• Copy number signatures and mutational processes in ovarian carcinoma.

      Macintyre, G; Goranova, T; De Silva, D; Ennis, D; Piskorz, A; Eldridge, M; Sie, D; Lewsley, L; Hanif, A; Wilson, C; et al. (2018-09)
      The genomic complexity of profound copy number aberrations has prevented effective molecular stratification of ovarian cancers. Here, to decode this complexity, we derived copy number signatures from shallow whole-genome sequencing of 117 high-grade serous ovarian cancer (HGSOC) cases, which were validated on 527 independent cases. We show that HGSOC comprises a continuum of genomes shaped by multiple mutational processes that result in known patterns of genomic aberration. Copy number signature exposures at diagnosis predict both overall survival and the probability of platinum-resistant relapse. Measurement of signature exposures provides a rational framework to choose combination treatments that target multiple mutational processes.
    • Correction: Safety and utility of image-guided research biopsies in relapsed high-grade serous ovarian carcinoma-experience of the BriTROC consortium

      Goranova, T; Ennis, D; Piskorz, A; Macintyre, G; Lewsley, L; Stobo, J; Wilson, C; Kay, D; Glasspool, R; Lockley, M; et al. (2019)
      This article was originally published under a CC BY NC SA License, but has now been made available under a CC BY 4.0 License. Erratum for: Safety and utility of image-guided research biopsies in relapsed high-grade serous ovarian carcinoma-experience of the BriTROC consortium. [Br J Cancer. 2017]
    • Inhibition of carboplatin-induced DNA interstrand cross-link repair by gemcitabine in patients receiving these drugs for platinum-resistant ovarian cancer.

      Ledermann, J A; Gabra, H; Jayson, Gordon C; Spanswick, V J; Rustin, G J S; Jitlal, Mark; James, L E; Hartley, J A; UCL Hospitals, UCL Cancer Institute, London, United Kingdom. j.ledermann@ctc.ucl.ac.uk (2010-10-01)
      BACKGROUND: The potential of gemcitabine to interact with carboplatin was explored in a phase II trial in platinum-resistant ovarian cancer. Peripheral blood lymphocytes were sampled after drug administration to measure DNA interstrand cross-link formation and repair. PATIENTS AND METHODS: Forty patients received carboplatin target area under concentration-time curve (AUC 4) followed by gemcitabine 1,000 mg/m(2) with a second dose of gemcitabine on day 8. Peripheral blood lymphocytes were obtained in 12 patients before and at intervals during the first cycle of chemotherapy. DNA cross-link formation and repair (unhooking) were measured by the single-cell gel electrophoresis (comet) assay following ex vivo incubation. RESULTS: The global response rate was 47% (Response Evaluation Criteria in Solid Tumors rate, 29%; CA125 rate, 63%). Delays in treatment were seen in 24% of cycles largely due to myelosuppression; 15% of day 8 administration was omitted. Peak carboplatin-induced DNA cross-linking was seen by 24 hours. Significant reduction was seen in the repair of in vivo carboplatin-induced DNA cross-links following administration of gemcitabine. CONCLUSION: An enhanced activity of carboplatin in platinum-resistant ovarian cancer may be due to synergy with gemcitabine through inhibition of repair of DNA cross-links. Future studies should explore coadministration of these drugs, as this may be a more effective schedule.
    • Safety and utility of image-guided research biopsies in relapsed high-grade serous ovarian carcinoma-experience of the BriTROC consortium.

      Goranova, T; Ennis, D; Piskorz, A; Macintyre, G; Lewsley, L; Stobo, J; Wilson, C; Kay, D; Glasspool, R; Lockley, M; et al. (2017-03-30)
      Investigating tumour evolution and acquired chemotherapy resistance requires analysis of sequential tumour material. We describe the feasibility of obtaining research biopsies in women with relapsed ovarian high-grade serous carcinoma (HGSC).
    • Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment (ICON8): primary progression free survival analysis results from a GCIG phase 3 randomised controlled trial

      Clamp, Andrew R; James, EC; McNeish, IA; Dean, A; Kim, JW; O'Donnell, DM; Hook, J; Coyle, C; Blagden, S; Brenton, JD; et al. (2019)
      BACKGROUND: Carboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer. METHODS: In this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC-IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m2 paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0á75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3). FINDINGS: Between June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m2 in group 1; 1233 mg/m2 in group 2; 1274 mg/m2 in group 3). By February, 2017, 1018 (65%) patients had experienced disease progression. No significant progression-free survival increase was observed with either weekly regimen (restricted mean survival time 24á4 months [97á5% CI 23á0-26á0] in group 1, 24á9 months [24á0-25á9] in group 2, 25á3 months [23á9-26á9] in group 3; median progression-free survival 17á7 months [IQR 10á6-not reached] in group 1, 20á8 months [11á9-59á0] in group 2, 21á0 months [12á0-54á0] in group 3; log-rank p=0á35 for group 2 vs group 1; group 3 vs 1 p=0á51). Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups. INTERPRETATION: Weekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly European populations.