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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Shallow Whole-Genome Sequencing to Assess Genomic Instability and Predict Treatment Response in Metastatic
Peter H J Slootbeek1, Yarah M Quint2, Julian J R Kokke1
1Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.
Genomic Instability Score (GIS) calculated via shallow whole-genome sequencing (sWGS) predicts treatment response in metastatic castration-resistant prostate cancer (mCRPC). Combining GIS with BRCA-complex status improves prediction of prostate-specific antigen (PSA) decline for poly (ADP-ribose) polymerase inhibitors (PARPis).
Area of Science:
- Oncology
- Genomics
- Cancer Therapeutics
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) patients with homologous recombination deficiency (HRD) benefit from PARP inhibitors (PARPis) or platinum chemotherapy (PlCh).
- Pathogenic variants in homologous recombination repair genes are commonly used as a proxy for HRD.
- Genomic Instability Score (GIS) quantifies the genomic effect of HRD.
Purpose of the Study:
- To evaluate the predictive value of GIS, calculated using cost-effective shallow whole-genome sequencing (sWGS), for treatment response to PARPis or PlCh in mCRPC.
- To assess if GIS can serve as a more comprehensive biomarker for HRD-related treatment sensitivity.
Main Methods:
- Shallow whole-genome sequencing (sWGS) was performed on 288 mCRPC tumor samples.
- Genomic Instability Score (GIS) was calculated as the sum of large-scale transitions, telomeric-allelic imbalances, and genomic loss of heterozygosity.
- GIS was correlated with treatment response (PSA decline, RECIST1.1) and BRCA-complex pathogenic variants.
Main Results:
- Median GIS was 26; samples with BRCA-complex variants had significantly higher GIS (median 38).
- Higher GIS was associated with significant PSA declines (≥50%) and partial responses by RECIST1.1 for both PARPi and PlCh.
- Combining GIS with BRCA-complex status improved prediction of PSA response to PARPis (AUC 0.849 vs 0.781).
Conclusions:
- Genomic Instability Score (GIS) assessment by sWGS is a feasible method for evaluating HRD.
- GIS is associated with treatment response to PARPis and PlCh in mCRPC patients.
- The combination of GIS and BRCA-complex status offers superior prediction of PSA response to PARPis compared to BRCA-complex status alone.
