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Clinical significance of homologous recombination deficiency score testing in endometrial Cancer

  • Jean H. Siedel
    Affiliations
    Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
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  • Kari L. Ring
    Affiliations
    Department of Obstetrics and Gynecology, Emily Couric Clinical Cancer Center, Charlottesville, VA, United States of America
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  • Wei Hu
    Affiliations
    Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
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  • Robert L. Dood
    Affiliations
    Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
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  • Ying Wang
    Affiliations
    Department of Bioinformatics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
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  • Keith Baggerly
    Affiliations
    Department of Bioinformatics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
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  • Kathleen M. Darcy
    Affiliations
    Gynecologic Cancer Center of Excellence, Department of Obstetrics & Gynecology, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, United States of America

    The Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., Bethesda, MD, United States of America
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  • Thomas P. Conrads
    Affiliations
    Gynecologic Cancer Center of Excellence, Department of Obstetrics & Gynecology, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, United States of America

    Women’s Health Integrated Research Center, Women’s Service Line, Inova Health System, Falls Church, VA, United States of America
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  • Shannon Gallagher
    Affiliations
    Myriad Genetics, Inc., Salt Lake, UT, United States of America
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  • Placede Tshiaba
    Affiliations
    Myriad Genetics, Inc., Salt Lake, UT, United States of America
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  • Chris Neff
    Affiliations
    Myriad Genetics, Inc., Salt Lake, UT, United States of America
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  • Kirsten M. Timms
    Affiliations
    Myriad Genetics, Inc., Salt Lake, UT, United States of America
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  • Selanere Mangala
    Affiliations
    Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
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  • Shannon N. Westin
    Affiliations
    Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
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  • Russell Broaddus
    Affiliations
    Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, United States of America
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  • Gabriel Lopez-Berestein
    Affiliations
    Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America

    Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, United States of America
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  • Karen H. Lu
    Affiliations
    Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
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  • Robert L. Coleman
    Affiliations
    Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
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  • George L. Maxwell
    Affiliations
    Gynecologic Cancer Center of Excellence, Department of Obstetrics & Gynecology, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, Bethesda, MD, United States of America

    Women’s Health Integrated Research Center, Women’s Service Line, Inova Health System, Falls Church, VA, United States of America
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  • Anil K. Sood
    Correspondence
    Corresponding author at: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.
    Affiliations
    Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America

    Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America

    Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, United States of America
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Published:February 06, 2021DOI:https://doi.org/10.1016/j.ygyno.2020.12.010

      Highlights

      • Patients with HRD score ≥ 4 trended toward worse survival as compared to those with HRD score < 4.
      • When grouped by molecular subtype, there was a significant difference between groups.
      • Using an HRD ≥4 cutoff in the initial (p = 0.0024) and replication (p = 0.042) cohorts.
      • The Hec1a model (HRD score = 19) was highly sensitive to olaparib in in vitro and in vivo experiments.
      • These findings suggest that HRD score may have clinical utility in patients with advanced or recurrent endometrial cancer.

      Abstract

      Background

      Homologous recombination deficiency (HRD) score is related to chemotherapy response in some cancers, but its role in endometrial cancer in not known. We determined frequency and clinical significance of alterations in the HR pathway in endometrial cancer.

      Methods

      253 endometrioid endometrial adenocarcinoma (EEA) samples from two independent cohorts (discovery and replication) were tested for HRD score using the Myriad HRD assay, microsatellite instability (MSI) and tumor mutation burden (TMB) using a next generation sequencing assay. HRD scores were also generated on endometrial cancer cell lines and in vivo response to olaparib was assessed.

      Results

      ROC curves were employed to determine optimal cutoffs of HRD in relation to survival impact in endometrial cancer and a cutoff of HRD ≥ 4 was suggested for DFS using the discovery cohort. Patients from two independent cohorts with HRD score ≥ 4 trended toward worse survival as compared to those with HRD score < 4. Both cohorts were further separated into four groups according to molecular subtypes (TMB positive; MSI positive; HRD positive; all others). When grouped by molecular subtype, there was a significant difference between groups using an HRD ≥4 cutoff in the initial (p = 0.0024) and replication (p = 0.042) cohorts. The Hec1a model (HRD score = 19) was highly sensitive to olaparib in in vitro and in vivo experiments.

      Conclusions

      High HRD score was associated with worse DFS in our patient cohort. These findings suggest that HRD score may have clinical utility in patients with advanced or recurrent endometrial cancer.

      Keywords

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