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Concordance of BRCA mutation detection in tumor versus blood, and frequency of bi-allelic loss of BRCA in tumors from patients in the phase III SOLO2 trial

Published:November 03, 2021DOI:https://doi.org/10.1016/j.ygyno.2021.10.002

      Highlights

      • There are limited data on the concordance between tumor BRCA (tBRCA) and germline BRCA (gBRCA) testing in ovarian cancer.
      • In SOLO2, concordance between tBRCA and gBRCA testing was very high (98%) in gBRCA-mutated patients.
      • Large insertions or deletions accounted for only a small subset (5%) of gBRCA mutations.
      • The near 100% rate of bi-allelic loss of BRCA suggests that routine testing for BRCA zygosity is not required.
      • Results are in keeping with BRCA loss being a driver of tumorigenesis in ovarian cancer.

      Abstract

      Objective

      Maintenance olaparib provided a progression-free survival benefit in the phase III SOLO2 trial (NCT01874353) in patients with platinum-sensitive relapsed ovarian cancer and a BRCA mutation (BRCAm). However, questions remain regarding tumor versus germline BRCA testing and the impact of heterozygous versus bi-allelic loss of BRCA1 or BRCA2 in the tumor.

      Methods

      Blood and tumor samples were analyzed. A concordance analysis of germline BRCAm status (BRACAnalysis® CLIA test) and tumor BRCAm status (myChoice® CDx test) was conducted (Myriad Genetic Laboratories, Inc.). Bi-allelic loss of BRCA1 and BRCA2 and a genomic instability score (GIS) (myChoice® CDx test) were also determined.

      Results

      289 of 295 enrolled patients had a germline BRCAm confirmed centrally and tumor BRCAm status was evaluable in 241 patients. There was 98% and 100% concordance between tumor and germline testing for BRCA1m and BRCA2m, respectively, with discordance found in four cases. Of 210 tumor samples evaluable for BRCA zygosity, 100% of germline BRCA1-mutated tumors (n = 144) and 98% of germline BRCA2-mutated tumors (n = 66) had bi-allelic loss of BRCA. One patient with a heterozygous BRCA2m had a GIS of 53, was progression free for 911 days and remained on olaparib at data cut-off.

      Conclusions

      Very high concordance was demonstrated between tumor and germline BRCA testing, supporting wider implementation of tumor BRCA testing in ovarian cancer. Near 100% rates of bi-allelic loss of BRCA in platinum-sensitive relapsed ovarian tumors suggest routine testing for BRCA zygosity is not required in this population and reflects BRCA loss being a driver of tumorigenesis.

      Keywords

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