mutations in two-thirds of patients, of which 41% are already druggable. Only 50% of druggable mutations are based on BRCA1/2 or ATM. NGS analysis should be integrated into the diagnostic armentarium following failure of first-line systemic therapy for mCRPC.
Insights
Next-generation sequencing (NGS) identified druggable mutations in nearly half of metastatic castration-resistant prostate cancer (mCRPC) patients. Integrating NGS into diagnostics can guide targeted therapies for improved outcomes.
Area of Science:
- Oncology
- Genetics
- Molecular Diagnostics
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) is an advanced stage of prostate cancer.
- Identifying actionable mutations is crucial for guiding treatment strategies in mCRPC.
Purpose of the Study:
- To determine the frequency and types of druggable mutations in patients with progressive mCRPC.
- To assess the utility of next-generation sequencing (NGS) for molecular profiling in mCRPC.
Main Methods:
- Conducted molecular panel analysis using NGS on 311 mCRPC patients' samples (prostatectomy or biopsy).
- Analyzed mutations in key cancer-related genes including AR, ATM, BRCA1/2, TP53, and HRD-related genes.
- Utilized databases like OncoKB and ClinVar to identify druggable mutations.
Main Results:
- Druggable mutations were found in 49.5% of patients.
- Homologous recombination deficiency (HRD) gene mutations and inactivating p53 mutations occurred in 22% of patients.
- Activating AR mutations (14%) and PTEN/PIK3CA alterations (8%) were also identified.
Conclusions:
- NGS analysis reveals actionable mutations in a significant proportion of mCRPC patients.
- Targeted therapies based on identified mutations, particularly BRCA1/2 or ATM, can improve progression-free survival.
- NGS should be incorporated into the diagnostic workup after first-line therapy failure in mCRPC.
