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Updated: Jul 13, 2026
Microarray-based Identification of Individual HERV Loci Expression: Application to Biomarker Discovery in Prostate Cancer
Published on: November 2, 2013
Comprehensive clinical cancer analysis of homologous recombination deficiency biomarkers in an academic molecular
Heura Domènech1,2, Sara Simonetti1,3, Paula Romero-Lozano4
1Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
Abstract:
PARP inhibitors (PARPi) are effective in tumors with homologous recombination repair (HRR) deficiency (HRD), typically identified by germline/tumor mutations. However, genetic testing may miss intrinsic PARPi sensitivity and resistance. We evaluated strategies to improve detection and longitudinal monitoring of HRD across >500 tumor samples and >20 paired liquid biopsies, integrating genetic, genomic, and functional readouts. HRD was more frequent in high-grade ovarian cancer (HGOC; 52%) than in metastatic breast (mBC; 12%) or prostate cancer (mPC; 20%). Assay concordance was low-to-moderate, underscoring complementarity. RAD51 testing and the genomic instability score identified HRD in tumors lacking pathogenic HRR mutations (6% and 30% in mBC, 38% and 46% in HGOC, 14% and 27% in mPC, respectively). Longitudinal ctDNA sequencing revealed BRCA1/BRCA2 reversion mutations in >30% of post-PARPi mBC samples, which were associated with poor response to subsequent platinum therapy. These findings support the use of complementary HRD biomarkers in tissue and liquid biopsy to guide PARPi use and monitor response.
Insights
PARP inhibitors (PARPi) are effective for homologous recombination repair deficient (HRD) tumors. Complementary biomarkers in tissue and liquid biopsies improve HRD detection and monitoring for PARPi therapy.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- PARP inhibitors (PARPi) show efficacy in tumors with homologous recombination repair (HRR) deficiency (HRD).
- Current genetic testing for HRD may not capture all cases of PARPi sensitivity or resistance.
- Improved methods for HRD detection and monitoring are needed to optimize PARPi treatment.
Purpose of the Study:
- To evaluate strategies for enhanced detection and longitudinal monitoring of HRD.
- To integrate genetic, genomic, and functional readouts for comprehensive HRD assessment.
- To assess the utility of complementary biomarkers in tissue and liquid biopsies for guiding PARPi therapy.
Main Methods:
- Analysis of over 500 tumor samples and 20 paired liquid biopsies.
- Integration of genetic, genomic, and functional assays for HRD detection.
- Longitudinal ctDNA sequencing to identify resistance mechanisms, such as reversion mutations.
Main Results:
- HRD prevalence varied by cancer type: 52% in high-grade ovarian cancer (HGOC), 12% in metastatic breast cancer (mBC), and 20% in metastatic prostate cancer (mPC).
- RAD51 testing and genomic instability score identified HRD in tumors without pathogenic HRR mutations, highlighting limitations of mutation-based testing alone.
- BRCA1/BRCA2 reversion mutations were detected in over 30% of post-PARPi mBC samples, correlating with poor response to subsequent platinum therapy.
Conclusions:
- Complementary HRD biomarkers in both tissue and liquid biopsies are crucial for accurate patient selection and monitoring of PARPi therapy.
- Genomic instability score and RAD51 testing can identify HRD in mutation-negative tumors.
- Longitudinal monitoring via ctDNA sequencing can reveal resistance mechanisms and guide subsequent treatment decisions.