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Advanced Ovarian Cancer Displays Functional Intratumor Heterogeneity That Correlates to Ex Vivo Drug Sensitivity
  1. Rachel L. O’Donnell, PhD,
  2. Angelika Kaufmann, MBBS,
  3. Laura Woodhouse, MBBS,
  4. Aiste McCormick, MBBS,
  5. Paul A. Cross, MBBS,
  6. Richard J. Edmondson, MD and
  7. Nicola J. Curtin, PhD
  1. * Northern Gynaecological Oncology Centre, Queen Elizabeth Hospital, Gateshead, United Kingdom;
  2. Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK; and
  3. Faculty Institute for Cancer Studies, University of Manchester, St Mary’s Hospital, Manchester, United Kingdom.
  1. Address correspondence and reprint requests to Richard J. Edmondson, MD, Faculty Institute for Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, St Mary’s Hospital, Research Floor (5), Oxford Rd, Manchester M13 9WL, United Kingdom. E-mail: Richard.Edmondson{at}manchester.ac.uk.

Abstract

Introduction Epithelial ovarian cancer is recognized to be heterogeneous but is currently treated with a single treatment strategy. Successful patient stratification of emerging chemotherapy agents is dependent upon the availability of reliable biomarkers indicative of the entire tumor.

Aim The aim of this study was to evaluate intertumor and intratumor heterogeneity within a series of epithelial ovarian cancer using homologous recombination (HR) DNA repair status.

Methods Primary cultures generated from ascites and solid tumor from multiple intra-abdominal sites were characterized by their morphology and expression of protein markers. Results were compared with Formalin fixed paraffin embedded tissue pathology.

Homologous recombination function was determined by quantification of nuclear Rad51 foci. Growth inhibition (sulforhodamine B) assays were used to calculate the GI50 for cisplatin and rucaparib.

Results Ascites with matched solid tumor were cultured from 25 patients.

Concordance in functional HR status between ascites and solid tumor subcultures was seen in only 13 (52%) of 25 patients. Heterogeneity in HR status was seen even in patients with homogeneous histological subtype. Homologous recombination defective cultures were significantly more sensitive to cisplatin and rucaparib.

Additionally, intertumor and intratumor heterogeneity was seen between the expression of epithelial and ovarian markers (EpCAM, cytokeratin, CA125, MOC-31, and vimentin). There was no relationship between heterogeneity of HR functional status and antigen expression.

Conclusions Intertumor and intratumor functional HR heterogeneity exists that cannot be detected using histological classification. This has implications for biomarker-directed treatment.

  • Ovarian cancer
  • Intratumoral heterogeneity
  • Intertumoral heterogeneity
  • Homologous recombination
  • Functional assessment
  • PARP inhibitor

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Footnotes

  • The authors declare no conflicts of interest.

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