Publications
328 results found
McGivern N, El-Helali A, Mullan P, et al., 2018, Activation of MAPK signalling results in resistance to saracatinib (AZD0530) in ovarian cancer, Oncotarget, Vol: 9, Pages: 4722-4736, ISSN: 1949-2553
SRC tyrosine kinase is frequently overexpressed and activated in late-stage, poor prognosis ovarian tumours, and preclinical studies have supported the use of targeted SRC inhibitors in the treatment of this disease. The SAPPROC trial investigated the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for the treatment of platinum resistant ovarian cancer; however, this drug combination did not provide any benefit to progression free survival (PFS) of women with platinum resistant disease. In this study we aimed to identify mechanisms of resistance to SRC inhibitors in ovarian cancer cells. Using two complementary strategies; a targeted tumour suppressor gene siRNA screen, and a phospho-receptor tyrosine kinase array, we demonstrate that activation of MAPK signalling, via a reduction in NF1 (neurofibromin) expression or overexpression of HER2 and the insulin receptor, can drive resistance to AZD0530. Knockdown of NF1 in two ovarian cancer cell lines resulted in resistance to AZD0530, and was accompanied with activated MEK and ERK signalling. We also show that silencing of HER2 and the insulin receptor can partially resensitize AZD0530 resistant cells, which was associated with decreased phosphorylation of MEK and ERK. Furthermore, we demonstrate a synergistic effect of combining SRC and MEK inhibitors in both AZD0530 sensitive and resistant cells, and that MEK inhibition is sufficient to completely resensitize AZD0530 resistant cells. This work provides a preclinical rationale for the combination of SRC and MEK inhibitors in the treatment of ovarian cancer, and also highlights the need for biomarker driven patient selection for clinical trials.
MacNab W, Glasspool RM, Shanbhag S, et al., 2018, Outcomes of women not receiving treatment for advanced ovarian cancer in the West of Scotland: a retrospective analysis, EUROPEAN JOURNAL OF GYNAECOLOGICAL ONCOLOGY, Vol: 39, Pages: 58-62, ISSN: 0392-2936
O'Malley DM, Coleman RL, Oza AM, et al., 2018, Results from the phase 3 study ARIEL3: mutations in non-<i>BRCA</i> homologous recombination repair genes confer sensitivity to maintenance treatment with the PARP inhibitor rucaparib in patients with recurrent platinum-sensitive high-grade ovarian carcinoma, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 1535-7163
- Author Web Link
- Cite
- Citations: 1
Weigert M, Binks A, Dowson S, et al., 2017, RIPK3 promotes adenovirus type 5 activity, Cell Death and Disease, Vol: 8, ISSN: 2041-4889
Oncolytic adenoviral mutants infect human malignant cells and replicate selectively within them. This induces direct cytotoxicity that can also trigger profound innate and adaptive immune responses. However, the mechanism by which adenoviruses produce cell death remains uncertain. We previously suggested that type 5 adenoviruses, including the E1A CR2 deletion mutant dl922-947, might induce a novel form of programmed death resembling necroptosis. Here we have investigated the roles of core necrosis proteins RIPK1, RIPK3 and MLKL in the cytotoxicity of dl922-947 and other adenovirus serotypes. By electron microscopy, we show that dl922-947 induces similar necrotic morphology as TSZ treatment (TNF-α, Smac mimetic, zVAD.fmk). However, dl922-947-mediated death is independent of TNF-α signalling, does not require RIPK1 and does not rely upon the presence of MLKL. However, inhibition of caspases, specifically caspase-8, induces necroptosis that is RIPK3 dependent and significantly enhances dl922-947 cytotoxicity. Moreover, using CRISPR/Cas9 gene editing, we demonstrate that the increase in cytotoxicity seen upon caspase inhibition is also MLKL dependent. Even in the absence of caspase inhibition, RIPK3 expression promotes dl922-947 and wild-type adenovirus type 5 efficacy both in vitro and in vivo. Together, these results suggest that adenovirus induces a form of programmed necrosis that differs from classical TSZ necroptosis.
Walton JB, Farquharson M, Mason S, et al., 2017, CRISPR/Cas9-derived models of ovarian high grade serous carcinoma targeting Brca1, Pten and Nf1, and correlation with platinum sensitivity., Scientific Reports, Vol: 7, ISSN: 2045-2322
Transplantable murine models of ovarian high grade serous carcinoma (HGSC) remain an important research tool. We previously showed that ID8, a widely-used syngeneic model of ovarian cancer, lacked any of the frequent mutations in HGSC, and used CRISPR/Cas9 gene editing to generate derivatives with deletions in Trp53 and Brca2. Here we have used one ID8 Trp53 -/- clone to generate further mutants, with additional mutations in Brca1, Pten and Nf1, all of which are frequently mutated or deleted in HGSC. We have also generated clones with triple deletions in Trp53, Brca2 and Pten. We show that ID8 Trp53 -/-;Brca1 -/- and Trp53 -/-;Brca2 -/- cells have defective homologous recombination and increased sensitivity to both platinum and PARP inhibitor chemotherapy compared to Trp53 -/-. By contrast, loss of Pten or Nf1 increases growth rate in vivo, and reduces survival following cisplatin chemotherapy in vivo. Finally, we have also targeted Trp53 in cells isolated from a previous transgenic murine fallopian tube carcinoma model, and confirmed that loss of p53 expression in this second model accelerates intraperitoneal growth. Together, these CRISPR-generated models represent a new and simple tool to investigate the biology of HGSC, and the ID8 cell lines are freely available to researchers.
Blagden SP, Cook A, Poole C, et al., 2017, QUALITY OF LIFE WITH WEEKLY, DOSE-DENSE VERSUS STANDARD CHEMOTHERAPY FOR OVARIAN CANCER IN THE ICON8 STUDY, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 14-14, ISSN: 1048-891X
- Author Web Link
- Cite
- Citations: 1
Bookman MA, Okamoto A, Stuart G, et al., 2017, Harmonising clinical trials within the Gynecologic Cancer InterGroup: consensus and unmet needs from the Fifth Ovarian Cancer Consensus Conference, ANNALS OF ONCOLOGY, Vol: 28, Pages: 30-35, ISSN: 0923-7534
- Author Web Link
- Cite
- Citations: 33
Blagden SP, Cook A, Poole C, et al., 2017, QUALITY OF LIFE WITH WEEKLY, DOSE-DENSE VERSUS STANDARD CHEMOTHERAPY FOR OVARIAN CANCER IN THE ICON8 STUDY, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 1919-1919, ISSN: 1048-891X
Coleman RL, Oza AM, Lorusso D, et al., 2017, Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial, Lancet, Vol: 390, Pages: 1949-1961, ISSN: 0140-6736
BACKGROUND: Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0-1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients wit
Cooke SL, Ennis D, Evers L, et al., 2017, The driver mutational landscape of ovarian squamous cell carcinomas arising in mature cystic teratoma., Clinical Cancer Research, Vol: 23, Pages: 7633-7640, ISSN: 1078-0432
PURPOSE: We sought to identify the genomic abnormalities in squamous cell carcinomas (SCC) arising in ovarian mature cystic teratoma (MCT), a rare gynaecological malignancy of poor prognosis. EXPERIMENTAL DESIGN: We performed copy number, mutational state and zygosity analysis of 151 genes in SCC arising in MCT (n=25) using next-generation sequencing. The presence of high/intermediate risk HPV genotypes was assessed by quantitative PCR. Genomic events were correlated with clinical features and outcome Results. MCT had a low mutation burden with a mean of only 1 mutation per case. Zygosity analyses of MCT indicated four separate patterns, suggesting that MCT can arise from errors at various stages of oogenesis. A total of 244 abnormalities were identified in 79 genes in MCT-associated SCC, and the overall mutational burden was high (mean 10.2 mutations per megabase). No SCC was positive for HPV. The most frequently altered genes in SCC were TP53 (20/25 cases, 80%), PIK3CA (13/25 cases, 52%) and CDKN2A (11/25 cases, 44%). Mutation in TP53 was associated with improved overall survival. In 8/20 cases with TP53 mutations, two or more variants were identified, which were bi-allelic. CONCLUSIONS: Ovarian SCC arising in MCT has a high mutational burden with TP53 mutation the most common abnormality. The presence TP53 mutation is a good prognostic factor. SCC arising in MCT share similar mutation profiles to other SCC. Given their rarity, they should be included in basket studies that recruit patients with SCC of other organs.
Oza AM, Tinker AV, Oaknin A, et al., 2017, Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: Integrated analysis of data from Study 10 and ARIEL2., Gynecologic Oncology, Vol: 147, Pages: 267-275, ISSN: 0090-8258
OBJECTIVE: An integrated analysis was undertaken to characterize the antitumor activity and safety profile of the oral poly(ADP-ribose) polymerase inhibitor rucaparib in patients with relapsed high-grade ovarian carcinoma (HGOC). METHODS: Eligible patients from Study 10 (NCT01482715) and ARIEL2 (NCT01891344) who received a starting dose of oral rucaparib 600mg twice daily (BID) with or without food were included in these analyses. The integrated efficacy population included patients with HGOC and a deleterious germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation who received at least two prior chemotherapies and were sensitive, resistant, or refractory to platinum-based chemotherapy. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR) and progression-free survival (PFS). The integrated safety population included patients with HGOC who received at least one dose of rucaparib 600mg BID, irrespective of BRCA1/2 mutation status and prior treatments. RESULTS: In the efficacy population (n=106), ORR was 53.8% (95% confidence interval [CI], 43.8-63.5); 8.5% and 45.3% of patients achieved complete and partial responses, respectively. Median DOR was 9.2months (95% CI, 6.6-11.6). In the safety population (n=377), the most frequent treatment-emergent adverse events (AEs) were nausea, asthenia/fatigue, vomiting, and anemia/hemoglobin decreased. The most common grade ≥3 treatment-emergent AE was anemia/hemoglobin decreased. Treatment-emergent AEs led to treatment interruption, dose reduction, and treatment discontinuation in 58.6%, 45.9%, and 9.8% of patients, respectively. No treatment-related deaths occurred. CONCLUSIONS: Rucaparib has antitumor activity in advanced BRCA1/2-mutated HGOC and a manageable safety profile.
Clamp AR, McNeish I, Dean A, et al., 2017, ICON8: A GCIG phase III randomised trial evaluating weekly dosedense chemotherapy integration in first- line epithelial ovarian/fallopian tube/primary peritoneal carcinoma (EOC) treatment: Results of primary progression- free survival (PFS) analysis, 42nd European-Society-for-Medical-Oncology Congress (ESMO), Publisher: OXFORD UNIV PRESS, ISSN: 0923-7534
- Author Web Link
- Cite
- Citations: 19
De Munck J, Binks A, McNeish IA, et al., 2017, Oncolytic virus-induced cell death and immunity: a match made in heaven?, Journal of Leukocyte Biology, Vol: 102, Pages: 631-643, ISSN: 0741-5400
Our understanding of the mechanisms responsible for cancer development has increased enormously over the last decades. However, for many cancers, this has not been translated into a significant improvement in overall survival, and overall mortality remains high. Treatment for many malignancies remains based on surgery, chemotherapy, and radiotherapy. Significant progress has been made toward the development of more specific, more potent, and less invasive treatment modalities, but such targeted therapies remain the exception for most cancers. Thus, cancer therapies based on a different mechanism of action should be explored. The immune system plays an important role in keeping tumor growth at bay. However, in many cases, these responses are not strong enough to keep tumor growth under control. Thus, immunotherapy aims to boost the immune system to suppress tumor growth efficiently. This has been demonstrated by the recent successes of immune checkpoint therapy in several cancers. Oncolytic viruses (OVs) are another exciting class of immunotherapy agent. As well as replicating selectively within and killing tumor cells, OVs are able to elicit potent anti-tumor immune responses. Therapeutic vaccination with OVs, also referred to as cancer virotherapy, can thus be tailored to elicit vigorous cellular immune responses and even target individual malignancies in a personalized manner. In this review, we will describe the intricate link among oncolytic virotherapy, tumor immunology, and immunogenic cell death (ICD) and discuss ways to harness optimally their potential for future cancer therapy.
Kondrashova O, Nguyen M, Shield-Artin K, et al., 2017, Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma, Cancer Discovery, Vol: 7, Pages: 984-998, ISSN: 2159-8290
High-grade epithelial ovarian carcinomas containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and PARP inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pretreatment and postprogression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase II study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed ovarian carcinoma. In 6 of 12 pretreatment biopsies, a truncation mutation in BRCA1, RAD51C, or RAD51D was identified. In five of six paired postprogression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft, as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations.
Swisher EM, Harrell MI, Lin K, et al., 2017, BRCA1 and RAD51C promoter hypermethylation confer sensitivity to the PARP inhibitor rucaparib in patients with relapsed, platinum-sensitive ovarian carcinoma in ARIEL2 Part 1, Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE, Pages: 5-5, ISSN: 0090-8258
- Author Web Link
- Cite
- Citations: 12
Konecny GE, Oza AM, Tinker AV, et al., 2017, Rucaparib in patients with relapsed, primary platinum-sensitive high-grade ovarian carcinoma with germline or somatic <i>BRCA</i> mutations: Integrated summary of efficacy and safety from the phase II study ARIEL2, Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE, Pages: 2-2, ISSN: 0090-8258
- Author Web Link
- Cite
- Citations: 13
Banerjee SN, Lewsley L-A, Clamp AR, et al., 2017, OCTOPUS: A randomised, multi-centre phase II umbrella trial of weekly paclitaxel plus /- novel agents in platinum-resistant ovarian cancer-Vistusertib (AZD2014)., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Glasspool RM, Blagden SP, Lockley M, et al., 2017, A phase I trial of the oral hedgehog inhibitor taladegib (LY2940680) in combination with weekly paclitaxel in patients with advanced, solid tumours., 53rd Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
- Author Web Link
- Cite
- Citations: 1
Babic A, Cramer DW, Kelemen LE, et al., 2017, Predictors of pretreatment CA125 at ovarian cancer diagnosis: a pooled analysis in the Ovarian Cancer Association Consortium, CANCER CAUSES & CONTROL, Vol: 28, Pages: 459-468, ISSN: 0957-5243
- Author Web Link
- Cite
- Citations: 15
McGee J, Bookman M, Harter P, et al., 2017, Fifth Ovarian Cancer Consensus Conference: individualized therapy and patient factors, ANNALS OF ONCOLOGY, Vol: 28, Pages: 702-710, ISSN: 0923-7534
Goranova T, Ennis D, Piskorz AM, et al., 2017, Safety and utility of image-guided research biopsies in relapsed high-grade serous ovarian carcinoma-experience of the BriTROC consortium, British Journal of Cancer, Vol: 116, Pages: 1294-1301, ISSN: 1532-1827
Background: 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).Methods: Women with relapsed ovarian HGSC underwent either image-guided biopsy or intra-operative biopsy during secondary debulking, and samples were fixed in methanol-based fixative. Tagged-amplicon sequencing was performed on biopsy DNA.Results: We screened 519 patients in order to enrol 220. Two hundred and two patients underwent successful biopsy, 118 of which were image-guided. There were 22 study-related adverse events (AE) in the image-guided biopsies, all grades 1 and 2; pain was the commonest AE. There were pre-specified significant AE in 3/118 biopsies (2.5%). 87% biopsies were fit-for-purpose for genomic analyses. Median DNA yield was 2.87 μg, and was higher in biopsies utilising 14 G or 16 G needles compared to 18 G. TP53 mutations were identified in 94.4% patients.Conclusions: Obtaining tumour biopsies for research in relapsed HGSC is safe and feasible. Adverse events are rare. The large majority of biopsies yield sufficient DNA for genomic analyses—we recommend use of larger gauge needles and methanol fixation for such biopsies, as DNA yields are higher but with no increase in AEs.
Phelan CM, Kuchenbaecker KB, Tyrer JP, et al., 2017, Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer, NATURE GENETICS, Vol: 49, Pages: 680-691, ISSN: 1061-4036
To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.
Sucheston-Campbell LE, Cannioto R, Clay AI, et al., 2017, No Evidence That Genetic Variation in the Myeloid-Derived Suppressor Cell Pathway Influences Ovarian Cancer Survival, CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, Vol: 26, Pages: 420-424, ISSN: 1055-9965
- Author Web Link
- Cite
- Citations: 2
Leung EY, Weigert M, Walton JB, et al., 2017, Role of innate immune responses in the effectiveness of oncolytic adenovirus as an anticancer agent, Spring Meeting on Clinician Scientists in Training, Publisher: ELSEVIER SCIENCE INC, Pages: 61-61, ISSN: 0140-6736
Hernandez-Fernaud JR, Ruengeler E, Casazza A, et al., 2017, Secreted CLIC3 drives cancer progression through its glutathione-dependent oxidoreductase activity., Nature Communications, Vol: 8, ISSN: 2041-1723
The secretome of cancer and stromal cells generates a microenvironment that contributes to tumour cell invasion and angiogenesis. Here we compare the secretome of human mammary normal and cancer-associated fibroblasts (CAFs). We discover that the chloride intracellular channel protein 3 (CLIC3) is an abundant component of the CAF secretome. Secreted CLIC3 promotes invasive behaviour of endothelial cells to drive angiogenesis and increases invasiveness of cancer cells both in vivo and in 3D cell culture models, and this requires active transglutaminase-2 (TGM2). CLIC3 acts as a glutathione-dependent oxidoreductase that reduces TGM2 and regulates TGM2 binding to its cofactors. Finally, CLIC3 is also secreted by cancer cells, is abundant in the stromal and tumour compartments of aggressive ovarian cancers and its levels correlate with poor clinical outcome. This work reveals a previously undescribed invasive mechanism whereby the secretion of a glutathione-dependent oxidoreductase drives angiogenesis and cancer progression by promoting TGM2-dependent invasion.
Oaknin A, Oza A, Tinker AV, et al., 2017, Integrated efficacy and safety analysis of the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib in patients (pts) with high-grade ovarian carcinoma (HGOC), ECCO European Cancer Congress, Publisher: ELSEVIER SCI LTD, Pages: S95-S95, ISSN: 0959-8049
- Author Web Link
- Cite
- Citations: 2
Kar SP, Adler E, Tyrer J, et al., 2017, Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci, BRITISH JOURNAL OF CANCER, Vol: 116, Pages: 524-535, ISSN: 0007-0920
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.
Swisher EM, Lin KK, Oza AM, et al., 2017, Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial, Lancet Oncology, Vol: 18, Pages: 75-87, ISSN: 1470-2045
BackgroundPoly(ADP-ribose) polymerase (PARP) inhibitors have activity in ovarian carcinomas with homologous recombination deficiency. Along with BRCA1 and BRCA2 (BRCA) mutations genomic loss of heterozygosity (LOH) might also represent homologous recombination deficiency. In ARIEL2, we assessed the ability of tumour genomic LOH, quantified with a next-generation sequencing assay, to predict response to rucaparib, an oral PARP inhibitor.MethodsARIEL2 is an international, multicentre, two-part, phase 2, open-label study done at 49 hospitals and cancer centres in Australia, Canada, France, Spain, the UK, and the USA. In ARIEL2 Part 1, patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma were classified into one of three predefined homologous recombination deficiency subgroups on the basis of tumour mutational analysis: BRCA mutant (deleterious germline or somatic), BRCA wild-type and LOH high (LOH high group), or BRCA wild-type and LOH low (LOH low group). We prespecified a cutoff of 14% or more genomic LOH for LOH high. Patients began treatment with oral rucaparib at 600 mg twice per day for continuous 28 day cycles until disease progression or any other reason for discontinuation. The primary endpoint was progression-free survival. All patients treated with at least one dose of rucaparib were included in the safety analyses and all treated patients who were classified were included in the primary endpoint analysis. This trial is registered with ClinicalTrials.gov, number NCT01891344. Enrolment into ARIEL2 Part 1 is complete, although an extension (Part 2) is ongoing.Findings256 patients were screened and 206 were enrolled between Oct 30, 2013, and Dec 19, 2014. At the data cutoff date (Jan 18, 2016), 204 patients had received rucaparib, with 28 patients remaining in the study. 192 patients could be classified into one of the three predefined homologous recombination deficiency subgroups: BRCA mutant (n=40), LOH high (n=82), or LOH low (n=70). Tum
Southey MC, Goldgar DE, Winqvist R, et al., 2016, <i>PALB2</i>, <i>CHEK2</i> and <i>ATM</i> rare variants and cancer risk: data from COGS, JOURNAL OF MEDICAL GENETICS, Vol: 53, Pages: 800-811, ISSN: 0022-2593
- Author Web Link
- Cite
- Citations: 148
Piskorz AM, Lin KK, Morris J, et al., 2016, Feasibility of monitoring response to the PARP inhibitor rucaparib with targeted deep sequencing of circulating tumor DNA (ctDNA) in women with high grade ovarian carcinoma on the ARIEL2 trial, 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Publisher: ELSEVIER SCI LTD, Pages: S123-S123, ISSN: 0959-8049
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.