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Genetic heterogeneity after first-line chemotherapy in high-grade serous ovarian cancer

  • Author Footnotes
    1 These authors contribute equally to this study.
    Sandrina Lambrechts
    Footnotes
    1 These authors contribute equally to this study.
    Affiliations
    Division of Gynecological Oncology, Leuven Cancer Institute, Department of Gynaecology and Obstetrics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
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  • Author Footnotes
    1 These authors contribute equally to this study.
    Dominiek Smeets
    Footnotes
    1 These authors contribute equally to this study.
    Affiliations
    Laboratory for Translational Genetics, Vesalius Research Center, VIB, Leuven, Herestraat 49, 3000 Leuven, Belgium

    Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Herestraat 49, 3000 Leuven, Belgium
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  • Matthieu Moisse
    Affiliations
    Laboratory for Translational Genetics, Vesalius Research Center, VIB, Leuven, Herestraat 49, 3000 Leuven, Belgium

    Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Herestraat 49, 3000 Leuven, Belgium
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  • Elena Ioana Braicu
    Affiliations
    Department of Gynecology and Obstetrics, European Competence Center for Ovarian Cancer, Charité-University Medicine of Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
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  • Adriaan Vanderstichele
    Affiliations
    Division of Gynecological Oncology, Leuven Cancer Institute, Department of Gynaecology and Obstetrics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium

    Laboratory for Translational Genetics, Vesalius Research Center, VIB, Leuven, Herestraat 49, 3000 Leuven, Belgium

    Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Herestraat 49, 3000 Leuven, Belgium
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  • Hui Zhao
    Affiliations
    Laboratory for Translational Genetics, Vesalius Research Center, VIB, Leuven, Herestraat 49, 3000 Leuven, Belgium

    Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Herestraat 49, 3000 Leuven, Belgium
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  • Els Van Nieuwenhuysen
    Affiliations
    Division of Gynecological Oncology, Leuven Cancer Institute, Department of Gynaecology and Obstetrics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
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  • Els Berns
    Affiliations
    Erasmus MC, Cancer Institute, Department Medical Oncology, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
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  • Jalid Sehouli
    Affiliations
    Department of Gynecology and Obstetrics, European Competence Center for Ovarian Cancer, Charité-University Medicine of Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
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  • Robert Zeillinger
    Affiliations
    Department of Obstetrics and Gynecology, Molecular Oncology Group, Comprehensive Cancer Center, Gynecologic Cancer Unit, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
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  • Silvia Darb-Esfahani
    Affiliations
    Department of Gynecology and Obstetrics, European Competence Center for Ovarian Cancer, Charité-University Medicine of Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
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  • Dan Cacsire Castillo-Tong
    Affiliations
    Erasmus MC, Cancer Institute, Department Medical Oncology, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
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  • Diether Lambrechts
    Correspondence
    Corresponding author: Laboratory for Translational Genetics, Department of Oncology, VIB, KU Leuven, Herestraat 49, bus 912, 3000 Leuven, Belgium. Tel.: +32 16 37 60 52.
    Affiliations
    Laboratory for Translational Genetics, Vesalius Research Center, VIB, Leuven, Herestraat 49, 3000 Leuven, Belgium

    Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Herestraat 49, 3000 Leuven, Belgium
    Search for articles by this author
  • Ignace Vergote
    Affiliations
    Division of Gynecological Oncology, Leuven Cancer Institute, Department of Gynaecology and Obstetrics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium
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  • Author Footnotes
    1 These authors contribute equally to this study.
Published:December 13, 2015DOI:https://doi.org/10.1016/j.ejca.2015.11.001

      Highlights

      • Substantial genetic heterogeneity underlies high-grade serous ovarian carcinoma (HGSOC) collected before and after platinum.
      • Biopsies collected at relapse are therefore needed to tailor treatment options to the underlying genetic profile.
      • Platinum-sensitive HGSOCs remain homologous recombination-deficient after first-line platinum, irrespective of their response.
      • Therefore, these tumours also qualify for second-line PARP inhibitors.
      • Chromosomal instability of specific regions contributes to acquired resistance to platinum.

      Abstract

      Background

      Most high-grade serous ovarian carcinoma (HGSOC) patients benefit from first-line platinum-based chemotherapy, but progressively develop resistance during subsequent lines. Re-activating BRCA1 or MDR1 mutations can underlie platinum resistance in end-stage patients. However, little is known about resistance mechanisms occurring after a single line of platinum, when patients still qualify for other treatments.

      Methods

      In 31 patients with primary platinum-sensitive HGSOC, we profiled tumours collected during debulking surgery before and after first-line chemotherapy using whole-exome sequencing and single nucleotide polymorphism profiling.

      Results

      Besides germline BRCA1/2 mutations, we observed frequent loss-of-heterozygosity in homologous recombination (HR) genes and mutation spectra characteristic of HR-deficiency in all tumours. At relapse, tumours differed considerably from their primary counterparts. There was, however, no evidence of events reactivating the HR pathway, also not in tumours resistant to second-line platinum. Instead, a platinum score of 13 copy number regions, among other genes including MECOM, CCNE1 and ERBB2, correlated with platinum-free interval (PFI) after first-line therapy, whereas an increase of this score in recurrent tumours predicted the change in PFI during subsequent therapy.

      Conclusions

      Already after a single line of platinum, there is huge variability between primary and recurrent tumours, advocating that in HGSOC biopsies need to be collected at relapse to tailor treatment options to the underlying genetic profile. Nevertheless, all primary platinum-sensitive HGSOCs remained HR-deficient, irrespective of whether they became resistant to second-line platinum, further suggesting these tumours qualify for second-line Poly APD ribose polymerase (PARP) inhibitor treatment. Finally, chromosomal instability contributes to acquired resistance after a single line of platinum therapy.

      Keywords

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