Genomic Stratification
Prognostic and predictive genomic factors for Lu-177-PSMA therapy based on current literature (2022-2025).
Evidence Update: Current data shows DDR mutations (BRCA, ATM) are NOT predictive of improved Lu-177-PSMA monotherapy outcomes. Combined TP53/RB1/PTEN loss predicts aggressive disease with shorter PFS/OS. AR amplification may indicate early progression risk.
Genomic Profile Input
Evidence-Based 2024Enter results from germline/somatic testing or liquid biopsy. Select "Unknown" if not tested.
Enter Genomic Data
Complete the form to see evidence-based stratification with risk assessment.
Based on current literature (2022-2025)
Evidence-Based Scientific Background
DNA Damage Repair (DDR) Mutations Current Evidence Does Not Support Superior Outcomes
Evidence Update (2022-2025): Multiple retrospective studies show no significant difference in PSA response, PFS, or OS between DDR-mutated and wild-type tumors treated with Lu-177-PSMA monotherapy.
Satapathy et al. (2022)
Study of 15 mCRPC patients: 67% had DDR mutations (ATM, BRCA2, TP53, PTEN). No significant difference in: • PSA50 response (67% vs 60%) • Median PFS (5.8 vs 6.1 months) • Median OS (11.2 vs 12.1 months)
Privé et al. (2021)
Study of 40 patients: DDR+ (BRCA1/2, ATM) vs DDR- showed similar: • PSA50 response (59% vs 65%) • Median PFS (5.9 vs 6.4 months) • Median OS (11.1 vs 10.7 months)
Clinical Implication: DDR mutations do NOT predict enhanced response to Lu-177-PSMA monotherapy. However, they remain important for:
- • PARP inhibitor combinations: Ongoing trials (NCT03874884) testing olaparib + Lu-177-PSMA
- • Germline implications: BRCA1/2 mutations have hereditary cancer risk implications
- • Theoretical radiosensitivity: Preclinical models show enhanced effect, not yet clinically validated
TP53, RB1, PTEN - Combined Prognostic Impact Strong Prognostic Markers
Ofner et al. (2025): Multi-center study showing combined TP53/RB1/PTEN loss correlates with significantly shorter outcomes after Lu-177-PSMA therapy.
| Genomic Pattern | Median PFS | Median OS | Clinical Risk |
|---|---|---|---|
| TP53+RB1+PTEN loss (triple) | 4.1 months | 9.8 months | Very High |
| TP53+RB1 loss (dual) | 5.2 months | 11.3 months | High |
| None of above | 8.2 months | 16.3 months | Standard |
RB1 Loss & NEPC Risk
Ajkunic 2024 & Hong 2024: RB1 loss drives neuroendocrine differentiation: • 10-20% of heavily treated mCRPC develop NEPC • PSMA downregulation common • Consider alternative targets: DLL3, CEACAM5, TROP2 • Monitor chromogranin A, NSE
AR Amplification Risk
De Giorgi 2021: AR amplification in plasma cfDNA: • Associated with shorter OS (7.6 vs 15.8 months) • May predict early progression • Consider serial liquid biopsy monitoring • AR-driven tumors often maintain PSMA expression
Treatment-Induced Genomic Evolution
Key Finding: Lu-177-PSMA and other therapies drive clonal evolution and genomic alterations during treatment.
Mechanisms of Evolution
- • Treatment-emergent NEPC: RB1/TP53 dual loss in 10-20% of CRPC
- • Clonal selection: Radiation eliminates sensitive clones
- • Secondary alterations: New DDR, PI3K, Wnt mutations
- • PSMA heterogeneity: Spatial/temporal PSMA variation
Monitoring Recommendations
- • Serial liquid biopsy: CTC RNAseq or cfDNA at progression (Sharifi 2025)
- • NEPC markers: Chromogranin A, NSE if RB1 loss
- • PSMA-PET: Repeat if discordant response
- • Alternative imaging: DOTATATE PET for suspected NEPC
Clinical Suspicion for NEPC: Rapid visceral progression, rising chromogranin/NSE, low PSA relative to disease burden, discordant PSMA-PET findings.
Ethnic/Genomic Context Considerations
Suh et al. (2025): Genomic alteration prevalence varies significantly by ancestry, affecting PSMA expression and therapeutic response patterns.
• Lower TP53/PTEN rates
• Higher FOXA1/SPOP
• Trial populations
• Standard reference
• Different AR variants
• Population-specific DDR
Key Evidence References (2022-2025)
DDR Mutation Evidence:
• Satapathy S et al. (2022) - No significant benefit in DDR-mutated tumors
• Privé BM et al. (2021) - Similar outcomes DDR+ vs DDR-
• Filippi L et al. (2022) - Systematic review of 7 studies
Prognostic Factors:
• Ofner H et al. (2025) - Combined TP53/RB1/PTEN loss predicts poor outcomes
• De Giorgi U et al. (2021) - AR amplification predicts early progression
• Ajkunic A et al. (2024) - NEPC transformation and alternative targets
Evolution & Monitoring:
• Sharifi MN et al. (2025) - CTC RNAseq for lineage phenotypes
• Hong YC et al. (2024) - NEPC subtypes and biomarkers
• Suh M et al. (2025) - Ethnic genomic differences
Treatment Selection:
• Jacob A et al. (2021) - AR-V7 and Lu-177-PSMA efficacy
• Militaru FC et al. (2023) - Biomarker validation studies
• Yanagisawa T et al. (2023) - Emerging systemic treatments
Alternative Targeted Therapies Based on Genomic Profile
Consider these options for specific genomic profiles or treatment-resistant disease.
DDR Mutations (BRCA, ATM)
- • PARP inhibitors (olaparib, rucaparib)
- • PARP + Lu-177-PSMA trials (NCT03874884)
- • Consider platinum chemotherapy
RB1 Loss / NEPC Risk
- • Platinum + etoposide chemotherapy
- • DLL3-targeted therapies (tarlatamab)
- • Lu-DOTATATE (if somatostatin receptor+)
- • TROP2/CEACAM5 targeting
AR Pathway Alterations
- • Novel ARATs (darolutamide)
- • AR degraders (PROTACs)
- • AR-V7-directed therapies
- • Continuation of effective ARATs