Kurzfassung

Background
Previous work demonstrated clinically relevant discordance of PD-L1 expression between primary tumors, lymph node metastases, and distant metastases. This suggests that additional predictive and therapeutic biomarkers may also vary across disease sites.
 
Objectives
Primary Objective:
To determine concordance/discordance rates of therapeutically relevant biomarkers between primary tumor, lymph node metastasis, and distant metastasis.
 
Secondary Objectives:
- Organ-specific...Background
Previous work demonstrated clinically relevant discordance of PD-L1 expression between primary tumors, lymph node metastases, and distant metastases. This suggests that additional predictive and therapeutic biomarkers may also vary across disease sites.
 
Objectives
Primary Objective:
To determine concordance/discordance rates of therapeutically relevant biomarkers between primary tumor, lymph node metastasis, and distant metastasis.
 
Secondary Objectives:
- Organ-specific patterns of biomarker shifts
- Impact of prior therapy exposure
- Proportion of patients in whom metastatic testing alters treatment eligibility
- Exploratory survival associations
 
Study Design
Retrospective observational study using archived FFPE tissue from primary tumors, lymph node metastases, and distant metastases.
 
Study Population
Inclusion:
Patients with invasive breast cancer and available matched tissue from primary tumor, lymph node metastasis, and at least one distant metastasis.
 
Biomarker Panel
A) Standard Predictors:
ER, PR, HER2, Ki-67
 
B) Immune Markers:
TILs, CD8, CD4, FOXP3, MHC-I
 
C) ADC Targets:
TROP2, HER2-low status, HER3, B7-H4, FOLR1, EPCAM, LY75
 
D) Resistance Pathways:
PIK3CA mutation, ESR1 mutation, PTEN
 
E) Metastasis-related Markers:
CD44, CXCR4
 
Methods
- Central pathology review
- Standardized IHC scoring
- Optional NGS/ddPCR for mutation analysis
- Concordance analysis using kappa statistics and paired tests
 
Endpoints
Primary:
Biomarker concordance rates and kappa values.
 
Secondary:
Organ-specific discordance, direction of shifts, predictors of biomarker change, and optional survival correlations.
 
Statistical Plan
Descriptive statistics, McNemar tests, kappa coefficients, logistic regression for predictors of discordance.
 
Clinical Impact
The study aims to provide evidence-based guidance on when metastatic re-biopsy is clinically relevant for therapy selection, particularly regarding ADC targets and resistance markers.
 
Timeline
Estimated project duration: 12–18 months including tissue processing, analysis, and publication.
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