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Simultaneous germline and somatic sequencing in ovarian carcinoma: mutation rate and impact on clinical decision-making

  • Soledad Jorge
    Correspondence
    Corresponding author at: Division of Gynecologic Oncology, Department of Obstetrics and Gynecologic, University of Washington, 1959 NE Pacific St, Box 356460, Seattle, WA 98195.
    Affiliations
    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, United States of America
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  • Andrew S. McFaddin
    Affiliations
    Division of Molecular Diagnostics, Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, WA 98195, United States of America
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  • Kemi M. Doll
    Affiliations
    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, United States of America
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  • Kathryn P. Pennington
    Affiliations
    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, United States of America
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  • Barbara M. Norquist
    Affiliations
    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, United States of America
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  • Robin L. Bennett
    Affiliations
    Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, United States of America
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  • Colin C. Pritchard
    Affiliations
    Division of Molecular Diagnostics, Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, WA 98195, United States of America
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  • Elizabeth M. Swisher
    Affiliations
    Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington School of Medicine, Seattle, WA 98195, United States of America
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Published:December 27, 2019DOI:https://doi.org/10.1016/j.ygyno.2019.12.010

      Highlights

      • Potentially actionable mutations were identified in half of ovarian cancer cases: 14% germline, 35% somatic, and 2% both.
      • Pathogenic BRCA1 and BRCA2 mutations accounted for 59% of all actionable mutations identified.
      • Sequencing results directly influenced clinical care in one fourth of new diagnoses and in one half of recurrences.

      Abstract

      Objective

      Germline and somatic BRCA1 and BRCA2 (BRCA) mutations predict treatment response in patients with epithelial ovarian, peritoneal or fallopian tube cancer (OC), yet only germline testing is routinely pursued or reimbursed at diagnosis. We report our experience with clinical testing of paired tumor and germline DNA for OC mutations.

      Methods

      Simultaneous sequencing using the BROCA assay of DNA from paired blood and neoplastic tissue became clinically available at our institution in 2017. We retrospectively reviewed the medical records of OC cases tested from 7/2017 to 7/2018. We calculated the rates of known pathogenic germline mutations and actionable somatic mutations, defined as those for which targeted therapies exist.

      Results

      We identified 43 women (36 new diagnoses, seven recurrences) who underwent testing. Average age at diagnosis was 60. OC samples came from surgical specimens in 31 cases (72.1%), from biopsy in 11 cases (25.6%), and from cytology in one case (2.3%). We identified pathogenic germline mutations in six cases (14%), actionable somatic mutations in 15 cases (35%), and both a somatic and germline mutation in one case (2%). BRCA mutations accounted for 59% of all mutations. Of 40 cases with sufficient follow-up, providers documented reviewing results of genetic testing in 34 (85%), which influenced clinical decisions in 12 (30%).

      Conclusions

      Simultaneous germline and tumor sequencing is an efficient way to provide enhanced information to guide the care of OC patients. This approach can identify somatic BRCA mutations at diagnosis, allowing physicians to provide PARP inhibitor maintenance and improve outcomes for those patients.

      Keywords

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