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

266 results found

Vergote I, Gonzalez-Martin A, Lorusso D, Gourley C, Mirza MR, Kurtz J-E, Okamoto A, Moore K, Kridelka F, McNeish I, Reuss A, Votan B, du Bois A, Mahner S, Ray-Coquard I, Kohn EC, Berek JS, Tan DSP, Colombo N, Zang R, Concin N, O'Donnell D, Rauh-Hain A, Herrington CS, Marth C, Poveda A, Fujiwara K, Stuart GCE, Oza AM, Bookman MA, participants of the 6th Gynecologic Cancer InterGroup GCIG Ovarian Cancer Consensus Conference on Clinical Researchet al., 2022, Clinical research in ovarian cancer: consensus recommendations from the Gynecologic Cancer InterGroup., Lancet Oncol, Vol: 23, Pages: e374-e384

The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer.

Journal article

McNeish I, Mirza H, 2022, A novel cell line panel reveals non-genetic mediators of platinum resistance and phenotypic diversity in high grade serous ovarian cancer, Gynecologic Oncology, ISSN: 0090-8258

Objectives: Resistance to cancer therapy is an enduring challenge and accurate and reliable preclinical models are lacking. We interrogated this unmet need using high grade serous ovarian cancer (HGSC) as a disease model. Methods: We created five in vitro and two in vivo platinum-resistant HGSC models and characterised the entire cell panel via whole genome sequencing, RNASeq and creation of intraperitoneal models. Results: Mutational signature analysis indicated that platinum-resistant cell lines evolved from a pre existing ancestral clone but a unifying mutational cause for drug resistance was not identified. However, cisplatin-resistant and carboplatin-resistant cells evolved recurrent changes in gene expression that significantly overlapped with independent samples obtained from multiple patients with relapsed HGSC. Gene Ontology Biological Pathways (GOBP) related to the tumour microenvironment, particularly the extracellular matrix, were repeatedly enriched in cisplatin50 resistant cells, carboplatin-resistant cells and also in human resistant/refractory samples. The majority of significantly over-represented GOBP however, evolved uniquely in either cisplatin- or carboplatin52 resistant cell lines resulting in diverse intraperitoneal behaviours that reflect different clinical manifestations of relapsed human HGSC. Conclusions: Our clinically relevant and usable models reveal a key role for non-genetic factors in theevolution of chemotherapy resistance. Biological pathways relevant to the extracellular matrix were repeatedly expressed by resistant cancer cells in multiple settings. This suggests that recurrent gene expression changes provide a fitness advantage during platinum therapy and also that cancer cell intrinsic mechanisms influence the tumour microenvironment during the evolution of drug resistance. Candidate genes and pathways identified here could reveal therapeutic opportunities in platinum60 resistant HGSC.

Journal article

Clamp AR, James EC, McNeish IA, Dean A, Kim J-W, O'Donnell DM, Gallardo-Rincon D, Blagden S, Brenton J, Perren TJ, Sundar S, Lord R, Dark G, Hall M, Banerjee S, Glasspool RM, Hanna CL, Williams S, Scatchard KM, Nam H, Essapen S, Parkinson C, McAvan L, Swart AM, Popoola B, Schiavone F, Badrock J, Fananapazir F, Cook AD, Parmar M, Kaplan R, Ledermann JAet al., 2022, Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal cancer treatment (ICON8): overall survival results from an open-label, randomised, controlled, phase 3 trial, The Lancet Oncology, Vol: 23, Pages: 919-930, ISSN: 1213-9432

BACKGROUND: Standard-of-care first-line chemotherapy for epithelial ovarian cancer is carboplatin and paclitaxel administered once every 3 weeks. The JGOG 3016 trial reported significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly (ie, once every 3 weeks) carboplatin. However, this benefit was not observed in the previously reported progression-free survival results of ICON8. Here, we present the final coprimary outcomes of overall survival and updated progression-free survival analyses of ICON8. METHODS: In this open-label, randomised, controlled, phase 3 trial (ICON8), women aged 18 years or older with newly diagnosed stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma (here collectively termed ovarian cancer, as defined by International Federation of Gynecology and Obstetrics [FIGO] 1988 criteria) and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited from 117 hospitals with oncology departments in the UK, Australia and New Zealand, Mexico, South Korea, and Ireland. Patients could enter the trial after immediate primary surgery (IPS) or with planned delayed primary surgery (DPS) during chemotherapy, or could have no planned surgery. Participants were randomly assigned (1:1:1), using the Medical Research Council Clinical Trials Unit at University College London randomisation line with stratification by Gynecologic Cancer Intergroup group, FIGO disease stage, and outcome and timing of surgery, to either 3-weekly carboplatin area under the curve (AUC)5 or AUC6 and 3-weekly paclitaxel 175 mg/m2 (control; group 1), 3-weekly carboplatin AUC5 or AUC6 and weekly paclitaxel 80 mg/m2 (group 2), or weekly carboplatin AUC2 and weekly paclitaxel 80 mg/m2 (group 3), all administered via intravenous infusion for a total of six 21-day cycles. Coprimary outcomes were progression-free survival and overall survival, with comparisons done between group 2 and group 1, and g

Journal article

Monk BJ, Parkinson C, Lim MC, O'Malley DM, Wilson MK, Coleman RL, Lorusso D, Bessette P, Ghamaande S, Christopoulou A, Provencher D, Prendergast E, Demirkiran F, Mikheeva O, Yeku O, Chudecka-Glaz A, Schenker M, Littell RD, Safra T, Chou H-H, Morgan MA, Drochytek V, Barlin JN, Van Gorp T, Ueland F, Lindahl G, Anderson C, Collins DC, Moore K, Marme F, Westin SN, McNeish I, Shih D, Lin KK, Goble S, Hume S, Fujiwara K, Kristeleit RSet al., 2022, A randomized, phase III trial to evaluate rucaparib monotherapy as maintenance treatment in patients with newly diagnosed ovarian cancer (ATHENA–MONO/GOG-3020/ENGOT-ov45), Journal of Clinical Oncology, Pages: 1-29, ISSN: 0732-183X

PURPOSE:ATHENA (ClinicalTrials.gov identifier: NCT03522246) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA–MONO comparison of rucaparib versus placebo.METHODS:Patients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and timing of surgery. The primary end point of investigator-assessed progression-free survival was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/loss of heterozygosity high tumor), and then in the intent-to-treat population.RESULTS:As of March 23, 2022 (data cutoff), 427 and 111 patients were randomly assigned to rucaparib or placebo, respectively (HRD population: 185 v 49). Median progression-free survival (95% CI) was 28.7 months (23.0 to not reached) with rucaparib versus 11.3 months (9.1 to 22.1) with placebo in the HRD population (log-rank P = .0004; hazard ratio [HR], 0.47; 95% CI, 0.31 to 0.72); 20.2 months (15.2 to 24.7) versus 9.2 months (8.3 to 12.2) in the intent-to-treat population (log-rank P < .0001; HR, 0.52; 95% CI, 0.40 to 0.68); and 12.1 months (11.1 to 17.7) versus 9.1 months (4.0 to 12.2) in the HRD-negative population (HR, 0.65; 95% CI, 0.45 to 0.95). The most common grade ≥ 3 treatment-emergent adverse events were anemia (rucaparib, 28.7% v placebo, 0%) and neutropenia (14.6% v 0.9%).CONCLUSION:Rucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ov

Journal article

Whelan E, Kalliala I, Semertzidou A, Raglan O, Bowden S, Kechagias K, Markozannes G, Cividini S, McNeish I, Marchesi J, MacIntyre D, Bennett P, Tsilidis K, Kyrgiou Met al., 2022, Risk Factors for Ovarian Cancer: An Umbrella Review of the Literature, Cancers, Vol: 14, Pages: 2708-2708

<jats:p>Several non-genetic factors have been associated with ovarian cancer incidence or mortality. To evaluate the strength and validity of the evidence we conducted an umbrella review of the literature that included systematic reviews/meta-analyses that evaluated the link between non-genetic risk factors and ovarian cancer incidence and mortality. We searched PubMed, EMBASE, Cochrane Database of Systematic Reviews and performed a manual screening of references. Evidence was graded into strong, highly suggestive, suggestive or weak based on statistical significance of the random effects summary estimate and the largest study in a meta-analysis, the number of cases, between-study heterogeneity, 95% prediction intervals, small study effects, and presence of excess significance bias. We identified 212 meta-analyses, investigating 55 non-genetic risk factors for ovarian cancer. Risk factors were grouped in eight broad categories: anthropometric indices, dietary intake, physical activity, pre-existing medical conditions, past drug history, biochemical markers, past gynaecological history and smoking. Of the 174 meta-analyses of cohort studies assessing 44 factors, six associations were graded with strong evidence. Greater height (RR per 10 cm 1.16, 95% confidence interval (CI) 1.11–1.20), body mass index (BMI) (RR ≥ 30 kg/m2 versus normal 1.27, 95% CI 1.17–1.38) and three exposures of varying preparations and usage related to hormone replacement therapy (HRT) use increased the risk of developing ovarian cancer. Use of oral contraceptive pill reduced the risk (RR 0.74, 95% CI 0.69–0.80). Refining the significance of genuine risk factors for the development of ovarian cancer may potentially increase awareness in women at risk, aid prevention and early detection.</jats:p>

Journal article

McNeish I, Clamp A, James EC, Dean A, Kim J-W, ODonnell DM, Gallardo-Rincon D, Blagden S, Brenton J, Perren TJ, Sundar S, Lord R, Dark G, Hall M, Banerjee S, Glasspool RM, Hanna L, Williams S, Scratchard KM, Nam H, Essapen S, Parkinson C, McAvan L, Swart AM, Popoola B, Schiavone F, Badrock J, Fananapazir F, Cook AD, Parmar M, Kaplan R, Ledermann JAet al., 2022, Overall survival results from ICON8, a GCIG phase 3 randomised controlled trial assessing weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal cancer treatment, The Lancet Oncology, ISSN: 1213-9432

Background:Standard of care first line chemotherapy for epithelial ovarian cancer (EOC) is carboplatin and paclitaxel administered once every three weeks. The JGOG3016 trial reported significant improvement in progression-free (PFS) and overall survival (OS) with dose-dense weekly paclitaxel andthree-weekly carboplatin. However, this benefit was not observed in the progression free survival results of ICON8, previously reported. Here, we present the final co-primary OS and updated PFS outcomes.Methods:Women aged 18 or above with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage IC-IV EOC were recruited. Patients were randomly assigned to one of three groups; group 1: 3-weekly carboplatin area under the curve (AUC) 5/6 and 3-weekly paclitaxel 175mg/m2, group 2: 3-weekly carboplatin AUC5/6 and weekly paclitaxel 80mg/m2, group 3: weekly carboplatin AUC2 and weekly paclitaxel 80mg/m2, all administered by intravenous infusion. Patientsentered the trial after immediate primary surgery (IPS) or received delayed primary surgery (DPS) during chemotherapy. Randomisation was performed using minimisation with stratification factors of GCIG group, disease stage and outcome and timing of surgery. Co-primary outcomes were PFS and OS, with comparisons performed between group 2 and group 1, and group 3 and group 1. Intention-to-treat analyses were powered to detect a hazard ratio of 0.75 in favour of the experimental groups. The trial is registered on clinicaltrials.gov as NCT01654146 and controlled-trials.com asISRCTN10356387.Findings:Between 6 Jun 2011 and 28 Nov 2014, 1566 women were recruited; group 1 (N=522), group 2 (N=523) and group 3 (N=521). Baseline characteristics include median age 62, 69% high grade serouscarcinoma, 72% stage IIIC-IV disease, 48% IPS. By March 2020, with a median follow up of 69 months (IQR 61-75 months), 324, 309 and 313 deaths had occurred in groups 1, 2 and 3 respectively. No significant difference in OS was observed

Journal article

Cheng Z, Mirza H, Ennis DP, Smith P, Morrill Gavarro L, Sokota C, Giannone G, Goranova T, Bradley T, Piskorz A, Lockley M, for the BriTROC-1 Investigators, Kaur B, Singh N, Tookman L, Krell J, McDermott J, Macintyre G, Markowetz F, Brenton JD, McNeish Iet al., 2022, The genomic landscape of early-stage ovarian high grade serous carcinoma, Clinical Cancer Research, Vol: 28, Pages: 2911-2922, ISSN: 1078-0432

Purpose: Ovarian high grade serous carcinoma (HGSC) is usually diagnosed at late stage. We investigated whether late-stage HGSC has unique genomic characteristics consistent with acquisition of volutionary advantage compared to early-stage tumours.Experimental Design: We performed targeted next generation sequencing and shallow whole genome sequencing (sWGS) on pre-treatment samples from 43 patients with FIGO stage I–IIA HGSC to investigate somatic mutations and copy number alterations (SCNA). We comparedresults to pre-treatment samples from 52 stage IIIC/IV HGSC patients from the BriTROC-1 study.Results: Age of diagnosis did not differ between early-stage and late-stage patients (median 61.3 years vs 62.3 years respectively). TP53 mutations were near-universal in both cohorts (89% early-stage, 100% late-stage) and there were no significant differences in the rates of other somatic mutations, including BRCA1 and BRCA2. We also did not observe cohort-specific focal SCNA that could explain biological behaviour. However, ploidy was higher in late-stage (median 3.0) than early-stage (median 1.9) samples. Copy number (CN) signature exposures were significantly different between cohorts, with greater relative signature 3 exposure in early-stage and greater signature 4 in late-stage. Unsupervised clustering based on CN signatures identified three clustersthat were prognostic.Conclusions: Early stage and late stage HGSC have highly similar patterns of mutation and focal SCNA. However, copy number signature analysis showed that late-stage disease has distinct signature exposures consistent with whole genome duplication. Further analyses will be required to ascertain whether these differences reflect genuine biological differences between early and late-stage or simply time-related markers of evolutionary fitness.

Journal article

Dareng EO, Tyrer JP, Barnes DR, Jones MR, Yang X, Aben KKH, Adank MA, Agata S, Andrulis IL, Anton-Culver H, Antonenkova NN, Aravantinos G, Arun BK, Augustinsson A, Balmana J, Bandera EV, Barkardottir RB, Barrowdale D, Beckmann MW, Beeghly-Fadiel A, Benitez J, Bermisheva M, Bernardini MQ, Bjorge L, Black A, Bogdanova NV, Bonanni B, Borg A, Brenton JD, Budzilowska A, Butzow R, Buys SS, Cai H, Caligo MA, Campbell I, Cannioto R, Cassingham H, Chang-Claude J, Chanock SJ, Chen K, Chiew Y-E, Chung WK, Claes KBM, Colonna S, Cook LS, Couch FJ, Daly MB, Dao F, Davies E, de la Hoya M, de Putter R, Dennis J, DePersia A, Devilee P, Diez O, Ding YC, Doherty JA, Domchek SM, Dork T, du Bois A, Durst M, Eccles DM, Eliassen HA, Engel C, Evans GD, Fasching PA, Flanagan JM, Fortner RT, Machackova E, Friedman E, Ganz PA, Garber J, Gensini F, Giles GG, Glendon G, Godwin AK, Goodman MT, Greene MH, Gronwald J, Hahnen E, Haiman CA, Hakansson N, Hamann U, Hansen TVO, Harris HR, Hartman M, Heitz F, Hildebrandt MAT, Hogdall E, Hogdall CK, Hopper JL, Huang R-Y, Huff C, Hulick PJ, Huntsman DG, Imyanitov EN, Isaacs C, Jakubowska A, James PA, Janavicius R, Jensen A, Johannsson OT, John EM, Jones ME, Kang D, Karlan BY, Karnezis A, Kelemen LE, Khusnutdinova E, Kiemeney LA, Kim B-G, Kjaer SK, Komenaka I, Kupryjanczyk J, Kurian AW, Kwong A, Lambrechts D, Larson MC, Lazaro C, Le ND, Leslie G, Lester J, Lesueur F, Levine DA, Li L, Li J, Loud JT, Lu KH, Lubinski J, Mai PL, Manoukian S, Marks JR, Matsuno RK, Matsuo K, May T, McGuffog L, McLaughlin JR, McNeish IA, Mebirouk N, Menon U, Miller A, Milne RL, Minlikeeva A, Modugno F, Montagna M, Moysich KB, Munro E, Nathanson KL, Neuhausen SL, Nevanlinna H, Yie JNY, Nielsen HR, Nielsen FC, Nikitina-Zake L, Odunsi K, Offit K, Olah E, Olbrecht S, Olopade OI, Olson SH, Olsson H, Osorio A, Papi L, Park SK, Parsons MT, Pathak H, Pedersen IS, Peixoto A, Pejovic T, Perez-Segura P, Permuth JB, Peshkin B, Peterlongo P, Piskorz A, Prokofyeva D, Radice P, Rantala J, Riggaet al., 2022, Polygenic risk modeling for prediction of epithelial ovarian cancer risk (vol 30, pg 349, 2021), EUROPEAN JOURNAL OF HUMAN GENETICS, Vol: 30, Pages: 630-631, ISSN: 1018-4813

Journal article

Vergote I, Gonzalez-Martin A, Ray-Coquard I, Harter P, Colombo N, Pujol P, Lorusso D, Mirza MR, Brasiuniene B, Madry R, Brenton JD, Ausems MGEM, Buettner R, Lambrechts Det al., 2022, European experts consensus: BRCA/homologous recombination deficiency testing in first-line ovarian cancer, ANNALS OF ONCOLOGY, Vol: 33, Pages: 276-287, ISSN: 0923-7534

Journal article

Dareng EO, Tyrer JP, Barnes DR, Jones MR, Yang X, Aben KKH, Adank MA, Agata S, Andrulis IL, Anton-Culver H, Antonenkova NN, Aravantinos G, Arun BK, Augustinsson A, Balmana J, Bandera E, Barkardottir RB, Barrowdale D, Beckmann MW, Beeghly-Fadiel A, Benitez J, Bermisheva M, Bernardini MQ, Bjorge L, Black A, Bogdanova N, Bonanni B, Borg A, Brenton JD, Budzilowska A, Butzow R, Buys SS, Cai H, Caligo MA, Campbell I, Cannioto R, Cassingham H, Chang-Claude J, Chanock SJ, Chen K, Chiew Y-E, Chung WK, Claes KBM, Colonna S, Cook LS, Couch FJ, Daly MB, Dao F, Davies E, de la Hoya M, de Putter R, Dennis J, DePersia A, Devilee P, Diez O, Ding YC, Doherty JA, Domchek SM, Dork T, du Bois A, Durst M, Eccles DM, Eliassen HA, Engel C, Evans GD, Fasching PA, Flanagan JM, Fortner R, Machackova E, Friedman E, Ganz PA, Garber J, Gensini F, Giles GG, Glendon G, Godwin AK, Goodman MT, Greene MH, Gronwald J, Group OS, AOCSGroup, Hahnen E, Haiman CA, Hakansson N, Hamann U, Hansen TVO, Harris HR, Hartman M, Heitz F, Hildebrandt MAT, Hogdall E, Hogdall CK, Hopper JL, Huang R-Y, Huff C, Hulick PJ, Huntsman DG, Imyanitov EN, Isaacs C, Jakubowska A, James PA, Janavicius R, Jensen A, Johannsson OT, John EM, Jones ME, Kang D, Karlan BY, Karnezis A, Kelemen LE, Khusnutdinova E, Kiemeney LA, Kim B-G, Kjaer SK, Komenaka I, Kupryjanczyk J, Kurian AW, Kwong A, Lambrechts D, Larson MC, Lazaro C, Le ND, Leslie G, Lester J, Lesueur F, Levine DA, Li L, Li J, Loud JT, Lu KH, Mai PL, Manoukian S, Marks JR, KimMatsuno R, Matsuo K, May T, McGuffog L, McLaughlin JR, McNeish IA, Mebirouk N, Menon U, Miller A, Milne RL, Minlikeeva A, Modugno F, Montagna M, Moysich KB, Munro E, Nathanson KL, Neuhausen SL, Nevanlinna H, Yie JNY, Nielsen HR, Nielsen FC, Nikitina-Zake L, Odunsi K, Offit K, Olah E, Olbrecht S, Olopade O, Olson SH, Olsson H, Osorio A, Papi L, Park SK, Parsons MT, Pathak H, Pedersen IS, Peixoto A, Pejovic T, Perez-Segura P, Permuth JB, Peshkin B, Peterlongo P, Piskorz A, Prokofyeva D, Radice P, Rantalaet al., 2022, Polygenic risk modeling for prediction of epithelial ovarian cancer risk, European Journal of Human Genetics, Vol: 30, Pages: 349-362, ISSN: 1018-4813

Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.

Journal article

McNeish I, 2022, Sixth ovarian cancer consensus conference on clinical research of the gynecologic cancer InterGroup, The Lancet Oncology, ISSN: 1213-9432

The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research (OCCC6) was held virtually in October 2021 following published consensus guidelines. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within 4 topic groups on clinical research including first line treatment, recurrent disease, disease subgroups and future trials. Unanimous consensus was obtained for 14 of 20 statements, with >90% concordance in the remaining 6 statements. The high acceptance rate following active deliberation amongst the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote harmonisation of international clinical research in ovarian cancer.

Journal article

McNeish I, Spiliopoulou P, Spear S, Mirza H, Garner I, grundland-freile F, Cheng Z, Ennis D, Iyer N, McNamara S, Natoli M, Fuchter M, Brown Ret al., 2022, Dual G9A/EZH2 inhibition stimulates anti-tumour immune response in ovarian high-grade serous carcinoma, Molecular Cancer Therapeutics, Vol: 21, Pages: 522-534, ISSN: 1535-7163

Ovarian high-grade serous carcinoma (HGSC) prognosis correlates directly with presence of intratumoral lymphocytes. However, cancer immunotherapy has yet to achieve meaningful survival benefit in patients with HGSC. Epigenetic silencing of immunostimulatory genes is implicated in immune evasion in HGSC and re-expression of these genes could promote tumour immune clearance. We discovered that simultaneous inhibition of the histone methyltransferases G9A and EZH2 activates the CXCL10-CXCR3 axis and increases homing of intratumoral effector lymphocytes and natural killer cells whilst suppressing tumour-promoting FoxP3+ CD4 T cells. The dual G9A/EZH2 inhibitor HKMTI-1-005 induced chromatin changes that resulted in the transcriptional activation of immunostimulatory gene networks, including the re-expression of elements of the ERV-K endogenous retroviral family. Importantly, treatment with HKMTI-1-005 improved the survival of mice bearing Trp53-/- null ID8 ovarian tumours and resulted in tumour burden reduction. These results indicate that inhibiting G9A and EZH2 in ovarian cancer alters the immune microenvironment and reduces tumour growth and therefore positions dual inhibition of G9A/EZH2 as a strategy for clinical development.

Journal article

Samani A, Bennett R, Eremeishvili K, Kalofonou F, Whear S, Montes A, Kristeleit R, Krell J, McNeish I, Ghosh S, Tookman Let al., 2022, Glomerular filtration rate estimation for carboplatin dosing in patients with gynaecological cancers, ESMO Open, Vol: 7, ISSN: 2059-7029

Background:Carboplatin remains integral for treatment of gynaecological malignancies and dosing is based on glomerular filtration rate (GFR). Measurement via radiotracer decay (nmGFR) is ideal. However, this may be unavailable. Therefore, GFR is often estimated using formulae that have not been validated in patients with cancer and/or specifically for gynaecological malignancies, leading to debate over optimal estimation. Suboptimal GFR estimation may affect efficacy or toxicity. Methods:We surveyed several UK National Health Service Trusts to assess carboplatin dosing practise. We then explored single-centre accuracy, bias and precision of various formulae for GFR estimation, relative to nmGFR, before validating our findings in an external cohort. Results:Across 18 Trusts, there was considerable heterogeneity in GFR estimation, including the formulae used (Cockcroft-Gault (CG) vs Wright), weight-adjustment and area under the curve (5 vs 6). We analysed 274 and 192 patients in two centres. Overall, CamGFR v2 (a novel formula for GFR estimation developed at Cambridge University Hospitals NHS Foundation Trust) excelled, showing the highest accuracy and precision. This translated into accuracy of hypothetical carboplatin dosing; nmGFR-derived carboplatin dose fell within 20% of the Cam GFR v2-derived dose in 86.5% and 87% of patients across the cohorts. Amongst the CG formula and its derivatives, using adjusted body weight in those with BMI ≥25 kg/m2 (CG-AdBW) was optimal. The Wright and unadjusted CG estimators performed most poorly. Conclusions:When compared with nmGFR assessment, accuracy, bias and precision varied widely between GFR estimators, with the newly developed Cam GFR v2 and CG-AdBW perfoming best. In general, weight (or body surface area)-adjusted formulae performed best, while the unadjusted CG and Wright formulae or the use of AUC6 (vs. nmGFR AUC5) produced risk of significant overdose. Thus, individual centres should validate their GFR estimation me

Journal article

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, Vol: 9, Pages: 1-14, ISSN: 2051-1426

Background Treatment outcomes remain poor in recurrent platinum-resistant ovarian cancer. Enadenotucirev, a tumor-selective and blood stable adenoviral vector, has demonstrated a manageable safety profile in phase 1 studies in epithelial solid tumors.Methods We conducted a multicenter, open-label, phase 1 dose-escalation and dose-expansion study (OCTAVE) to assess enadenotucirev plus paclitaxel in patients with platinum-resistant epithelial ovarian cancer. During phase 1a, the maximum tolerated dose of intraperitoneally administered enadenotucirev monotherapy (three doses; days 1, 8 and 15) was assessed using a 3+3 dose-escalation model. Phase 1b included a dose-escalation and an intravenous dosing dose-expansion phase assessing enadenotucirev plus paclitaxel. For phase 1a/b, the primary objective was to determine the maximum tolerated dose of enadenotucirev (with paclitaxel in phase 1b). In the dose-expansion phase, the primary endpoint was progression-free survival (PFS). Additional endpoints included response rate and T-cell infiltration.Results Overall, 38 heavily pretreated patients were enrolled and treated. No dose-limiting toxicities were observed at any doses. However, frequent catheter complications led to the discontinuation of intraperitoneal dosing during phase 1b. Intravenous enadenotucirev (1×1012 viral particles; days 1, 3 and 5 every 28-days for two cycles) plus paclitaxel (80 mg/m2; days 9, 16 and 23 of each cycle) was thus selected for dose-expansion. Overall, 24/38 (63%) patients experienced at least 1 Grade ≥3 treatment-emergent adverse event (TEAE); most frequently neutropenia (21%). Six patients discontinued treatment due to TEAEs, including one patient due to a grade 2 treatment-emergent serious AE of catheter site infection (intraperitoneal enadenotucirev monotherapy). Among the 20 patients who received intravenous enadenotucirev plus paclitaxel, 4-month PFS rate was 64% (median 6.2 months), objective response rate was

Journal article

McNeish I, 2021, Characterization of patients with long-term responses to rucaparib treatment in recurrent ovarian cancer, Gynecologic Oncology, Vol: 163, Pages: 490-497, 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

Kwan TT, Oza AM, Tinker A, Ray-Coquard I, Oaknin A, Aghajanian C, Lorusso D, Colombo N, Dean A, Weberpals J, Severson E, Lan-Thanh V, 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 ONCOLOGY, Vol: 7, Pages: 1772-1781, ISSN: 2374-2437

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, Marme F, 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, INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, Vol: 31, Pages: 1589-1594, ISSN: 1048-891X

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

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

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