Imperial College London

ProfessorIainMcNeish

Faculty of MedicineDepartment of Surgery & Cancer

Chair in Oncology
 
 
 
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Contact

 

+44 (0)20 7594 2185i.mcneish Website

 
 
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Assistant

 

Ms Sophie Lions +44 (0)20 7594 2792

 
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Location

 

G036Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

194 results found

Clamp AR, James EC, McNeish IA, Dean A, Kim J-W, O'Donnell DM, Hook J, Coyle C, Blagden S, Brenton JD, Naik R, Perren T, Sundar S, Cook AD, Gopalakrishnan GS, Gabra H, Lord R, Dark G, Earl HM, Hall M, Banerjee S, Glasspool RM, Jones R, Williams S, Swart AM, Stenning S, Parmar M, Kaplan R, Ledermann JAet al., 2019, 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, The Lancet, Vol: 394, Pages: 2084-2095, ISSN: 0140-6736

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 0·75 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 (med

Journal article

Spear S, McNeish IA, Capasso M, 2019, Generation of orthotopic pancreatic tumors and ex vivo characterization of tumor-infiltrating T cell cytotoxicity., Journal of Visualized Experiments, Vol: 154, Pages: 1-11, ISSN: 1940-087X

In vivo models of pancreatic cancer provide invaluable tools for studying disease dynamics, immune infiltration and new therapeutic strategies. The orthotopic murine model can be performed on large cohorts of immunocompetent mice simultaneously, is relatively inexpensive and preserves the cognate tissue microenvironment. The quantification of T cell infiltration and cytotoxic activity within orthotopic tumors provides a useful indicator of an antitumoral response. This protocol describes the methodology for surgical generation of orthotopic pancreatic tumors by injection of a low number of syngeneic tumor cells resuspended in 5 µL basement membrane directly into the pancreas. Mice bearing orthotopic tumors take approximately 30 days to reach endpoint, at which point tumors can be harvested and processed for characterization of tumor-infiltrating T cell activity. Rapid enzymatic digestion using collagenase and DNase allows a single-cell suspension to be extracted from tumors. The viability and cell surface markers of immune cells extracted from the tumor are preserved; therefore, it is appropriate for multiple downstream applications, including flow-assisted cell sorting of immune cells for culture or RNA extraction, flow cytometry analysis of immune cell populations. Here, we describe the ex vivo stimulation of T cell populations for intracellular cytokine quantification (IFNγ and TNFα) and degranulation activity (CD107a) as a measure of overall cytotoxicity. Whole-tumor digests were stimulated with phorbol myristate acetate and ionomycin for 5 h, in the presence of anti-CD107a antibody in order to upregulate cytokine production and degranulation. The addition of brefeldin A and monensin for the final 4 h was performed to block extracellular transport and maximize cytokine detection. Extra- and intra-cellular staining of cells was then performed for flow cytometry analysis, where the proportion of IFNγ+, TNFα+ and CD107a+ CD4+ and CD8+

Journal article

Li C, Course MM, McNeish IA, Drescher CW, Valdmanis PN, Lieber Aet al., 2019, Prophylactic in vivo hematopoietic stem cell gene therapy with an immune checkpoint inhibitor reverses tumor growth in syngeneic mouse tumor models., Cancer Res

Population-wide testing for cancer-associated mutations has established that more than one-fifth of ovarian and breast carcinomas are associated with inherited risk. Salpingo-oophorectomy and/or mastectomy are currently the only effective options offered to women with high-risk germ-line mutations. Our goal here is to develop a long-lasting approach that provides immuno-prophylaxis for mutation carriers. Our approach leverages the fact that at early stages, tumors recruit hematopoietic stem/progenitor cells (HSPCs) from the bone marrow and differentiate them into tumor-supporting cells. We developed a technically simple technology to genetically modify HSPCs in vivo. The technology involves HSPC mobilization and intravenous injection of an integrating HDAd5/35++ vector. In vivo HSPC transduction with a GFP-expressing vector and subsequent implantation of syngeneic tumor cells showed >80% GFP-marking in tumor infiltrating leukocytes. To control expression of transgenes, we developed a miRNA regulation system that is activated only when HSPCs are recruited to and differentiated by the tumor. We tested our approach using the immune checkpoint inhibitor antiPD-L1-gamma1 as an effector gene. In in vivo HSPC-transduced mice with implanted mouse mammary carcinoma (MMC) tumors, after initial tumor growth, tumors regressed and did not recur. Conventional treatment with an anti-PD-L1 monoclonal antibody had no significant anti-tumor effect, indicating that early, self-activating expression of antiPD-L1-gamma1 can overcome the immunosuppressive environment in MMC tumors. The efficacy and safety of this approach was further validated in an ovarian cancer model with typical germ-line mutations (ID8 p53-/- brca2-/-), both in a prophylactic and therapeutic setting. This HSPC gene therapy approach has potential for clinical translation.

Journal article

Macintyre G, Goranova TE, De Silva D, Ennis D, Piskorz AM, Eldridge M, Sie D, Lewsley L-A, Hanif A, Wilson C, Dowson S, Glasspool RM, Lockley M, Brockbank E, Montes A, Walther A, Sundar S, Edmondson R, Hall GD, Clamp A, Gourley C, Hall M, Fotopoulou C, Gabra H, Paul J, Supernat A, Millan D, Hoyle A, Bryson G, Nourse C, Mincarelli L, Sanchez LN, Ylstra B, Jimenez-Linan M, Moore L, Hofmann O, Markowetz F, McNeish IA, Brenton JDet al., 2019, COPY-NUMBER SIGNATURES AND MUTATIONAL PROCESSES IN HIGH GRADE SEROUS OVARIAN CARCINOMA, 12th Rivkin-Centre Biennial Ovarian Cancer Research Symposium, Publisher: AMER ASSOC CANCER RESEARCH, Pages: 64-64, ISSN: 1078-0432

Conference paper

Kristeleit RS, Oaknin A, Ray-Coquard I, Leary A, Balmaña J, Drew Y, Oza AM, Shapira-Frommer R, Domchek SM, Cameron T, Maloney L, Goble S, Lorusso D, Ledermann JA, McNeish IAet al., 2019, Antitumor activity of the poly(ADP-ribose) polymerase inhibitor rucaparib as monotherapy in patients with platinum-sensitive, relapsed, BRCA-mutated, high-grade ovarian cancer, and an update on safety, International Journal of Gynecologic Cancer, Vol: 29, Pages: 1396-1404, ISSN: 1048-891X

Objective To report results from an integrated efficacy and safety analysis supporting the European Commission's approval of the poly(ADP-ribose) polymerase inhibitor rucaparib as monotherapy treatment for relapsed, platinum-sensitive, BRCA-mutated ovarian cancer.Methods Efficacy was analyzed in platinum-sensitive patients from Study 10 (NCT01482715) and ARIEL2 (NCT01891344) who had high-grade serous or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer and a deleterious BRCA1 or BRCA2 mutation and received two or more prior chemotherapies (including two or more platinum-based therapies). The primary end point was investigator-assessed, confirmed objective response rate (visit cut-off: April 10, 2017). Safety was analyzed in patients with ovarian cancer, regardless of BRCA mutation status or lines of prior chemotherapies, who received at least one dose of rucaparib 600 mg in either study (visit cut-off: December 31, 2017).Results In the integrated platinum-sensitive efficacy population (n=79), objective response rate was 64.6% (95% CI, 53.0 to 75.0); 10.1% (8/79) of patients had a complete response and 54.4% (43/79) had a partial response. Median duration of response was 294 days (95% CI, 224 to 393). In the integrated safety population (n=565), the most common any-grade treatment-emergent adverse events were nausea (77.7%, 439/565), asthenia/fatigue (74.7%, 422/565), vomiting (45.8%, 259/565), and hemoglobin decreased (44.2%, 250/565). Treatment-emergent adverse events led to treatment interruption, dose reduction, or discontinuation in 60.2% (340/565), 46.0% (260/565), and 16.8% (95/565) of patients.Conclusions In patients with platinum-sensitive, BRCA-mutated ovarian cancer, rucaparib demonstrated antitumor activity and is the first and currently the only poly(ADP-ribose) polymerase inhibitor approved by the European Commission as treatment for this population. The safety analysis used a more recent visit cut-off date and

Journal article

McNeish IA, Moreno V, Jayson G, Roxburgh P, Barretina Ginesta MP, Garcia-Donas J, Anton Torres A, Michael A, Brown R, Krige D, Bendall J, Di Genova G, McElwaine-Johnn Het al., 2019, OCTAVE: A phase I study of enadenotucirev, an oncolytic group B adenovirus, in combination with weekly paclitaxel in platinum-resistant epithelial ovarian cancer, 44th Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: OXFORD UNIV PRESS, Pages: 421-421, ISSN: 0923-7534

Conference paper

Kristeleit RS, Oza AM, Oaknin A, Aghajanian C, Tinker AV, Tredan O, O'Malley DM, Leary A, Konecny GE, Lorusso D, Weberpals JI, Goble S, Maloney L, Cameron T, Swisher E, McNeish IA, Shapira-Frommer R, Ledermann JA, Coleman RLet al., 2019, Integrated safety analysis of the poly (ADP-ribose) polymerase (PARP) inhibitor rucaparib in patients (pts) with ovarian cancer in the treatment and maintenance settings, 44th Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: OXFORD UNIV PRESS, Pages: 409-+, ISSN: 0923-7534

Conference paper

Spiliopoulou P, Spear S, Dowson S, Mason S, Blyth K, Fuchter M, Brown B, McNeish IAet al., 2019, Inhibiting Ehmt2 and Ezh2 histone methyltransferases alters the immune microenvironment in a Trp53-/- murine ovarian cancer model, 44th Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: OXFORD UNIV PRESS, Pages: 784-784, ISSN: 0923-7534

Conference paper

Banerjee S, Lewsley L-A, Clamp AR, Krell J, Herbertson R, Glasspool RM, Orbegoso C, Green C, Kristeleit RS, Gourley C, Cambell C, Banerji U, Shepherd C, Brugger W, Chudleigh L, Hanif A, McNeish IA, Paul Jet al., 2019, OCTOPUS: A randomised, multi-centre phase II umbrella trial of weekly paclitaxel plus /- novel agents in platinum-resistant ovarian cancer: Vistusertib, 44th Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: OXFORD UNIV PRESS, Pages: 403-+, ISSN: 0923-7534

Conference paper

McNeish I, Gabra H, ICON8: A GCIG phase III randomised controlled trial evaluating weekly dose- dense chemotherapy in first-line epithelial ovarian/fallopian tube/primary peritoneal carcinoma (EOC) treatment: primary progression free survival analysis results, The Lancet, ISSN: 0140-6736

Background Carboplatin and paclitaxel administered every three weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer (EOC). The Japanese JGOG3016 trial demonstrated a significant improvement in progression-free (PFS) and overall survival (OS) with dose-dense weekly paclitaxel and three-weekly carboplatin. We compared efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European EOC population. Methods In this phase 3 trial, women with newly diagnosed FIGO stage Ic-IV EOC were randomised 1:1:1 toArm 1 (carboplatin (AUC5/6) and paclitaxel (175mg/m2) every 3 weeks), Arm 2 (carboplatin (AUC5/6)every 3 weeks and paclitaxel (80mg/m2) weekly) or Arm 3 (carboplatin (AUC2) and paclitaxel (80mg/m2) weekly). Patients entered after immediate primary surgery, or prior to neo-adjuvant chemotherapy before planned delayed primary surgery. An intention-to-treat primary PFS efficacy analysis compared Arm 2 vs 1 and Arm 3 vs 1. Findings 1566 women were randomised. 72%, 60% and 63% completed 6 protocol-defined treatment cycles in Arms 1, 2 and 3 respectively, although 90%, 89% and 85% completed 6 platinum-based chemotherapy cycles. Paclitaxel dose-intensification was achieved with weekly treatment (mediantotal paclitaxel dose 1011; 1234; 1274 mg/m2). Although Grade 3/4 toxicity increased with weekly treatment, this was predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across arms. By February 2017, 64% patients had experienced disease progression. No significant PFS increase was observed with either weekly regimen (log-rank Arm 2vs1 p=0.3532; Arm 3vs1 p=0.5130, non-proportionality p=0.0297, restricted mean survival time = 24.4; 24.9; 25.3 months in Arms 1, 2, 3 with 97.5% CI: 23.0 to 26.0; 24.0 to 25.9; 23.9 to 26.9 months respectively). Interpretation Weekly dose-dense chemotherapy can be delivered successfully as first-line EOC treatment but does not significa

Journal article

Cohen PA, Powell A, Böhm S, Gilks CB, Stewart CJR, Meniawy TM, Bulsara M, Avril S, Brockbank EC, Bosse T, de Azevedo Focchi GR, Ganesan R, Glasspool RM, Howitt BE, Kim H-S, Lee J-Y, Le ND, Lockley M, Manchanda R, Mandalia T, McCluggage WG, McNeish I, Midha D, Srinivasan R, Tan YY, van der Griend R, Yunokawa M, Zannoni GF, HGSC CRS Collaborative Network Supplementary 1, Singh Net al., 2019, Pathological chemotherapy response score is prognostic in tubo-ovarian high-grade serous carcinoma: a systematic review and meta-analysis of individual patient data, Gynecologic Oncology, Vol: 154, Pages: 441-448, ISSN: 0090-8258

ObjectiveThere is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT.MethodsWe established an international collaboration to conduct a systematic review and meta-analysis, pooling individual patient data from 16 sites in 11 countries. Patients had stage IIIC/IV HGSC, 3–4 NACT cycles and >6-months follow-up. Random effects models were used to derive combined odds ratios in the pooled population to investigate associations between CRS and progression free and overall survival (PFS and OS).Results877 patients were included from published and unpublished studies. Median PFS and OS were 15 months (IQR 5–65) and 28 months (IQR 7–92) respectively. CRS3 was seen in 249 patients (28%). The pooled hazard ratios (HR) for PFS and OS for CRS3 versus CRS1/CRS2 were 0·55 (95% CI, 0·45–0·66; P < 0·001) and 0·65 (95% CI 0·50–0·85, P = 0·002) respectively; no heterogeneity was identified (PFS: Q = 6·42, P = 0·698, I2 = 0·0%; OS: Q = 6·89, P = 0·648, I2 = 0·0%). CRS was significantly associated with PFS and OS in multivariate models adjusting for age and stage. Of 306 patients with known germline BRCA1/2 status, those with BRCA1/2 mutations (n = 80) were more likely to achieve CRS3 (P = 0·027).ConclusionsCRS3 was significantly associated with improved PFS and OS compared to CRS1/2. This validation of CRS in a real-world setting demonstrates it to be a robust and reproducible biomarker with potential to be incorporated into therapeutic decision-making and clinical

Journal article

Colombo N, Sessa C, du Bois A, Ledermann J, McCluggage WG, McNeish I, Morice P, Pignata S, Ray-Coquard I, Vergote I, Baert T, Belaroussi I, Dashora A, Olbrecht S, Planchamp F, Querleu Det al., 2019, ESMO-ESGO consensus conference recommendations on ovarian cancer: Pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease, International Journal of Gynecological Cancer, Vol: 29, Pages: 728-760, ISSN: 1048-891X

The development of guidelines is one of the core activities of the European Society for Medical Oncology (ESMO) and European Society of Gynaecologial Oncology (ESGO), as part of the mission of both societies to improve the quality of care for patients with cancer across Europe. ESMO and ESGO jointly developed clinically-relevant and evidence-based guidelines in several selected areas in order to improve the quality of care for women with ovarian cancer. The ESMO-ESGO consensus conference on ovarian cancer was held on 12-14 April 2018 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of ovarian cancer. Before the conference, the expert panel worked on five clinically relevant questions regarding ovarian cancer relating to each of the following four areas: pathology and molecular biology, early-stage and borderline tumours, advanced stage disease and recurrent disease. Relevant scientific literature, as identified using a systematic search, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. The recommendations presented here are thus based on the best available evidence and expert agreement. This article presents the recommendations of this ESMO-ESGO consensus conference, together with a summary of evidence supporting each recommendation.

Journal article

Goranova T, Ennis D, Piskorz AM, Macintyre G, Lewsley LA, Stobo J, Wilson C, Kay D, Glasspool RM, Lockley M, Brockbank E, Montes A, Walther A, Sundar S, Edmondson R, Hall GD, Clamp A, Gourley C, Hall M, Fotopoulou C, Gabra H, Freeman S, Moore L, Jimenez-Linan M, Paul J, Brenton JD, McNeish IA, BriTROC investigatorset al., 2019, Correction: 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: 120, ISSN: 0007-0920

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.

Journal article

Bagnoli M, Shi TY, Gourley C, Speiser P, Reuss A, Nijman HW, Creutzberg CL, Scholl S, Negrouk A, Brady MF, Hasegawa K, Oda K, McNeish IA, Kohn EC, Oza AM, MacKay H, Millan D, Bennett K, Scott C, Mezzanzanica Det al., 2019, Gynecological cancers translational, research implementation, and harmonization: Gynecologic Cancer InterGroup consensus and still open questions, Cells, Vol: 8, ISSN: 2073-4409

In the era of personalized medicine, the introduction of translational studies in clinical trials has substantially increased their costs, but provides the possibility of improving the productivity of trials with a better selection of recruited patients. With the overall goal of creating a roadmap to improve translational design for future gynecological cancer trials and of defining translational goals, a main discussion was held during a brainstorming day of the Gynecologic Cancer InterGroup (GCIG) Translational Research Committee and overall conclusions are here reported. A particular emphasis was dedicated to the new frontier of the immunoprofiling of gynecological cancers. The discussion pointed out that to maximize patients’ benefit, translational studies should be integral to clinical trial design with standardization and optimization of procedures including a harmonization program of Standard Operating Procedures. Pathology-reviewed sample collection should be mandatory and ensured by dedicated funding. Biomarker validation and development should be made public and transparent to ensure rapid progresses with positive outcomes for patients. Guidelines/templates for patients’ informed consent are needed. Importantly for the public, recognized goals are to increase the involvement of advocates and to improve the reporting of translational data in a forum accessible to patients.

Journal article

Yang Y, Wu L, Shu X, Lu Y, Shu X-O, Cai Q, Beeghly-Fadiel A, Li B, Ye F, Berchuck A, Anton-Culver H, Banerjee S, Benitez J, Bjørge L, Brenton JD, Butzow R, Campbell IG, Chang-Claude J, Chen K, Cook LS, Cramer DW, DeFazio A, Dennis J, Doherty JA, Dork T, Eccles DM, Velez Edwards D, Fasching PA, Fortner RT, Gayther SA, Giles GG, Glasspool RM, Goode EL, Goodman MT, Gronwald J, Harris HR, Heitz F, Hildebrandt MAT, Høgdall E, Høgdall CK, Huntsman DG, Kar SP, Karlan BY, Kelemen LE, Kiemeney LA, Kjaer SK, Koushik A, Lambrechts D, Le ND, Levine DA, Massuger LFAG, Matsuo K, May T, McNeish IA, Menon U, Modugno F, Monteiro AN, Moorman PG, Moysich KB, Ness RB, Nevanlinna H, Olsson H, Onland-Moret NC, Park SK, Paul J, Pearce CL, Pejovic T, Phelan CM, Pike MC, Ramus SJ, Riboli E, Rodríguez-Antona C, Romieu I, Sandler DP, Schildkraut JM, Setiawan VW, Shan K, Siddiqui N, Sieh W, Stampfer MJ, Sutphen R, Swerdlow AJ, Szafron LM, Teo SH, Tworoger SS, Tyrer JP, Webb PM, Wentzensen N, White E, Willett WC, Wolk A, Woo YL, Wu AH, Yan L, Yannoukakos D, Chenevix-Trench G, Sellers TA, Pharoah PDP, Zheng W, Long Jet al., 2019, Genetic data from nearly 63,000 women of European descent predicts DNA methylation biomarkers and epithelial ovarian cancer risk, Cancer Research, Vol: 79, Pages: 505-517, ISSN: 1538-7445

DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N=1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P<7.94×10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27 and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression.

Journal article

Lin KK, Harrell MI, Oza AM, Oaknin A, Ray-Coquard I, Tinker AV, Helman E, Radke MR, Say C, Vo L-T, Mann E, Isaacson JD, Maloney L, O'Malley DM, Chambers SK, Kaufmann SH, Scott CL, Konecny GE, Coleman RL, Sun JX, Giordano H, Brenton JD, Harding TC, McNeish IA, Swisher EMet al., 2019, BRCA reversion mutations in circulating tumor DNA predict primary and acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma, Cancer Discovery, Vol: 9, Pages: 210-219, ISSN: 2159-8274

A key resistance mechanism to platinum-based chemotherapies and PARP inhibitors in BRCA-mutant cancers is the acquisition of BRCA reversion mutations that restore protein function. To estimate the prevalence of BRCA reversion mutations in high-grade ovarian carcinoma (HGOC), we performed targeted next-generation sequencing of circulating cell-free DNA (cfDNA) extracted from pretreatment and postprogression plasma in patients with deleterious germline or somatic BRCA mutations treated with the PARP inhibitor rucaparib. BRCA reversion mutations were identified in pretreatment cfDNA from 18% (2/11) of platinum-refractory and 13% (5/38) of platinum-resistant cancers, compared to 2% (1/48) of platinum-sensitive cancers (P = 0.049). Patients without BRCA reversion mutations detected in pretreatment cfDNA had significantly longer rucaparib progression-free survival than those with reversion mutations (median, 9.0 vs. 1.8 months; HR, 0.12; P < 0.0001). To study acquired resistance, we sequenced 78 postprogression cfDNA, identifying eight additional patients with BRCA reversion mutations not found in pretreatment cfDNA.

Journal article

Macintyre G, Piskorz A, Ross E, Morse D, Yuan K, Ennis D, Pike J, Goranova T, McNeish I, Brenton J, Markowetz Fet al., 2018, frenchFISH: Poisson models for quantifying DNA copy-number from fluorescence in situ hybridisation of tissue sections

Chromosomal aberration and DNA copy number change are robust hallmarks of cancer. Imaging of spots generated using fluorescence in situ hybridisation (FISH) of locus specific probes is routinely used to detect copy number changes in tumour nuclei. However, it often does not perform well on solid tumour tissue sections, where partially represented or overlapping nuclei are common. To overcome these challenges, we have developed a computational approach called FrenchFISH, which comprises a nuclear volume correction method coupled with two types of Poisson models: either a Poisson model for improved manual spot counting without the need for control probes; or a homogenous Poisson Point Process model for automated spot counting. We benchmarked the performance of FrenchFISH against previous approaches in a controlled simulation scenario and exemplify its use in 12 ovarian cancer FFPE-tissue sections, for which we assess copy number alterations in three loci (c-Myc, hTERC and SE7). We show that FrenchFISH outperforms standard spot counting approaches and that the automated spot counting is significantly faster than manual without loss of performance. FrenchFISH is a general approach that can be used to enhance clinical diagnosis on sections of any tissue.

Working paper

Sierra Gonzalez P, OPrey J, Cardaci S, Barthet V, Sakamaki J-I, Beaumatin F, Roseweir A, Gay D, Mackay G, Malviya G, Kania E, Ritchie S, Baudot A, Zunino B, Mrowinska A, Nixon C, Ennis D, Hoyle A, Millan D, McNeish I, Sansom O, Edwards J, Ryan Ket al., 2018, Mannose impairs tumour growth and enhances chemotherapy, Nature, Vol: 563, Pages: 719-723, ISSN: 0028-0836

It is now well established that tumours undergo changes in cellular metabolism1. As this can reveal tumour cell vulnerabilities and because many tumours exhibit enhanced glucose uptake2, we have been interested in how tumour cells respond to different forms of sugar. Here we report that the monosaccharide mannose causes growth retardation in several tumour types in vitro, and enhances cell death in response to major forms of chemotherapy. We then show that these effects also occur in vivo in mice following the oral administration of mannose, without significantly affecting the weight and health of the animals. Mechanistically, mannose is taken up by the same transporter(s) as glucose3 but accumulates as mannose-6-phosphate in cells, and this impairs the further metabolism of glucose in glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway and glycan synthesis. As a result, the administration of mannose in combination with conventional chemotherapy affects levels of anti-apoptotic proteins of the Bcl-2 family, leading to sensitization to cell death. Finally we show that susceptibility to mannose is dependent on the levels of phosphomannose isomerase (PMI). Cells with low levels of PMI are sensitive to mannose, whereas cells with high levels are resistant, but can be made sensitive by RNA-interference-mediated depletion of the enzyme. In addition, we use tissue microarrays to show that PMI levels also vary greatly between different patients and different tumour types, indicating that PMI levels could be used as a biomarker to direct the successful administration of mannose. We consider that the administration of mannose could be a simple, safe and selective therapy in the treatment of cancer, and could be applicable to multiple tumour types.

Journal article

McNeish IA, 2018, Neoantigens in ovarian cancer: embarrassment of riches or needles in a haystack?, Clinical Cancer Research, Vol: 24, Pages: 5493-5495, ISSN: 1078-0432

Comprehensive genomic and transcriptomic analysis demonstrates that tumor-infiltrating T lymphocytes that react to mutated neo-epitopes could be identified in recurrent ovarian cancer. Two of these T cell populations reacted against TP53 hotspot missense mutations that are present in a wide variety of malignancies.

Journal article

Mcneish IA, Lin KK, Radke MR, Oza AM, Oaknin A, Ray-Coquard I, Tinker AV, Helman E, Isaacson J, Maloney L, O'malley DM, Chambers SK, Kaufmann SH, Scott C, Konecny GE, Coleman RL, Giordano H, Brenton JD, Harding TC, Swisher EMet al., 2018, BRCA reversion mutations in circulating cell-free tumour DNA predict primary and acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma (HGOC), 30th EORTC-NCI-AACR Symposium, Publisher: ELSEVIER SCI LTD, Pages: E28-E28, ISSN: 0959-8049

Conference paper

Ennis D, Cooke S, Evers L, Dowson S, Chan MY, Paul J, Hirschowitz L, Glasspool R, Singh N, Bell S, Day E, Kiochman A, Wilkinson N, Beer P, Martin S, Millan D, Biankin AV, McNeish IAet al., 2018, The driver mutational landscape of ovarian squamous cell carcinomas arising in mature cystic teratoma, Publisher: BMJ PUBLISHING GROUP, Pages: 56-56, ISSN: 1048-891X

Conference paper

Leary A, Ledermann JA, Oaknin A, Oza AM, Lorusso D, Colombo N, Dean A, Clamp A, Scambia G, Casado Herraez A, Amenedo Gancedo M, Maria Guerra E, Balmana J, Floquet A, Fong PC, Holloway RW, Poelcher M, Roxburgh P, Shapira-Frommer R, Tamberi S, Tinker AV, Cameron T, Maloney L, Goble S, Kristeleit RS, Swisher EM, McNeish IA, Coleman RLet al., 2018, Use of the Poly (ADP-Ribose) Polymerase Inhibitor Rucaparib in Women with Recurrent Ovarian Carcinoma with Endometrioid and Other Nonserous Histopathologic Subtypes, Publisher: BMJ PUBLISHING GROUP, Pages: 200-201, ISSN: 1048-891X

Conference paper

Clamp AR, McNeish IA, Dean A, Gallardo-Rincon D, Kim J-W, O'Donnell DM, Hook J, Blagden S, Brenton JD, Naik R, Perren TJ, Sundar S, Cook AD, James EC, Gabra H, Lord R, Hall M, Dark G, Kaplan RS, Ledermann JAet al., 2018, Response to neoadjuvant chemotherapy in ICON8: A GCIG phase III randomised trial evaluating weekly dose-dense chemotherapy integration in first-line epithelial ovarian/fallopian tube/primary peritoneal carcinoma (EOC) treatment, 43rd ESMO Congress (ESMO), Publisher: OXFORD UNIV PRESS, Pages: 336-336, ISSN: 0923-7534

Conference paper

Rust K, Spiliopoulou P, Tang CY, Bell C, Stirling D, Phang THF, Davidson R, Mackean M, Nussey F, Glasspool R, Reed N, Sadozye A, Porteous M, McGoldrick T, Ferguson M, Miedzybrodzka Z, McNeish IA, Gourley Cet al., 2018, Routine germline BRCA1 and BRCA2 testing in ovarian carcinoma patients: analysis of the Scottish real life experience, BJOG: An International Journal of Obstetrics and Gynaecology, Vol: 125, Pages: 1451-1548, ISSN: 1470-0328

Objective:To determine the rate of germline BRCA1 and BRCA2 mutations in Scottish ovarian cancer patients before and after a change in testing policy.Design:Retrospective cohort study.Setting:Four cancer/genetics centres in Scotland.Population:Ovarian cancer patients undergoing germline BRCA1 and BRCA2 (gBRCA1/2) gene sequencing before 2013 (‘old criteria’; selection based solely on family history), after 2013 (‘new criteria’; sequencing offered to newly presenting non-mucinous ovarian cancer patients) and the ‘prevalent population’ (who presented before 2013, were not eligible for sequencing under the old criteria but were sequenced under the new criteria).Methods:Clinicopathological and sequence data were collected before and for 18 months after this change in selection criteria.Main Outcome Measures:Frequency of germline BRCA1, BRCA2, RAD51C and RAD51D mutations.Results:Of 599 patients sequenced, 205, 236 and 158 were in the ‘old criteria’, ‘new criteria’ and ‘prevalent’ populations respectively. The frequency of gBRCA1/2 mutations was 30.7%, 13.1% and 12.7% respectively. The annual rate of gBRCA1/2 mutation detection was 4.2 before and 20.7 after the policy change. 48% (15/31) ‘new criteria’ patients with gBRCA1/2 mutations had a Manchester score <15 and would not have been offered sequencing based on family history criteria. In addition, 20 gBRCA1/2 patients were identified in the prevalent population. The prevalence of gBRCA1/2 mutations in patients >70 years was 8.2%.Conclusions:Sequencing all non-mucinous ovarian cancer patients produces much higher annual gBRCA1/2 mutation detection with the frequency of positive tests still exceeding the 10% threshold upon which many family history based models operate.

Journal article

McNeish IA, Kondrashova O, Topp M, Nesic K, Lieschke E, Ho G-Y, Harrell MI, Zapparoli GV, Hadley A, Holian R, Boehm E, Heong V, Sanij E, Pearson RB, Krais JJ, Johnson N, McNally O, Ananda S, Alsop K, Hutt KJ, Kaufmann SH, Lin KK, Harding TC, Traficante N, DeFazio A, Bowtell DD, Swisher EM, Dobrovic A, Wakefield MJ, Scott CLet al., 2018, Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma, Nature Communications, Vol: 9, ISSN: 2041-1723

Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naïve BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit and facilitate tailoring of PARPi therapy.

Journal article

Lu Y, Beeghly-Fadiel A, Wu L, Guo X, Li B, Schildkraut JM, Im HK, Chen YA, Permuth JB, Reid BM, Teer JK, Moysich KB, Andrulis IL, Anton-Culver H, Arun BK, Bandera EV, Barkardottir RB, Barnes DR, Benitez J, Bjørge L, Brenton J, Butzow R, Caldes T, Caligo MA, Campbell IG, Chang-Claude J, Claes KBM, Couch FJ, Cramer DW, Daly MB, DeFazio A, Dennis J, Díez O, Domchek SM, Dork T, Easton DF, Eccles DM, Fasching PA, Fortner RT, Fountzilas G, Friedman E, Ganz PA, Garber J, Giles GG, Godwin AK, Goldgar DE, Goodman MT, Greene MH, Gronwald J, Hamann U, Heitz F, Hildebrandt MAT, Høgdall CK, Hollestelle A, Hulick PJ, Huntsman DG, Imyanitov EN, Isaacs C, Jakubowska A, James P, Karlan BY, Kelemen LE, Kiemeney LA, Kjaer SK, Kwong A, Le ND, Leslie G, Lesueur F, Levine DA, Mattiello A, May T, McGuffog L, McNeish IA, Merritt MA, Modugno F, Montagna M, Neuhausen SL, Nevanlinna H, Cilius Nielsen FC, Nikitina-Zake L, Nussbaum RL, Offit K, Olah E, Olopade OI, Olson SH, Olsson H, Osorio A, Park SK, Parsons MT, Peeters PHM, Pejovic T, Peterlongo P, Phelan CM, Pujana MA, Ramus SJ, Rennert G, Risch H, Rodriguez GC, Rodríguez-Antona C, Romieu I, Rookus MA, Rossing MA, Rzepecka IK, Sandler DP, Schmutzler RK, Setiawan VW, Sharma P, Sieh W, Simard J, Singer CF, Song H, Southey MC, Spurdle AB, Sutphen R, Swerdlow AJ, Teixeira MR, Teo SH, Thomassen M, Tischkowitz M, Toland AE, Trichopoulou A, Tung N, Tworoger SS, van Rensburg EJ, Vanderstichele A, Vega A, Velez Edwards D, Webb PM, Weitzel JN, Wentzensen N, White E, Wolk A, Wu AH, Yannoukakos D, Zorn KK, Gayther SA, Antoniou AC, Berchuck A, Goode EL, Chenevix-Trench G, Sellers TA, Pharoah PDP, Zheng W, Long Jet al., 2018, A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk, Cancer Research, Vol: 78, Pages: 5419-5430, ISSN: 1538-7445

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in non-coding regions, and causal genes underlying these associations remain largely unknown. Here we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian-tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P<2.2×10-6, we identified 35 genes including FZD4 at 11q14.2 (Z=5.08, P=3.83×10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly-associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and 3 genes remained (P<1.47 x 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.

Journal article

Kelemen LE, Earp M, Fridley BL, Chenevix-Trench G, Australian Ovarian Cancer Study Group, Fasching PA, Beckmann MW, Ekici AB, Hein A, Lambrechts D, Lambrechts S, Van Nieuwenhuysen E, Vergote I, Rossing MA, Doherty JA, Chang-Claude J, Behrens S, Moysich KB, Cannioto R, Lele S, Odunsi K, Goodman MT, Shvetsov YB, Thompson PJ, Wilkens LR, Dörk T, Antonenkova N, Bogdanova N, Hillemanns P, Runnebaum IB, du Bois A, Harter P, Heitz F, Schwaab I, Butzow R, Pelttari LM, Nevanlinna H, Modugno F, Edwards RP, Kelley JL, Ness RB, Karlan BY, Lester J, Orsulic S, Walsh C, Kjaer SK, Jensen A, Cunningham JM, Vierkant RA, Giles GG, Bruinsma F, Southey MC, Hildebrandt MAT, Liang D, Lu K, Wu X, Sellers TA, Levine DA, Schildkraut JM, Iversen ES, Terry KL, Cramer DW, Tworoger SS, Poole EM, Bandera EV, Olson SH, Orlow I, Vestrheim Thomsen LC, Bjorge L, Krakstad C, Tangen IL, Kiemeney LA, Aben KKH, Massuger LFAG, van Altena AM, Pejovic T, Bean Y, Kellar M, Cook LS, Le ND, Brooks-Wilson A, Gronwald J, Cybulski C, Jakubowska A, Lubiński J, Wentzensen N, Brinton LA, Lissowska J, Hogdall E, Engelholm SA, Hogdall C, Lundvall L, Nedergaard L, Pharoah PDP, Dicks E, Song H, Tyrer JP, McNeish I, Siddiqui N, Carty K, Glasspool R, Paul J, Campbell IG, Eccles D, Whittemore AS, McGuire V, Rothstein JH, Sieh W, Narod SA, Phelan CM, McLaughlin JR, Risch HA, Anton-Culver H, Ziogas A, Menon U, Gayther SA, Gentry-Maharaj A, Ramus SJ, Wu AH, Pearce CL, Lee AW, Pike MC, Kupryjanczyk J, Podgorska A, Plisiecka-Halasa J, Sawicki W, Goode EL, Berchuck A, Ovarian Cancer Association Consortiumet al., 2018, rs495139 in the TYMS-ENOSF1 region and risk of Ovarian carcinoma of mucinous histologo, International Journal of Molecular Sciences, Vol: 19, ISSN: 1422-0067

Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97⁻1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03⁻1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 × 10-28), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.

Journal article

Macintyre G, Goranova TE, De Silva D, Ennis D, Piskorz AM, Eldridge M, Sie D, Lewsley L-A, Hanif A, Wilson C, Dowson S, Glasspool RM, Lockley M, Brockbank E, Montes A, Walther A, Sundar SS, Edmondson R, Hall GD, Clamp A, Gourley C, Hall M, Fotopoulou C, Gabra H, Paul J, Supernat A, Millan D, Hoyle A, Bryson G, Nourse C, Mincarelli L, Navarro Sanchez L, Ylstra B, Jimenez-Linan M, Moore L, Hofmann O, Markowetz F, McNeish IA, Brenton JDet al., 2018, Copy-number signatures and mutational processes in ovarian carcinoma, Nature Genetics, Vol: 50, Pages: 1262-1270, ISSN: 1061-4036

The genomic complexity of profound copy-number aberration has prevented effective molecular stratification of ovarian cancers. 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. Measuring signature exposures provides a rational framework to choose combination treatments that target multiple mutational processes.

Journal article

Ennis D, Cooke SL, Evers L, Dowson S, Chan MY, Paul J, Hirschowitz L, Glasspool R, Singh N, Bell S, Day E, Kochman A, Wilkinson N, Beer P, Martin S, Millan D, Biankin AV, McNeish IAet al., 2018, The driver mutational landscape of ovarian squamous cell carcinomas arising in mature cystic teratoma., AACR Special Conference on Addressing Critical Questions in Ovarian Cancer Research and Treatment, Publisher: AMER ASSOC CANCER RESEARCH, Pages: 34-+, ISSN: 1078-0432

Conference paper

Leung EYL, Ennis DP, Athineos D, Kennedy PR, Hansell CA, Blyth K, Davis DM, Graham GJ, McNeish IAet al., 2018, Oncolytic adenovirus infection leads to contact-dependent activation of natural killer cells and augments virotherapy effectiveness for ovarian cancer., AACR Special Conference on Addressing Critical Questions in Ovarian Cancer Research and Treatment, Publisher: AMER ASSOC CANCER RESEARCH, Pages: 97-98, ISSN: 1078-0432

Conference paper

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