Ovarian cancer patients with deficiencies in the DNA repair pathway have shown to have a higher probability to respond to PARP inhibitors. Pathogenic mutations in the genes BRCA1 and BRCA2 lead to defects in the DNA repair pathway. It has been shown that the prevalence of mutations in the BRCA genes is higher in the tumor cells than in germline. Thus, a tumor-based test could identify a higher number of potential responders than a germline test.
This study assessed 354 consecutive individuals undergoing BRCA1 and BRCA2 full sequencing and large rearrangement analysis of DNA derived from FFPE tumor tissue in a DAkkS accredited laboratory in Munich, Germany from Jan 2015 through April 2016. The tumor-based BRCA test consists of sequencing and large rearrangement analyses of the BRCA1 and BRCA2 genes using next generation sequencing (NGS). The large rearrangements are detected by NGS dosage analysis to determine copy number abnormalities indicative of deletion or duplication mutations.
Out of the 354 analyzed samples, 93 (26,5%) tested positive for a laboratory classified pathogenic mutation; 57 were found in BRCA1 and 37 in BRCA2. One specimen contained a pathogenic mutation in both BRCA1 and BRCA2. Due to different quality and age of the tumor samples, large rearrangement analysis could not be completed in 24 cases (6,8%). VUS rate in the analyzed tumors was 4.2%. Of the pathogenic mutations detected, 93,6% were sequencing variants and 6,4% were large rearrangements. Overall cancellation rate due to insufficient tumor, insufficient DNA, incorrect tumor type or other cancellation reasons is less than 9% in the observed timespan of 16 months.
The current study demonstrates that a robust diagnostic platform can detect BRCA-related mutations in ovarian tumors. While the quality of specimens received into a commercial laboratory is quite variable, a positive rate of over 26% and an overall success rate (result generated) of over 91% indicates that tumor BRCA testing should be considered for ovarian cancer patients. In addition, a small but significant number of large rearrangements indicates that tumor BRCA testing should include dosage analysis for large rearrangements.
Clinical trial identification
Legal entity responsible for the study
K.L. Copeland: Employee of Myriad Genetics GmbH including stock ownership. S.B. Wehnelt, L.E. Wange, B. Anwald, A. Weicht, A. Pfeufer: Myriad Employee.