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

253 results found

McNeish I, 2021, Safety and efficacy of the tumour-selective adenovirus enadenotucirev with or without paclitaxel in platinum-resistant ovarian cancer: a phase 1 clinical trial, Journal for ImmunoTherapy of Cancer, ISSN: 2051-1426

Journal article

You B, Freyer G, Gonzalez-Martin A, Lheureux S, McNeish I, Penson RT, Pignata S, Pujade-Lauraine Eet al., 2021, The role of the tumor primary chemosensitivity relative to the success of the medical-surgical management in patients with advanced ovarian carcinomas, CANCER TREATMENT REVIEWS, Vol: 100, ISSN: 0305-7372

Journal article

Kwan TT, Oza AM, Tinker AV, Ray-Coquard I, Oaknin A, Aghajanian C, Lorusso D, Colombo N, Dean A, Weberpals J, Severson E, Vo L-T, Goble S, Maloney L, Harding T, Kaufmann SH, Ledermann JA, Coleman RL, McNeish IA, Lin KK, Swisher EMet al., 2021, Preexisting TP53-Variant Clonal Hematopoiesis and Risk of Secondary Myeloid Neoplasms in Patients With High-grade Ovarian Cancer Treated With Rucaparib., JAMA Oncol

Importance: A total of 1% to 3% of patients treated with a poly(adenosine diphosphate-ribose) polymerase inhibitor for high-grade ovarian cancer (HGOC) develop therapy-related myeloid neoplasms (t-MNs), which are rare but often fatal conditions. Although the cause of these t-MNs is unknown, clonal hematopoiesis of indeterminate potential (CHIP) variants can increase the risk of primary myeloid malignant neoplasms and are more frequent among patients with solid tumors. Objectives: To examine whether preexisting CHIP variants are associated with the development of t-MNs after rucaparib treatment and how these CHIP variants are affected by treatment. Design, Setting, and Participants: This retrospective genetic association study used peripheral blood cell (PBC) samples collected before rucaparib treatment from patients in the multicenter, single-arm ARIEL2 (Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer) (n = 491; between October 30, 2013, and August 9, 2016) and the multicenter, placebo-controlled, double-blind ARIEL3 (Study of Rucaparib as Switch Maintenance Following Platinum-Based Chemotherapy in Patients With Platinum-Sensitive, High-Grade Serous or Endometrioid Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer) (n = 561; between April 7, 2014, and July 19, 2016), which tested rucaparib as HGOC therapy in the treatment and maintenance settings, respectively. The follow-up data cutoff date was September 1, 2019. Of 1052 patients in ARIEL2 and ARIEL3, PBC samples from 20 patients who developed t-MNs (cases) and 44 randomly selected patients who did not (controls) were analyzed for the presence of CHIP variants using targeted next-generation sequencing. Additional longitudinal analysis was performed on available ARIEL2 samples collected during treatment and at the end of treatment. Main Outcomes and Measures: Enrichment analysis of

Journal article

Sun L, Kees T, Santos Almeida A, Liu B, He X-Y, Ng D, Han X, Spector D, Wilkinson E, McNeish I, Gimotty P, Adams S, Egeblad Met al., 2021, Activating a collaborative innate-adaptive immune response to control metastasis, Cancer Cell, Vol: 39, Pages: 1361-1374.e9, ISSN: 1535-6108

Tumor-associated macrophages (TAMs) promote metastasis and inhibit cytotoxic T cells. Yet, macrophages can be polarized to kill cancer cells. Macrophage polarization could therefore be a strategy for controlling cancer. Here, we show that macrophages from metastatic pleural effusions of breast cancer patients could be polarized in vitro to kill cancer cells with monophosphoryl lipid A (MPLA, a lipopolysaccharide [LPS] derivative) and IFNγ. Intratumoral injection with MPLA+IFNγ reduced primary tumor growth, greatly suppressed metastasis, and enhanced chemotherapy response in breast and ovarian cancer mouse models. Both macrophages and T cells were critical for the anti-metastatic effects of MPLA+IFNγ. The MPLA+IFNγ treatment stimulated type I interferon signaling, reprogramed CD206+ TAMs to iNOS+ macrophages, and activated cytotoxic T cells through macrophage-secreted interleukin 12 (IL-12) and tumor necrosis factor α (TNFα). MPLA and IFNγ are used individually in clinical practice and together represent a previously unexplored approach to engage a systemic anti-tumor immune response.

Journal article

Monk BJ, Coleman RL, Fujiwara K, Wilson MK, Oza AM, Oaknin A, O'Malley DM, Lorusso D, Westin SN, Safra T, Herzog TJ, Marmé F, N Eskander R, Lin KK, Shih D, Goble S, Grechko N, Hume S, Maloney L, McNeish IA, Kristeleit RSet al., 2021, ATHENA (GOG-3020/ENGOT-ov45): a randomized, phase III trial to evaluate rucaparib as monotherapy (ATHENA-MONO) and rucaparib in combination with nivolumab (ATHENA-COMBO) as maintenance treatment following frontline platinum-based chemotherapy in ovarian cancer., Int J Gynecol Cancer

BACKGROUND: The optimal treatment strategy for women with newly diagnosed ovarian cancer has yet to be determined. Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated substantial improvement in progression-free survival as monotherapy maintenance treatment in the frontline setting versus active surveillance. Furthermore, preclinical and early clinical studies have shown that PARP inhibitors and immune checkpoint inhibitors have synergistic antitumor activity and may provide an additional therapeutic option for patients in this population. PRIMARY OBJECTIVES: In women with newly diagnosed ovarian, fallopian tube, or peritoneal cancer, we wish to assess the efficacy of frontline maintenance treatment with the PARP inhibitor rucaparib versus placebo following response to platinum-based chemotherapy (ATHENA-MONO), and to assess the combination of rucaparib plus nivolumab (a programmed death receptor 1 (PD-1)-blocking monoclonal antibody) versus rucaparib alone (ATHENA-COMBO). STUDY HYPOTHESIS: (1) Maintenance therapy with rucaparib monotherapy may extend progression-free survival following standard treatment for ovarian cancer in the frontline setting. (2) The combination of nivolumab plus rucaparib may extend progression-free survival following standard treatment for ovarian cancer in the frontline setting compared with rucaparib alone. TRIAL DESIGN: ATHENA is an international, randomized, double-blind, phase III trial consisting of two independent comparisons (ATHENA-MONO and ATHENA-COMBO) in patients with newly diagnosed platinum-sensitive ovarian cancer. Patients are randomized 4:4:1:1 to the following: oral rucaparib+ intravenous nivolumab (arm A); oral rucaparib + intravenous placebo (arm B); oral placebo+ intravenous nivolumab (arm C); and oral placebo + intravenous placebo (arm D). The starting dose of rucaparib is 600 mg orally twice a day and nivolumab 480 mg intravenously every 4 weeks. ATHENA-MONO compares arm B with arm D to evalua

Journal article

McNeish I, 2021, Characterization of patients with long-term responses to rucaparib treatment in recurrent ovarian cancer, Gynecologic Oncology, ISSN: 0090-8258

Objective. To describe molecular and clinical characteristics of patients with high-grade recurrent ovarian carcinoma (HGOC) who had long-term responses to the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib. Methods. This post hoc analysis pooled patients from Study 10 (NCT01482715; Parts 2A and 2B; n = 54) and ARIEL2 (NCT01891344; Parts 1 and 2; n = 491). Patients with investigator-assessed complete or partial response per RECIST were classified based on duration of response (DOR): long (≥1 year), intermediate (6 months to <1 year), or short (<6 months). Next-generation sequencing was used to detect deleterious mutations and loss of heterozygosity (LOH) in tumors. Results. Overall, 25.3% (138/545) of enrolled patients were responders. Of these, 27.5% (38/138) had long-term responses; 28.3% (39/138) were intermediate- and 34.8% (48/138) were short-term responders. Most of the long-term responders harbored a BRCA1 or BRCA2 (BRCA) mutation (71.1%, 27/38), and BRCA structural variants were most frequent among long-term responders (14.8%; 4/27). Responders with HGOC harboring a BRCA structural variant (n = 5) had significantly longer DOR than patients with other mutation types (n = 81; median not reached vs 0.62 years; HR, 0.21; 95% CI, 0.10–0.43; unadjusted p = 0.014). Among responders with BRCA wild-type HGOC, most long- and intermediate-term responders had high genome-wide LOH: 81.8% (9/11) and 76.9% (10/13), respectively, including 7 with deleterious RAD51C, RAD51D, or CDK12 mutations.Conclusion. Among patients who responded to rucaparib, a substantial proportion achieved responses lasting ≥1 year. These analyses demonstrate the relationship between DOR to PARP inhibitor treatment and molecular characteristics in HGOC, such as presence of reversion-resistant BRCA structural variants.

Journal article

Leung EYL, McNeish IA, 2021, Strategies to Optimise Oncolytic Viral Therapies: The Role of Natural Killer Cells, VIRUSES-BASEL, Vol: 13

Journal article

McNeish I, 2021, Preexisting TP53-Mutated Clonal Hematopoiesis as a Risk Factor for the Development of Secondary Myeloid Malignancies in High-grade Ovarian Cancer Patients Treated With the Poly(ADP-Ribose) Polymerase Inhibitor Rucaparib, JAMA Oncology, ISSN: 2374-2445

Journal article

Braund M, Barras D, Mina M, Ghisoni E, Morotti M, Lantis E, Fahr N, Desbuisson M, Grimm A, Zhang H, Chong C, Dagher J, Chee S, Tsianou T, Dorier J, Stevenson BJ, Iseli C, Ronet C, Bobisse S, Genolet R, Walton J, Bassani-Sternberg M, Kandalaft LE, Ren B, McNeish I, Swisher E, Harari A, Delorenzi M, Ciriello G, Irving M, Rusakiewicz S, Foukas PG, Martinon F, Dangaj D, Coukos Get al., 2021, Cell-autonomous inflammation of BRCA1-deficient ovarian cancers drives both tumor-intrinsic immunoreactivity and immune resistance through STING, Cell Reports, Vol: 36, Pages: 1-31, ISSN: 2211-1247

We investigated mechanisms leading to inflammation and immunoreactivity in ovarian tumors with homologous recombination deficiency. BRCA1lossis found to lead to transcriptional reprogramming in tumor cells and cell-intrinsic inflammation involving type I IFN and STING.BRCA1-mutated (BRCA1mut) tumors are thus T-cell inflamed at baseline. Genetic deletion or methylation of DNA-sensing/IFN genes or CCL5chemokineare identified as potential mechanism to attenuate T cell inflammation. Alternatively, in BRCA1mutcancersretaining inflammation, STING up regulates VEGF-A, mediating immune resistance and tumor progression. Tumor intrinsic STING elimination reduces neoangiogenesis, increasesCD8+T cell infiltration and reverts therapeutic resistance to dual immune checkpoint blockade(ICB). VEGF-A blockade phenocopies genetic STING loss and synergizes with IC Band/or PARP inhibitors to control the outgrowth of Trp53-/-Brca1-/-but notBrca1+/+ovarian tumors in vivo, offering rational combinatorial therapies for HRD cancers

Journal article

McNeish I, 2021, Characterization of a RAD51C-Silenced High Grade Serous Ovarian Cancer Model During Development of PARP Inhibitor Resistance, NAR Cancer

Acquired PARP inhibitor (PARPi) resistance in BRCA1- or BRCA2-mutant ovarian canceroften results from secondary mutations that restore expression of functional protein. RAD51C is aless commonly studied ovarian cancer susceptibility gene whose promoter is sometimesmethylated, leading to homologous recombination (HR) deficiency and PARPi sensitivity. For thisstudy, the PARPi-sensitive patient-derived ovarian cancer xenograft PH039, which lacks HR genemutations but harbors RAD51C promoter methylation, was selected for PARPi resistance bycyclical niraparib treatment in vivo. PH039 acquired PARPi resistance by the third treatment cycleand grew through subsequent treatment with either niraparib or rucaparib. Transcriptional profilingthroughout the course of resistance development showed widespread pathway level changes alongwith a marked increase in RAD51C mRNA, which reflected loss of RAD51C promotermethylation. Analysis of ovarian cancer samples from the ARIEL2 Part 1 clinical trial of rucaparibmonotherapy likewise indicated an association between loss of RAD51C methylation prior to onstudy biopsy and limited response. Interestingly, the PARPi resistant PH039 model remainedplatinum sensitive. Collectively, these results not only indicate that PARPi treatment pressure canreverse RAD51C methylation and restore RAD51C expression, but also provide a model forstudying the clinical observation that PARPi and platinum sensitivity are sometimes dissociated.

Journal article

Garner IM, Su Z, Hu S, Wu Y, McNeish IA, Fuchter MJ, Brown Ret al., 2021, Modulation of homologous recombination repair pathway gene expression by a dual EZH2 and EHMT2 histone methyltransferase inhibitor and synergy with PARP inhibitors in ovarian cancer., Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472

Conference paper

Ewing A, Meynert A, Churchman M, Grimes GR, Hollis RL, Herrington CS, Rye T, Bartos C, Croy I, Ferguson M, Lennie M, McGoldrick T, McPhail N, Siddiqui N, Dowson S, Glasspool R, Mackean M, Nussey F, McDade B, Ennis D, McMahon L, Matakidou A, Dougherty B, March R, Barrett JC, McNeish IA, Scottish Genomes Partnership, Biankin AV, Roxburgh P, Gourley C, Semple CAet al., 2021, Structural variants at the BRCA1/2 loci are a common source of homologous repair deficiency in high grade serous ovarian carcinoma, Clinical Cancer Research, Vol: 27, Pages: 3201-3214, ISSN: 1078-0432

Purpose: The abundance and effects of structural variation at BRCA1/2 in tumors are not well understood. In particular, the impact of these events on homologous recombination repair deficiency (HRD) has yet to be demonstrated.Experimental Design: Exploiting a large collection of whole-genome sequencing data from high-grade serous ovarian carcinoma (N = 205) together with matched RNA sequencing for the majority of tumors (N = 150), we have comprehensively characterized mutation and expression at BRCA1/2.Results: In addition to the known spectrum of short somatic mutations (SSM), we discovered that multi-megabase structural variants (SV) were a frequent, unappreciated source of BRCA1/2 disruption in these tumors, and we found a genome-wide enrichment for large deletions at the BRCA1/2 loci across the cohort. These SVs independently affected a substantial proportion of patients (16%) in addition to those affected by SSMs (24%), conferring HRD and impacting patient survival. We also detail compound deficiencies involving SSMs and SVs at both loci, demonstrating that the strongest risk of HRD emerges from combined SVs at both BRCA1 and BRCA2 in the absence of SSMs. Furthermore, these SVs are abundant and disruptive in other cancer types.Conclusions: These results extend our understanding of the mutational landscape underlying HRD, increase the number of patients predicted to benefit from therapies exploiting HRD, and suggest there is currently untapped potential in SV detection for patient stratification.

Journal article

Konecny GE, Oza AM, Tinker AV, Oaknin A, Shapira-Frommer R, Ray-Coquard I, Aghajanian C, Coleman RL, O'Malley DM, Leary A, Chen L-M, Provencher D, Ma L, Brenton JD, Castro C, Green M, Simmons AD, Beltman J, Harding T, Lin KK, Goble S, Maloney L, Kristeleit RS, McNeish IA, Swisher EM, Xiao JJet al., 2021, Population exposure-efficacy and exposure-safety analyses for rucaparib in patients with recurrent ovarian carcinoma from Study 10 and ARIEL2, Gynecologic Oncology, Vol: 161, Pages: 668-675, ISSN: 0090-8258

ObjectiveTo evaluate correlations between rucaparib exposure and selected efficacy and safety endpoints in patients with recurrent ovarian carcinoma using pooled data from Study 10 and ARIEL2.MethodsEfficacy analyses were limited to patients with carcinomas harboring a deleterious BRCA1 or BRCA2 mutation who had received ≥2 prior lines of chemotherapy. Safety was evaluated in all patients who received ≥1 rucaparib dose. Steady-state daily area under the concentration-time curve (AUCss) and maximum concentration (Cmax,ss) for rucaparib were calculated for each patient and averaged by actual dose received over time (AUCavg,ss and Cmax,avg,ss) using a previously developed population pharmacokinetic model.ResultsRucaparib exposure was dose-proportional and not associated with baseline patient weight. In the exposure-efficacy analyses (n = 121), AUCavg,ss was positively associated with independent radiology review-assessed RECIST response in the subgroup of patients with platinum-sensitive recurrent disease (n = 75, p = 0.017). In the exposure-safety analyses (n = 393, 40 mg once daily to 840 mg twice daily [BID] starting doses), most patients received a 600 mg BID rucaparib starting dose, with 27% and 21% receiving 1 or ≥2 dose reductions, respectively. Cmax,ss was significantly correlated with grade ≥2 serum creatinine increase, grade ≥3 alanine transaminase/aspartate transaminase increase, platelet decrease, fatigue/asthenia, and maximal hemoglobin decrease (p < 0.05).ConclusionThe exposure-response analyses provide support for the approved starting dose of rucaparib 600 mg BID for maximum clinical benefit with subsequent dose modification only following the occurrence of a treatment-emergent adverse event in patients with BRCA-mutated recurrent ovarian carcinoma.

Journal article

Lythgoe MP, Krell J, McNeish IA, Tookman Let al., 2021, Safe administration of chemotherapy in mast cell activation syndrome, Journal of Oncology Pharmacy Practice, Vol: 27, Pages: 1005-1010, ISSN: 1078-1552

IntroductionMast Cell Activation Syndrome (MCAS) is an immunogenic disorder typically presenting with episodic multi-organ symptoms, caused by the inappropriate and aberrant release of mast cell mediators. Symptoms may be severe, including anaphylaxis and often occur in response to specific triggers which include many drugs and potentially chemotherapeutic agents. The administration of adjuvant chemotherapy and radiotherapy in endometrial cancer significantly reduces the risk of reoccurrence in patients with high risk disease. Currently there is no evidence or case reports to guide the safe administration of chemotherapy in MCAS patients.Case reportWe present the case of a 59-year-old lady with stage 3 A grade 2 endometroid endometrial cancer who underwent successful surgical management. She then received 4 cycles of adjuvant chemotherapy in the form of carboplatin and paclitaxel. This case describes a staged approach to chemotherapy administration and the utilisation of a carboplatin desensitization regimen to reduce the risk of immediate and delayed hypersensitivity sequalae.Management & outcome: Utilising an enhanced pre-medication strategy and a staged approach to chemotherapy administration, she was able to complete adjuvant treatment without any serious complications. At the date of censoring (May 2020) she has not shown any evidence of disease re-occurrence.Discussion & conclusion: Administering chemotherapy to patients with any mast cell disorder remains challenging. We hope that this case may provide the framework for safer chemotherapy administration for any patients at high risk of serious hypersensitivity sequalae in endometrial cancer and beyond.

Journal article

Spiliopoulou P, Hinsley S, McNeish IA, Roxburgh P, Glasspool Ret al., 2021, Metronomic oral cyclophosphamide in relapsed ovarian cancer, International Journal of Gynecological Cancer, Vol: 31, Pages: 1037-1044, ISSN: 1048-891X

OBJECTIVES: To describe the clinical activity of metronomic cyclophosphamide in a population of patients with recurrent ovarian cancer, and to identify predictors of clinical response. METHODS: We retrospectively reviewed all patients treated at our institution with oral metronomic cyclophosphamide for relapsed ovarian cancer between January 2012 and December 2016. These were identified from electronic chemotherapy prescription records. The primary endpoint was response rate by combined Gynecologic Cancer InterGroup (GCIG) criteria. Data on patient demographics, previous therapies, platinum resistance, germline BRCA1/2 (gBRCA1/2) status, disease response by radiological or cancer antigen 125 (CA125) criteria alone, adverse events secondary to metronomic cyclophosphamide treatment, progression-free survival, and overall survival were also evaluated. RESULTS: 50 out of 68 patients treated with oral metronomic cyclophosphamide were evaluable for disease response. By combination criteria (radiological plus CA125), complete response was 0%, partial response 32%, stable disease 16%, and progressive disease 52%. In the intention-to-treat population (n=68), progression-free survival and overall survival were 2.6 months and 6 months, respectively. Having a gBRCA1/2 mutation reduced the risk of disease progression by radiological criteria (OR 0.07, 95% CI 0.008 to 0.67, p=0.02), and patients with gBRCA1/2 mutations had improved progression-free survival (7.9 vs 2.5 months, HR 0.4, 95% CI 0.23 to 0.74, p=0.003) and overall survival (15.5 vs 6 months, HR 0.49, 95% CI 0.28 to 0.85, p=0.02) with metronomic cyclophosphamide when compared with patients without gBRCA1/2 mutations (or unknown gBRCA1/2 status). CONCLUSION: Oral metronomic cyclophosphamide showed a clinical benefit in 48% of patients with recurrent ovarian cancer. gBRCA1/2 status can be an independent predictor of response.

Journal article

Swisher EM, Kwan TT, Oza AM, Tinnker AV, Ray-Coquard I, Oaknin A, Coleman RL, Aghajanian C, Konecny GE, O'Malley DM, Leary A, Provencher D, Welch S, Chen L-M, Wahner Hendrickson AE, Ma L, Ghatage P, Kristeleit RS, Dorigo O, Musafer A, Kaufmann SH, Elvin JA, Lin DI, Chambers SK, Dominy E, Vo L-T, Goble S, Maloney L, Giordano H, Harding T, Dobrovic A, Scott CL, Lin KK, McNeish Iet al., 2021, Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2), Nature Communications, Vol: 12, ISSN: 2041-1723

ARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity.

Journal article

Lindzen M, Ghosh S, Noronha A, Drago D, Nataraj NB, Leitner O, Carvalho S, Zmora E, Sapoznik S, Shany KB, Levanon K, Aderka D, Ramirez BS, Dahlhoff M, McNeish I, Yarden Yet al., 2021, Targeting autocrine amphiregulin robustly and reproducibly inhibits ovarian cancer in a syngeneic model: roles for wildtype p53, ONCOGENE, Vol: 40, Pages: 3665-3679, ISSN: 0950-9232

Journal article

Laird BJ, McMillan D, Skipworth RJE, Fallon MT, Paval R, McNeish I, Gallagher IJet al., 2021, The emerging role of Interleukin 1β (IL-1β) in cancer cachexia, Inflammation, Vol: 44, Pages: 1223-1228, ISSN: 0360-3997

Treatment of cancer cachexia remains an unmet need. The host-tumour interface and the resulting sequestration of the pro-inflammatory cytokine Il-1β is critical in cachexia development. Neuroinflammation mediated via IL-1β through the hypothalamic pituitary axis results in increased muscle proteolysis and adipose lipolysis, thus creating a prolonged stress-like environment with loss of appetite and increased resting energy expenditure. Recent trials using a monoclonal antibody targeting IL-1β, canakinumab, have shown a potential role in lung cancer however a potential role of targeting IL-1β to treat cachexia in patients with lung cancer is unclear; yet the underlying pathophysiology provides a sound rationale that this may be a viable therapeutic approach.

Journal article

Cohen PA, Powell A, Bohm S, Gilks CB, Stewart CJR, Meniawy TM, Bulsara M, Avril S, Brockbank EC, Bosse T, Focchi GRDA, 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, Singh Net al., 2021, Pathological chemotherapy response score is prognostic in tubo-ovarian high-grade serous carcinoma: A systematic review and meta-analysis of individual patient data (vol 154, pg 441, 2019), GYNECOLOGIC ONCOLOGY, Vol: 161, Pages: 328-329, ISSN: 0090-8258

Journal article

Macintyre G, Piskorz AM, Berman A, Ross E, Morse DB, Yuan K, Ennis D, Pike JA, Goranova T, McNeish I, Brenton JD, Markowetz Fet al., 2021, FrenchFISH: Poisson models for quantifying DNA copy-number from fluorescence in situ hybridisation of tissue sections, Journal of Clinical Oncology, Vol: 5, Pages: 176-186, ISSN: 0732-183X

PURPOSEChromosomal aberration and DNA copy number change are robust hallmarks of cancer. The gold standard for detecting copy number changes in tumor cells is fluorescence in situ hybridization (FISH) using locus-specific probes that are imaged as fluorescent spots. However, spot counting often does not perform well on solid tumor tissue sections due to partially represented or overlapping nuclei.MATERIALS AND METHODSTo 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 homogeneous Poisson point process model for automated spot counting.RESULTSWe benchmarked the performance of FrenchFISH against previous approaches using a controlled simulation scenario and tested it experimentally in 12 ovarian carcinoma FFPE-tissue sections for copy number alterations at three loci (c-Myc, hTERC, and SE7). FrenchFISH outperformed standard spot counting with 74% of the automated counts having < 1 copy number difference from the manual counts and 17% having < 2 copy number differences, while taking less than one third of the time of manual counting.CONCLUSIONFrenchFISH is a general approach that can be used to enhance clinical diagnosis on sections of any tissue by both speeding up and improving the accuracy of spot count estimates.

Journal article

Al Harbi R, McNeish IA, El-Bahrawy M, 2021, Ovarian sex cord-stromal tumors: an update on clinical features, molecular changes, and management, International Journal of Gynecological Cancer, Vol: 31, Pages: 161-168, ISSN: 1048-891X

Sex cord stromal-tumors are rare tumors of the ovary that include numerous tumor subtypes of variable histological features and biological behavior. Surgery is the main therapeutic modality for the management of these tumors, while chemotherapy and hormonal therapy may be used in some patients with progressive and recurrent tumors. Several studies investigated molecular changes in the different tumor types. Understanding molecular changes underlying the development and progression of sex cord-stromal tumors provides valuable information for diagnostic and prognostic biomarkers and potential therapeutic targets for these tumors. In this review, we provide an update on the clinical presentation, molecular changes, and management of sex cord-stromal tumors.

Journal article

Morgan RD, McNeish IA, Cook AD, James EC, Lord R, Dark G, Glasspool RM, Krell J, Parkinson C, Poole CJ, Hall M, Gallardo-Rincón D, Lockley M, Essapen S, Summers J, Anand A, Zachariah A, Williams S, Jones R, Scatchard K, Walther A, Kim J-W, Sundar S, Jayson GC, Ledermann JA, Clamp ARet al., 2021, Objective responses to first-line neoadjuvant carboplatin-paclitaxel regimens for ovarian, fallopian tube, or primary peritoneal carcinoma (ICON8): post-hoc exploratory analysis of a randomised, phase 3 trial, The Lancet Oncology, Vol: 22, Pages: 277-288, ISSN: 1213-9432

BACKGROUND: Platinum-based neoadjuvant chemotherapy followed by delayed primary surgery (DPS) is an established strategy for women with newly diagnosed, advanced-stage epithelial ovarian cancer. Although this therapeutic approach has been validated in randomised, phase 3 trials, evaluation of response to neoadjuvant chemotherapy using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and cancer antigen 125 (CA125) has not been reported. We describe RECIST and Gynecologic Cancer InterGroup (GCIG) CA125 responses in patients receiving platinum-based neoadjuvant chemotherapy followed by DPS in the ICON8 trial. METHODS: ICON8 was an international, multicentre, randomised, phase 3 trial done across 117 hospitals in the UK, Australia, New Zealand, Mexico, South Korea, and Ireland. The trial included women aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, life expectancy of more than 12 weeks, and newly diagnosed International Federation of Gynecology and Obstetrics (FIGO; 1988) stage IC-IIA high-grade serous, clear cell, or any poorly differentiated or grade 3 histological subtype, or any FIGO (1988) stage IIB-IV epithelial cancer of the ovary, fallopian tube, or primary peritoneum. Patients were randomly assigned (1:1:1) to receive intravenous carboplatin (area under the curve [AUC]5 or AUC6) and intravenous paclitaxel (175 mg/m2 by body surface area) on day 1 of every 21-day cycle (control group; group 1); intravenous carboplatin (AUC5 or AUC6) on day 1 and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 2); or intravenous dose-fractionated carboplatin (AUC2) and intravenous dose-fractionated paclitaxel (80 mg/m2 by body surface area) on days 1, 8, and 15 of every 21-day cycle (group 3). The maximum number of cycles of chemotherapy permitted was six. Randomisation was done with a minimisation method, and patients were stratified accordi

Journal article

Glubb DM, Thompson DJ, Aben KKH, Alsulimani A, Amant F, Annibali D, Attia J, Barricarte A, Beckmann MW, Berchuck A, Bermisheva M, Bernardini MQ, Bischof K, Bjorge L, Bodelon C, Brand AH, Brenton JD, Brinton LA, Bruinsma F, Buchanan DD, Burghaus S, Butzow R, Cai H, Carney ME, Chanock SJ, Chen C, Chen XQ, Chen Z, Cook LS, Cunningham JM, De Vivo I, DeFazio A, Doherty JA, Dork T, du Bois A, Dunning AM, Durst M, Edwards T, Edwards RP, Ekici AB, Ewing A, Fasching PA, Ferguson S, Flanagan JM, Fostira F, Fountzilas G, Friedenreich CM, Gao B, Gaudet MM, Gawelko J, Gentry-Maharaj A, Giles GG, Glasspool R, Goodman MT, Gronwald J, Harris HR, Harter P, Hein A, Heitz F, Hildebrandt MAT, Hillemanns P, Hogdall E, Hogdall CK, Holliday EG, Huntsman DG, Huzarski T, Jakubowska A, Jensen A, Jones ME, Karlan BY, Karnezis A, Kelley JL, Khusnutdinova E, Killeen JL, Kjaer SK, Klapdor R, Kobel M, Konopka B, Konstantopoulou I, Kopperud RK, Koti M, Kraft P, Kupryjanczyk J, Lambrechts D, Larson MC, Le Marchand L, Lele S, Lester J, Li AJ, Liang D, Liebrich C, Lipworth L, Lissowska J, Lu L, Lu KH, Macciotta A, Mattiello A, May T, McAlpine JN, McGuire V, McNeish IA, Menon U, Modugno F, Moysich KB, Nevanlinna H, Odunsi K, Olsson H, Orsulic S, Osorio A, Palli D, Park-Simon T-W, Pearce CL, Pejovic T, Permuth JB, Podgorska A, Ramus SJ, Rebbeck TR, Riggan MJ, Risch HA, Rothstein JH, Runnebaum IB, Scott RJ, Sellers TA, Senz J, Setiawan VW, Siddiqui N, Sieh W, Spiewankiewicz B, Sutphen R, Swerdlow AJ, Szafron LM, Teo SH, Thompson PJ, Thomsen LCV, Titus L, Tone A, Tumino R, Turman C, Vanderstichele A, Edwards DV, Vergote I, Vierkant RA, Wang Z, Wang-Gohrke S, Webb PM, White E, Whittemore AS, Winham SJ, Wu X, Wu AH, Yannoukakos D, Spurdle AB, O'Mara TAet al., 2021, Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers, CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, Vol: 30, Pages: 217-228, ISSN: 1055-9965

Journal article

Semertzidou A, Brosens JJ, McNeish I, Kyrgiou Met al., 2020, Organoid models in gynaecological oncology research, CANCER TREATMENT REVIEWS, Vol: 90, ISSN: 0305-7372

Journal article

Konecny GE, Oza AM, Tinker AV, Oaknin A, Shapira-Frommer R, Ray-Coquard I, Aghajanian C, Coleman RL, O'Malley DM, Leary A, Chen LM, Provencher D, Ma L, Brenton JD, Castro CM, Green M, Simmons AD, Beltman J, Harding T, Goble S, Maloney L, Kristeleit R, McNeish IA, Swisher EM, Xiao JJet al., 2020, Population exposure-safety and exposure-efficacy analyses for rucaparib in patients (pts) with recurrent ovarian carcinoma (rOC) from Study 10 and ARIEL2, Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE, Pages: 92-93, ISSN: 0090-8258

Conference paper

Marth C, Vulsteke C, Rubio MJR, Makker V, Braicu EI, McNeish IA, Madry R, Ayhan A, Hasegawa K, Wu X, Dutta L, Xu C, Keefe S, Lee J, Pignata Set al., 2020, ENGOT-en9/LEAP-001: A phase III, randomized, active-controlled, open-label study of pembrolizumab plus lenvatinib versus paclitaxel plus carboplatin for newly diagnosed advanced or recurrent endometrial cancer, Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE, Pages: 221-221, ISSN: 0090-8258

Conference paper

McNeish I, Ennis D, Stronach E, 2020, Development and validation of the gene-expression Predictor of high-grade-serous Ovarian carcinoma molecular subTYPE (PrOTYPE), Clinical Cancer Research, Vol: 26, Pages: 5411-5423, ISSN: 1078-0432

Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features.Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting.Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations.Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications.

Journal article

McNeish I, Morgan RD, Cook AD, James EC, Lord R, Dark G, Glasspool RM, Krell J, Parkinson C, Poole CJ, Hall M, Gallardo-Rincón D, Lockley M, Essapen S, Summers J, Anand A, Zachariah A, Williams S, Jones R, Scatchard K, Walther A, Kim J-W, Sundar S, Jayson GC, Ledermann JA, Clamp ARet al., 2020, An exploratory analysis of objective responses to neoadjuvant chemotherapy: results from a randomised phase III trial evaluating first-line carboplatin-paclitaxel regimens for ovarian, fallopian tube or primary peritoneal carcinoma (ICON8), The Lancet Oncology, ISSN: 1213-9432

BackgroundPlatinum-based neoadjuvant chemotherapy (NACT) followed by delayed primary surgery (DPS) is an established strategy for women with newly diagnosed, advanced stage epithelial ovarian cancer. Although this therapeutic approach has been validated in randomised, phase III trials,evaluation of response to NACT using Response Evaluation Criteria in Solid Tumours (RECIST)and CA125 was not reported. We describeRECIST and Gynecologic Cancer InterGroup (GCIG)CA125 responses in patients receiving platinum-based NACT followed by DPS in the phase III trial, ICON8.MethodsICON8 was an international, multicentre, randomised, phase III trial in which women ≥18 years old with an Eastern Cooperative Oncology Group performance status of 0-2, life expectancy >12 weeks and newly diagnosed International Federation of Gynecology and Obstetrics (FIGO;1988) stage IC-IIA high-grade serous, clear cell or any poorly differentiated/grade 3 histological subtype or any FIGO (1988) stage IIB-IV epithelial cancer of the ovary, fallopian tube or primary peritoneum were randomised (1:1:1) to receive either intravenous (IV) carboplatin (AUC5/6)and IV paclitaxel (175mg/m2by body surface area [BSA])on day 1 of every 21-day cycle(control arm)or IV carboplatin (AUC5/6)on day 1 and IV paclitaxel (80mg/m2by BSA)on days 1, 8 and 15 of every 21-day cycle(dose-fractionated paclitaxelarm) or IV carboplatin (AUC2)and IV paclitaxel (80mg/m2by BSA)on days 1, 8 and 15 of every 21-day cycle(dose-fractionated carboplatin and paclitaxelarm). Randomisation occurred using a minimisation method and patients where stratified according to GCIG group, disease stage and timing and outcome of cytoreductive surgery. Neither patients nor clinicians were masked to their allocated group. The scheduling of surgery and use of NACTwere determined by local multidisciplinary case review. In this post-hoc 5exploratory analysis of ICON8, progression-free survival (PFS) was analysed using the landmark method and defined as

Journal article

James EC, McNeish IA, Cook AD, Kaplan R, Clamp ARet al., 2020, Progression-free survival in the ICON8 trial - Authors' reply, The Lancet, Vol: 396, Pages: 757-757, ISSN: 0140-6736

Journal article

Millstein J, Budden T, Goode EL, Anglesio MS, Talhouk A, Intermaggio MP, Leong HS, Chen S, Elatre W, Gilks B, Nazeran T, Volchek M, Bentley RC, Wang C, Chiu DS, Kommoss S, Leung SCY, Senz J, Lum A, Chow V, Sudderuddin H, Mackenzie R, George J, AOCS Group, Fereday S, Hendley J, Traficante N, Steed H, Koziak JM, Köbel M, McNeish IA, Goranova T, Ennis D, Macintyre G, Silva D, Ramón Y Cajal T, García-Donas J, Polo SH, Rodriguez GC, Cushing-Haugen KL, Harris HR, Greene CS, Zelaya RA, Behrens S, Fortner RT, Sinn P, Herpel E, Lester J, Lubiński J, Oszurek O, Tołoczko A, Cybulski C, Menkiszak J, Pearce CL, Pike MC, Tseng C, Alsop J, Rhenius V, Song H, Jimenez-Linan M, Piskorz A, Gentry-Maharaj A, Karpinskyj C, Widschwendter M, Singh N, Kennedy CJ, Sharma R, Harnett PR, Gao B, Johnatty SE, Sayer R, Boros J, Winham SJ, Keeney GL, Kaufmann SH, Larson MC, Luk H, Hernandez BY, Thompson PJ, Wilkens LR, Carney ME, Trabert B, Lissowska J, Brinton L, Sherman ME, Bodelon C, Hinsley S, Lewsley LA, Glasspool R, Banerjee SN, Stronach EA, Haluska P, Ray-Coquard I, Mahner S, Winterhoff B, Slamon D, Levine DA, Kelemen LE, Benitez J, Chang-Claude J, Gronwald J, Wu AH, Menon U, Goodman MT, Schildkraut JM, Wentzensen N, Brown R, Berchuck A, Chenevix-Trench G, A deFazio, Gayther SA, García MJ, Henderson M, Rossing MA, Beeghly-Fadiel A, Fasching PA, Orsulic S, Karlan BY, Konecny GE, Huntsman DG, Bowtell DD, Brenton JD, Doherty JA, Pharoah PDP, Ramus SJet al., 2020, Prognostic gene expression signature for high-grade serous ovarian cancer, Annals of Oncology, Vol: 31, Pages: 1240-1250, ISSN: 0923-7534

BackgroundMedian overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is approximately four years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for overall survival in HGSOC patients.Patients and methodsExpression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, were measured using NanoString technology from formalin-fixed, paraffin-embedded (FFPE) tumour tissue from 3,769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from fifteen studies and evaluated on an independent set of 1067 tumours from six studies.ResultsExpression levels of 276 genes were associated with OS [false discovery rate (FDR) < 0.05] in covariate-adjusted single gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1, and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score (GES) conferred a greater than two-fold increase in risk of death [HR = 2.35 (2.02, 2.71); P < 0.001]. Median survival by GES quintile was 9.5 (8.3, --), 5.4 (4.6, 7.0), 3.8 (3.3, 4.6), 3.2 (2.9, 3.7) and 2.3 (2.1, 2.6) years.ConclusionThe OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

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