Karen Carty

Cediranib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial

Summary Background Patients treated with standard chemotherapy for metastatic or relapsed cervical cancer respond poorly to conventional chemotherapy (response achieved in 20–30% of patients) with an overall survival of less than 1 year. High tumour angiogenesis and high concentrations of intratumoural VEGF are adverse prognostic features. Cediranib is a potent tyrosine kinase inhibitor of VEGFR1, 2, and 3. In this trial, we aimed to assess the effect of the addition of cediranib to carboplatin and paclitaxel chemotherapy in patients with metastatic or recurrent cervical cancer. Methods In this randomised, double-blind, placebo-controlled phase 2 trial, which was done in 17 UK cancer treatment centres, patients aged 18 years or older initially diagnosed with metastatic carcinoma or who subsequently developed metastatic disease or local pelvic recurrence after radical treatment that was not amenable to exenterative surgery were recruited. Eligible patients received carboplatin AUC of 5 plus paclitaxel 175 mg/m2 by infusion every 3 weeks for a maximum of six cycles and were randomised centrally (1:1) through a minimisation approach to receive cediranib 20 mg or placebo orally once daily until disease progression. The stratification factors were disease site, disease-free survival after primary therapy or primary stage IVb disease, number of lines of previous treatment, Eastern Cooperative Oncology Group performance status, and investigational site. All patients, investigators, and trial personnel were masked to study drug allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat, and the safety analysis included all patients who received at least one dose of study drug. This trial is registered with the ISCRTN registry, number ISRCTN23516549, and has been completed. Findings Between Aug 19, 2010, and July 27, 2012, 69 patients were enrolled and randomly assigned to cediranib (n=34) or placebo (n=35). After a median follow-up of 24·2 months (IQR 21·9–29·5), progression-free survival was longer in the cediranib group (median 8·1 months [80% CI 7·4–8·8]) than in the placebo group (6·7 months [6·2–7·2]), with a hazard ratio (HR) of 0·58 (80% CI 0·40–0·85; one-sided p=0·032). Grade 3 or worse adverse events that occurred in the concurrent chemotherapy and trial drug period in more than 10% of patients were diarrhoea (five [16%] of 32 patients in the cediranib group vs one [3%] of 35 patients in the placebo group), fatigue (four [13%] vs two [6%]), leucopenia (five [16%] vs three [9%]), neutropenia (10 [31%] vs four [11%]), and febrile neutropenia (five [16%] vs none). The incidence of grade 2–3 hypertension was higher in the cediranib group than in the control group (11 [34%] vs four [11%]). Serious adverse events occurred in 18 patients in the placebo group and 19 patients in the cediranib group. Interpretation Cediranib has significant efficacy when added to carboplatin and paclitaxel in the treatment of metastatic or recurrent cervical cancer. This finding was accompanied by an increase in toxic effects (mainly diarrhoea, hypertension, and febrile neutropenia). Funding Cancer Research UK and AstraZeneca.

Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes: Findings from the Ovarian Cancer Association Consortium

Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. Experimental Design: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. Results: Five SNPs were significantly associated (P ≤ 1.0 × 10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10−6). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤6 × 10−3). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res; 21(23); 5264–76. ©2015 AACR.

First-line therapy for ovarian cancer with carboplatin followed by paclitaxel–gemcitabine (SCOTROC5): A feasibility study and comparative analysis of the SCOTROC series

BACKGROUND We have conducted a series of four feasibility studies in stage Ic-IV ovarian cancer exploring six sequential first-line schedules with the same entry criteria in a total of 339 patients. Here we present the results of the sixth study, and an analysis of the overall series. METHODS In this trial patients received 4 cycles of carboplatin AUC 7 every 3 weeks, followed by 4 cycles of concurrent paclitaxel 175 mg/m(2) (day 1) and gemcitabine 1000 mg/m(2) (days 1 and 8) every 3 weeks. The primary end-point of the trial was feasibility of administering all cycles of planned chemotherapy to >60% of patients. RESULTS Fifty-four patients were recruited to the trial between June 05 and June 06. A total of 40 (74.1%) patients received all 8 cycles of treatment. Reasons for early discontinuation included toxicity (n=8) and disease progression (n=4). The overall response rate was 73.7%, and the median progression free survival (PFS) was 14.2 months with a median follow-up of 24 months. A comparative analysis of all six regimens from the SCOTROC series suggests that the sequential schedule in which paclitaxel was given weekly (median PFS 19.5m) is most effective. CONCLUSION The sequential schedule explored in this trial is feasible, but comparative efficacy analysis suggests that trials involving weekly paclitaxel should be prioritised for further study.

Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci.

Background:Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis.Methods:All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals).Results:The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10−5 (including six with P<5 × 10−8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation.Conclusions:Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.