The synthetic lethal interaction between PARP inhibition and Homologous Recombination Repair (HRR) deficiency is being successfully exploited therapeutically in ovarian cancer, whereby three PARP inhibitors—olaparib, rucaparib, and niraparib—have received U.S. Food and Drug Administration (FDA) approval as monotherapy either in patients with germline or somatic BRCA1/2 mutations, or as maintenance therapy in platinum-sensitive recurrent disease, regardless of BRCA mutation status. The FDA also approved olaparib for patients with germline BRCA-mutated HER2-negative metastatic breast cancer previously treated with chemotherapy. Furthermore, olaparib has been granted breakthrough therapy designation as a single agent for the treatment of BRCA or ATM gene–mutated, castration-resistant metastatic prostate cancer in patients who have received a prior taxane-based chemotherapy and at least one newer hormonal agent. Patient selection for PARP inhibitor therapy is based on FDA-approved companion diagnostics such as FoundationFocus CDxBRCA and BRACAnalysis CDx.
NovoFocus™ PARPi CDx is a next-generation sequencing (NGS)-based companion diagnostic assay for PARP inhibitor (PARPi) therapies in several types of cancer. This assay is an integrated workflow from sample processing, sequencing, analysis to report generation.
NovoFocus™ PARPi CDx Advantages
- Rigorous validation: The accuracy, reproducibility and stability have been validated with Horizon’s Reference Standards, Novogene’s internal BRCA reference standards and the Chinese National Reference Standards for BRCA Gene Mutation.
- Reliable Pathogenicity Interpretation: Based on ACMG/AMP guidelines and an in-house Novogene Chinese BRCA variant database, the NovoACMG pathogenicity interpretation pipeline ensures accuracy and reliability of the test results. It has been validated through the GenQA Classification of BRCA Variants Test.
- Short Turn-around Time: 10 and 13 calendar days from sample receipt to report delivery for germline and somatic mutation detection, respectively.
NovoFocus™ PARPi CDx Service Overview
- Germline Mutation Detection: 2 mL whole blood or 1 μg germline DNA
- Somatic Mutation Detection:
- FFPE tissue: Approximately ten 4-μm sections, each with tissue area ≥ 25 mm2 and tumor content ≥ 20%
- Extracted tumor DNA: 500ng
- NovaSeq 6000, PE150
- All coding exons and ± 20 bp intron regions
- Germline Mutation Detection: 10 calendar days from sample receipt to report delivery
- Somatic Mutation Detection: 13 calendar days from sample receipt to report delivery
Variant Types Detected
- SNV, InDel, and CNV
- 45 genes including BRCA1/2, ATM, homologous recombination repair genes, mismatch repair genes and others that are related to the efficacy of PARPi therapies according to clinical trials and/or the medical literature.
The NovoACMG Pipeline is a genetic pathogenicity interpretation pipeline developed by Novogene for this test. With the ACMG guideline as its framework, this pipeline also incorporates the rules from ENIGMA Criteria, China BRCA Interpretation Consensus and NICPBP Criteria. In addition, special consideration is given to Chinese population-specific BRCA variants according to the Novogene Chinese BRCA variant database.
The Novogene Chinese BRCA variant database is constructed by Novogene to improve the accuracy of variant pathogenicity interpretation for the Chinese population. More than half of the variants in this database are not yet included in the existing public databases (e.g. BIC, ClinVar, ENIGMA and UMD).
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This test demonstrated 100% accuracy in validation experiments using the following reference sample sets:
- Horizon BRCA Germline I Reference Standard gDNA (1 sample with 16 variants)
- Horizon BRCA Somatic Multiplex Reference Standard gDNA (1 sample with 16 variants
- Novogene’s internal BRCA Somatic Reference Standards (4 samples with 16 variants)
- Novogene’s internal BRCA Germline Reference Standards (10 samples with 10 variants)
- The Chinese National Reference Standards for BRCA Gene Mutation (25 samples with 32 variants)
Test results for the Horizon BRCA Germline I Reference Standard gDNA, Horizon BRCA Somatic Multiplex Reference Standard gDNA, Novogene’s internal BRCA Germline Reference Standards and Novogene’s internal BRCA Somatic Reference Standards were 100% reproducible in intra-run, inter-run and inter-reagent batch/operator/instrument reproducibility tests.
No interference on the test results was found with common interferents in regular clinical blood samples including EDTA, bilirubin, triglyceride, Escherichia coli and Staphylococcus aureus.