title: Genetic heterogeneity after first-line chemotherapy in high-grade serous ovarian cancer.
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.
authors.affiliation: Division of Gynecological Oncology, Leuven Cancer Institute, Department of Gynaecology and Obstetrics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Sandrina
authors.initials: S
authors.lastname: Lambrechts
authors.affiliation: 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.
authors.forename: Dominiek
authors.initials: D
authors.lastname: Smeets
authors.affiliation: 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.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Moisse
authors.affiliation: Department of Gynecology and Obstetrics, European Competence Center for Ovarian Cancer, Charité-University Medicine of Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Elena Ioana
authors.initials: EI
authors.lastname: Braicu
authors.affiliation: 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.
authors.forename: Adriaan
authors.initials: A
authors.lastname: Vanderstichele
authors.affiliation: 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.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Division of Gynecological Oncology, Leuven Cancer Institute, Department of Gynaecology and Obstetrics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Els
authors.initials: E
authors.lastname: Van Nieuwenhuysen
authors.affiliation: Erasmus MC, Cancer Institute, Department Medical Oncology, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: Els
authors.initials: E
authors.lastname: Berns
authors.affiliation: Department of Gynecology and Obstetrics, European Competence Center for Ovarian Cancer, Charité-University Medicine of Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Jalid
authors.initials: J
authors.lastname: Sehouli
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Zeillinger
authors.affiliation: Department of Gynecology and Obstetrics, European Competence Center for Ovarian Cancer, Charité-University Medicine of Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Darb-Esfahani
authors.affiliation: Erasmus MC, Cancer Institute, Department Medical Oncology, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: Dan
authors.initials: D
authors.lastname: Cacsire Castillo-Tong
authors.affiliation: 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. Electronic address: Diether.Lambrechts@vib-kuleuven.be.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Division of Gynecological Oncology, Leuven Cancer Institute, Department of Gynaecology and Obstetrics, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Ignace
authors.initials: I
authors.lastname: Vergote
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000077216:Carcinoma, Ovarian Epithelial; D004268:DNA-Binding Proteins / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018740:Genetic Heterogeneity; D006801:Humans; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics*; D017671:Platinum Compounds / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C498471:FANCA protein, human; D052217:Fanconi Anemia Complementation Group A Protein; D017671:Platinum Compounds; C448305:RAD51C protein, human
keywords: Carboplatin; Clonal evolution; Drug resistance; Genetic heterogeneity; Genomic instability; Ovarian cancer