Abstract
BackgroundSince the approval of the first poly (adenosine diphosphate [ADP]) ribose polymerase inhibitor (PARPi; olaparib [Lynparza™]) for platinum-sensitive relapsed high grade ovarian cancer, with either germline or somatic BRCA1/2 deleterious variants, the strategies for BRCA1/2 are dynamically changing. Along with germline testing within the context of familial or sporadic ovarian cancer, patients are now being referred for BRCA1/2 genetic assay above all for treatment decisions: in this setting tumour BRCA assay can allow to identify an estimated 3–9% of patients with peculiar somatic BRCA1/2 mutations. These women could also benefit from PARPi therapy. This new type of approach is really challenging, in particular due to the technical and analytical difficulties regarding low quality DNA deriving from formalin-fixed, paraffin-embedded (FFPE) specimens.Aimin this manuscript, we try to a) underline many issues related to BRCA1/2 analysis by next generation sequencing technologies (NGS), b) provide some responses to many questions regarding this new paradigm related to OvCa patients’ management. Some considerations for incorporating genetic analysis of ovarian tumour samples into the patient pathway and ethical requirements are also provided.Methodswe used our retrospective data based on thousands of ovarian cancer women sequenced for BRCA1/2 genes.Discussiontumor BRCA1/2 assay should be rapidly introduced in routine laboratory practice as first line testing by using harmonized pipelines based on consensus guidelines.
Highlights
Tumor BRCA testing is emerging as a powerful tool to discover and identify more mutations in high serous ovarian cancer patients which have been shown to benefit from treatment with poly ADP ribose polymerase (PARP) inhibitors [1, 2]
Somatic BRCA1/2 pathogenic variants are reported to be present in about 7% of ovarian cancers in the first line or platinum-sensitive relapsing patients [3]
Despite its clinical utility, using of some NEXT GENERATION SEQUENCING (NGS)-based technologies, able to enrich somatic mutation from FFPE samples, still requires peculiar adjustments before being completely www.oncotarget.com implemented as validated routine assays [4]
Summary
Tumor BRCA testing (tBRCA) is emerging as a powerful tool to discover and identify more mutations in high serous ovarian cancer patients which have been shown to benefit from treatment with poly ADP ribose polymerase (PARP) inhibitors [1, 2]. Along with germline testing within the context of familial or sporadic ovarian cancer, patients are being referred for BRCA1/2 genetic assay above all for treatment decisions: in this setting tumour BRCA assay can allow to identify an estimated 3‒9% of patients with peculiar somatic BRCA1/2 mutations. These women could benefit from PARPi therapy. This new type of approach is really challenging, in particular due to the technical and analytical difficulties regarding low quality DNA deriving from formalin-fixed, paraffin-embedded (FFPE) specimens
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