244 results found
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.
Lythgoe MP, Krell J, McNeish IA, et 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.
Ewing A, Meynert A, Churchman M, et 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.
Konecny GE, Oza AM, Tinker AV, et 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.
Braund M, Barras D, Mina M, et al., 2021, Cell-autonomous inflammation of BRCA1-deficient ovarian cancers drives both tumor-intrinsic immunoreactivity and immune resistance through STING, Cell Reports, 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
Spiliopoulou P, Hinsley S, McNeish IA, et al., 2021, Metronomic oral cyclophosphamide in relapsed ovarian cancer, International Journal of Gynecological Cancer, 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.
Swisher EM, Kwan TT, Oza AM, et 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.
Lindzen M, Ghosh S, Noronha A, et 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
Cohen PA, Powell A, Bohm S, et 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
Macintyre G, Piskorz AM, Berman A, et 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.
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.
Morgan RD, McNeish IA, Cook AD, et 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
Laird BJ, McMillan D, Skipworth RJE, et al., 2021, The emerging role of Interleukin 1β (IL-1β) in cancer cachexia, Inflammation, 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.
Glubb DM, Thompson DJ, Aben KKH, et 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
Semertzidou A, Brosens JJ, McNeish I, et al., 2020, Organoid models in gynaecological oncology research, CANCER TREATMENT REVIEWS, Vol: 90, ISSN: 0305-7372
Konecny GE, Oza AM, Tinker AV, et 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
Marth C, Vulsteke C, Rubio MJR, et 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
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.
McNeish I, Morgan RD, Cook AD, et 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
James EC, McNeish IA, Cook AD, et al., 2020, Progression-free survival in the ICON8 trial - Authors' reply, The Lancet, Vol: 396, Pages: 757-757, ISSN: 0140-6736
Millstein J, Budden T, Goode EL, et 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.
Blagden SP, Cook AD, Poole C, et al., 2020, Weekly platinum-based chemotherapy versus 3-weekly platinum-based chemotherapy for newly diagnosed ovarian cancer (ICON8): quality-of-life results of a phase 3, randomised, controlled trial, The Lancet Oncology, Vol: 21, Pages: 969-977, ISSN: 1213-9432
BACKGROUND: The ICON8 study reported no significant improvement in progression-free survival (a primary endpoint) with weekly chemotherapy compared with standard 3-weekly treatment among patients with epithelial ovarian cancer. All ICON8 patients were eligible to take part in the accompanying health-related quality-of-life study, which measured the effect of treatment on self-reported wellbeing, reported here. METHODS: In this open-label, randomised, controlled, phase 3, three-arm, Gynecologic Cancer Intergroup (GCIG) trial done at 117 hospital sites in the UK, Australia, New Zealand, Mexico, South Korea, and Republic of Ireland, women (aged at least 18 years) with newly diagnosed, histologically confirmed International Federation of Gynecology and Obstetrics stage IC-IV ovarian cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were randomly assigned (1:1:1) centrally using minimisation to group 1 (intravenous carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 intravenous paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 weekly and 80 mg/m2 paclitaxel weekly). Randomisation was stratified by GCIG group, disease stage, and outcome and timing of surgery. Patients and clinicians were not masked to treatment assignment. Patients underwent immediate or delayed primary surgery according to clinicians' choice. Patients were asked to complete European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 questionnaires at enrolment, before each chemotherapy cycle, then 6-weekly up to 9 months, 3-monthly up to 2 years, and 6-monthly up to 5 years. Quality of life was a prespecified secondary outcome of the ICON8 study. Within the quality-of-life study, the co-primary endpoints were QLQ-C30 global health score at 9 months (cross-sectional analysis) and mean QLQ-C30 global health score from randomisation to 9 months (longitudinal analysis)
Greggi S, Falcone F, Scaffa C, et al., 2020, Evaluation of surgical resection in advanced ovarian, fallopian tube, and primary peritoneal cancer: laparoscopic assessment. A European Network of Gynaecological Oncology Trial (ENGOT) group survey, International Journal of Gynecological Cancer, Vol: 30, Pages: 819-824, ISSN: 1048-891X
OBJECTIVE: Laparoscopy is one of the diagnostic tools available for the complex clinical decision-making process in advanced ovarian, fallopian tube, and peritoneal carcinoma. This article presents the results of a survey conducted within the European Network of Gynaecological Oncology Trial (ENGOT) group aimed at reviewing the current patterns of practice at gynecologic oncology centers with regard to the evaluation of resection in advanced ovarian, fallopian tube, and peritoneal carcinoma. METHODS: A 24-item questionnaire was sent to the chair of the 20 cooperative groups that are currently part of the ENGOT group, and forwarded to the members within each group. RESULTS: A total of 142 questionnaires were returned. Only 39 respondents (27.5%) reported using some form of clinical (not operative) score for the evaluation of resection. The frequency of use of diagnostic laparoscopy to assess disease status and feasibility of resection was as follows: never, 21 centers (15%); only in select cases, 83 centers (58.5%); and routinely, 36 centers (25.4%). When laparoscopy was performed, 64% of users declared they made the decision to proceed with maximal effort cytoreductive surgery based on their personal/staff opinion, and 36% based on a laparoscopic score. To the question of whether laparoscopy should be considered the gold standard in the evaluation of resection, 71 respondents (50%) answered no, 66 respondents (46.5%) answered yes, whereas 5 respondents (3.5%) did not provide an answer. CONCLUSIONS: This study found that laparoscopy was routinely performed to assess feasibility of cytoreduction in only 25.4% of centers in Europe. However, it was commonly used to select patients and in a minority of centers it was never used . When laparoscopy was adopted, the treatment strategy was based on laparoscopic scores only in a minority of centers.
Tookman L, Krell J, Nkolobe B, et al., 2020, Practical guidance for the management of side effects during rucaparib therapy in a multidisciplinary UK setting, Therapeutic Advances in Medical Oncology, Vol: 12, ISSN: 1758-8340
The use of targeted therapeutics known as poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in the management of ovarian cancer is currently transforming clinical practice. The PARP inhibitor rucaparib is indicated in the UK, European Union and the United States for use in the treatment and maintenance settings for patients with relapsed ovarian cancer. Here, we discuss some of the real-world challenges and side effects that we have encountered while prescribing rucaparib, and we provide practical guidance on how the individual members of our multidisciplinary team (MDT), including a clinician, chemotherapy nurse practitioner, and clinical pharmacist, collaborate to manage these side effects. If recognized early, the side effects experienced by patients during rucaparib therapy, which include fatigue, nausea and vomiting, liver enzyme elevations, and anemia, can be easily managed. For example, providing patients with prophylactic antiemetics can help them avoid nausea, and early detection of decreases in hemoglobin levels allows for proactive interventions to alleviate anemia. The MDT should work together with the patient to identify potential side effects early and manage them effectively. The aim of this proactive approach is to maintain patients on rucaparib for optimal clinical benefit, while minimizing the potential negative impact of side effects on patient quality of life.
Swisher EM, Kristeleit RS, Oza AM, et al., 2020, Characterization of patients (pts) with long-term responses to rucaparib in recurrent ovarian cancer (OC)., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
Marth C, Vulsteke C, Perez MJR, et al., 2020, ENGOT-en9/LEAP-001: A phase III study of first-line pembrolizumab plus lenvatinib versus chemotherapy in advanced or recurrent endometrial cancer., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
McNeish I, 2020, Tumors defective in homologous recombination rely on oxidative metabolism: Relevance to treatments with PARP inhibitors, EMBO Molecular Medicine, Vol: 12, Pages: 1-23, ISSN: 1757-4676
Mitochondrial metabolism and the generation of reactive oxygen species (ROS) contribute to the acquisition of DNA mutations and genomic instability in cancer. How genomic instability influences the metabolic capacity of cancer cells is nevertheless poorly understood. Here, we show that homologous recombination‐defective (HRD) cancers rely on oxidative metabolism to supply NAD+ and ATP for poly(ADP‐ribose) polymerase (PARP)‐dependent DNA repair mechanisms. Studies in breast and ovarian cancer HRD models depict a metabolic shift that includes enhanced expression of the oxidative phosphorylation (OXPHOS) pathway and its key components and a decline in the glycolytic Warburg phenotype. Hence, HRD cells are more sensitive to metformin and NAD+ concentration changes. On the other hand, shifting from an OXPHOS to a highly glycolytic metabolism interferes with the sensitivity to PARP inhibitors (PARPi) in these HRD cells. This feature is associated with a weak response to PARP inhibition in patient‐derived xenografts, emerging as a new mechanism to determine PARPi sensitivity. This study shows a mechanistic link between two major cancer hallmarks, which in turn suggests novel possibilities for specifically treating HRD cancers with OXPHOS inhibitors.
Lau TS, Chan LK-Y, Man GC-W, et al., 2020, Paclitaxel induces immunogenic cell death in ovarian cancer via TLR4/IKK2/SNARE-dependent exocytosis, Cancer Immunology Research, Vol: 8, Pages: 1099-1111, ISSN: 2326-6066
Emerging evidence shows that the efficacy of chemotherapeutic drugs are reliant on their capability to induce immunogenic cell death (ICD), thus transforming dying tumor cells into antitumor vaccines. We wanted to uncover potential therapeutic strategies that target ovarian cancer by having a better understanding of the standard-of-care chemotherapy treatment. Here, we showed in ovarian cancer that paclitaxel induced ICD-associated DAMPs (i.e. damage-associated molecular patterns, such as CALR exposure, ATP secretion and HMGB1 release) in vitro and elicited significant antitumor responses in tumor vaccination assays in vivo. Paclitaxel-induced TLR4 signaling was essential to the release of DAMPs, which lead to the activation of NF-κB-mediated CCL2 transcription and IKK2-mediated SNARE-dependent vesicle exocytosis, thus exposing CALR on the cell surface. Paclitaxel induced ER stress, which triggered PERK activation and eIF2α phosphorylation independent of TLR4. Paclitaxel chemotherapy induced T cell infiltration in ovarian tumors of the responsive patients; CALR expression in primary ovarian tumors also correlated with patients' survival and patient response to chemotherapy. These findings suggest that the effectiveness of paclitaxel relied upon the activation of antitumor immunity through ICD via TLR4 and highlighted the importance of CALR expression in cancer cells as an indicator of response to paclitaxel chemotherapy in ovarian cancer.
McNeish I, 2020, Quality of Life with weekly platinum-based chemotherapy in newly diagnosed Ovarian Cancer: the ICON8 phase III randomised controlled clinical trial, The Lancet Oncology, ISSN: 1213-9432
Background: The ICON8 study compared standard 3-weekly carboplatin and paclitaxel (arm 1) to 3-weekly carboplatin and weekly dose-dense paclitaxel (arm 2) or weekly dose-dense carboplatin and paclitaxel (arm 3) in patients with newly diagnosed, advanced or high-risk early stage ovarian cancer. All patients were invited into the accompanying health-related quality of life (QOL) study, designed to compare the impact of the treatment arms on their self-reported wellbeing. Methods: Patients were randomised 1:1:1 to study arms 1, 2 or 3. They underwent immediate or delayed primary surgery (IPS or DPS) according to clinicians’ choice. Patients were asked to complete EORTC-QLQ-C30 and OV28 questionnaires at enrolment, before each chemotherapy cycle, every 6 weeks to 9 months, every 3 months to 2 years and then every 6 months for up to 5 years. QOL was a pre-specified secondary outcome of the ICON8 study. Within the QOL study, co-primary endpoints were global QOL score at 9 months (cross-sectional analysis) and average global QOL score from randomisation to 9 months (longitudinal analysis). Secondary endpoints were four QOL subscores: fatigue, neuropathy, social and emotional functioning. Findings: 17,515 QOL questionnaires were completed by 1,540 patients. There was no significant difference in global QOL at 9 months between the study arms (arm 2 vs 1, diff=2.3, 95% CI (-0.4 to 4.9), p=0.095; arm 3 vs 1, diff=-0.8, 95%CI (-3.8 to 2.2), p=0.613). However, using longitudinal analysis, there was marginally poorer global QOL for those receiving weekly paclitaxel (arms 2 and 3) from randomisation to 9 months (arm 2 vs 1, diff=-1.8, 95%CI (-3.6 to -0.1), p=0.043; arm 3 vs 1, -2.9, 95%CI (-4.7 to -1.1), p=0.002). Peripheral neuropathy was of later onset in arms 2 and 3 but was more severe and persisted for at least nine months. QOL differences were less marked in patients who underwent DPS. Interpretation: Although there was no evidence of a difference between treatment arm
Leung EYL, Ennis D, Kennedy PR, et al., 2020, NK cells augment oncolytic adenovirus cytotoxicity in ovarian cancer, Molecular Therapy - Oncolytics, Vol: 16, Pages: 289-301, ISSN: 2372-7705
Oncolytic viruses (OVs) can trigger profound innate and adaptive immune responses, which have the potential both to potentiate and reduce the activity of OVs. Natural killer (NK) cells can mediate potent anti-viral and anti-tumoral responses, but there are no data on the role of NK cells in oncolytic adenovirus activity. Here, we have used two different oncolytic adenoviruses—the Ad5 E1A CR2-deletion mutant dl922-947 (group C) and the chimeric Ad3/Ad11p mutant enadenotucirev (group B)—to investigate the effect of NK cells on overall anti-cancer efficacy in ovarian cancer. Because human adenoviruses do not replicate in murine cells, we utilized primary human NK cells from peripheral blood and ovarian cancer ascites. Our results show that dl922-947 and enadenotucirev do not infect NK cells, but induce contact-dependent activation and anti-cancer cytotoxicity against adenovirus-infected ovarian cancer cells. Moreover, manipulation of NK receptors DNAM-1 (DNAX accessory molecule-1) and TIGIT (T cell immunoreceptor with Ig and ITIM domains) significantly influences NK cytotoxicity against adenovirus-infected cells. Together, these results indicate that NK cells act to increase the activity of oncolytic adenovirus in ovarian cancer and suggest that strategies to augment NK activity further via the blockade of inhibitory NK receptor TIGIT could enhance therapeutic potential of OVs.
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