Showing papers by "Jonathan A. Ledermann published in 2022"
TL;DR: In this article , the ESMO Clinical Practice Guideline provides key recommendations for managing endometrial cancer, including clinical and pathological diagnosis, staging and risk assessment, treatment and follow-up.
63 citations
TL;DR: In the SOLO2 trial as mentioned in this paper , maintenance olaparib in patients with relapsed ovarian cancer (PSROC) and BRCA mutation significantly improved progression-free survival (PFS) and prolonged overall survival (OS).
24 citations
TL;DR: In this paper , the authors defined hereditary breast and ovarian cancer syndrome (HBOC) by family history criteria and molecularly defined by identification of germline pathogenic variants (PVs) in clinically validated HBOC genes.
15 citations
TL;DR: The phase IIIb OPINION trial (NCT03402841) as mentioned in this paper investigated olaparib maintenance monotherapy in patients without a deleterious BRCA1/BRCA2 mutation.
11 citations
TL;DR: The ARIEL3 trial as mentioned in this paper showed that rucaparib treatment was associated with exceptional benefit compared with placebo: 79/375 (21.1%) vs 4/189 (2.1%), respectively (p < 0.0001).
8 citations
TL;DR: Some of the challenges in treating patients with platinum resistance are described and refinements in the selection of patients most likely to benefit from targeting a DNA damage response, angiogenesis or immune modulation are suggested.
Abstract: Definitions of platinum resistance have been questioned and changed over the last five years, even though no predictive biomarker of resistance exists. These have sculpted how we approach platinum retreatment and, consequently, how we devise new treatment strategies for those patients with tumour progression on platinum therapy. Platinum-non-eligible ovarian cancer is treated with single-agent non-platinum drugs. When bevacizumab can be added to chemotherapy, progression-free survival improves significantly. For patients with a BRCA mutation, PARP inhibitor monotherapy is an option compared to chemotherapy. There is currently no clearly identified role for immune-checkpoint inhibition in this patient population. This review describes some of the challenges in treating patients with platinum resistance and suggests refinements in the selection of patients most likely to benefit from targeting a DNA damage response, angiogenesis or immune modulation. It also describes novel agents of interest and possible mechanisms of the synergy of therapeutic combinations.
6 citations
TL;DR: The effects of chemotherapy on symptoms and health-related quality of life (HRQL) in women having chemotherapy for platinum resistant/refractory recurrent ovarian cancer and potentially platinum sensitive with ≥3 lines of chemotherapy was evaluated.
Abstract: Objective The Gynecologic Cancer InterGroup (GCIG)-Symptom Benefit Study was designed to evaluate the effects of chemotherapy on symptoms and health-related quality of life (HRQL) in women having chemotherapy for platinum resistant/refractory recurrent ovarian cancer (PRR-ROC) and potentially platinum sensitive with ≥3 lines of chemotherapy (PPS-ROC ≥3). Methods Participants completed the Measure of Ovarian Cancer Symptoms and Treatment (MOST) and European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 questionnaires at baseline and every 3–4 weeks until progression. Participants were classified symptomatic if they rated ≥4 of 10 in at least one-third of symptoms in the MOST index. Improvement in MOST was defined as two consecutive scores of ≤3 in at least half of the symptomatic items at baseline. Improvement in HRQL was defined as two consecutive scores ≥10 points above baseline in the QLQ-C30 summary score scale (range 0–100). Results Of 948 participants enrolled, 910 (96%) completed baseline questionnaires: 546 with PRR-ROC and 364 with PPS-ROC ≥3. The proportions of participants symptomatic at baseline as per MOST indexes were: abdominal 54%, psychological 53%, and disease- or treatment-related 35%. Improvement was reported in MOST indexes: abdominal 40%, psychological 35%, and disease- or treatment-related 38%. Median time to improvement in abdominal symptoms occurred earlier for PRR-ROC than for PPS-ROC ≥3 (4 vs 6 weeks, p=0.044); median duration of improvement was also similar (9.0 vs 11.7 weeks, p=0.65). Progression-free survival was longer among those with improvement in abdominal symptoms than in those without (median 7.2 vs 2.5 months, p<0.0001). Improvements in HRQL were reported by 77/448 (17%) with PRR-ROC and 61/301 (20%) with PPS-ROC ≥3 (p=0.29), and 102/481 (21%) of those with abdominal symptoms at baseline. Conclusion Over 50% of participants reported abdominal and psychological symptoms at baseline. Of those, 40% reported an improvement within 2 months of starting chemotherapy. Approximately one in six participants reported an improvement in HRQL. Symptom monitoring and supportive care is important as chemotherapy palliated less than half of symptomatic participants.
6 citations
01 Oct 2022
TL;DR: The ARIEL3 study as mentioned in this paper showed that progression-free survival (PFS) improved significantly with rucaparib maintenance treatment versus placebo, and the PFS benefit was maintained through the next subsequent line of therapy.
Abstract:
Introduction/Background
In ARIEL3 (NCT01968213), progression-free survival (PFS) improved significantly with rucaparib maintenance treatment versus placebo. We present updated PFS2 and preplanned final overall survival (OS) analyses.Methodology
ARIEL3 enrolled patients with platinum-sensitive, high-grade ovarian carcinoma who had received ≥2 previous platinum-based chemotherapy regimens and had responded to their last platinum-based regimen. Patients were randomised 2:1 to receive rucaparib 600 mg twice daily or placebo, with 3 protocol-defined nested cohorts: BRCA-mutant, homologous recombination deficient (HRD) and intent-to-treat (ITT). Efficacy outcomes for the nested cohorts included the secondary endpoint of OS (with analysis planned after 70% of events) and the exploratory endpoint of PFS2 (defined as time from randomisation to second event of investigator-assessed disease progression or death due to any cause). Patients were followed for the incidence of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Data cutoff dates were 31 December 2019 (safety), 4 April 2022 (efficacy) and 12 April 2022 (monitoring of MDS/AML).Results
After a median follow-up of 77.0 months in the ITT population, 410/564 (72.7%) of OS events had occurred. OS and PFS2 are presented in table 1. A PARP inhibitor was administered as subsequent treatment to ≈45% of patients who received placebo. Safety data were consistent with those of prior reports. MDS/AML was reported in 14 (3.8%) and 6 (3.2%) patients in the rucaparib and placebo arms, respectively (P=0.72). Among these, 8 patients in the rucaparib arm and 6 in the placebo arm developed MDS/AML after completion of study drug treatment.Conclusion
These data support the use of rucaparib as a maintenance treatment for recurrent ovarian carcinoma. Although no OS benefit was observed, the PFS benefit for rucaparib was maintained through the next subsequent line of therapy.6 citations
01 Dec 2022
TL;DR: Rucaparib as discussed by the authors showed that maintenance treatment significantly improved progression-free survival (PFS) vs placebo compared to placebo, and the PFS benefit was maintained through subsequent line of therapy.
Abstract:
Objectives
In ARIEL3 (NCT01968213), rucaparib maintenance treatment significantly improved progression-free survival (PFS) vs placebo. We present updated PFS2 and preplanned final overall survival (OS) analyses.Methods
Patients were randomized to receive rucaparib 600 mg BID or placebo. Efficacy was analyzed across the 3 protocol-defined nested cohorts (BRCA-mutant, homologous recombination deficient [HRD], and intent-to-treat [ITT]). PFS2 was an exploratory endpoint, defined as time from randomization to second event of investigator-assessed disease progression, or death due to any cause. OS was a secondary endpoint with analysis planned after 70% of death events. The data cutoff was April 4, 2022, for efficacy and December 31, 2019, for safety. Patients were followed after treatment discontinuation for incidence of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML); MDS/AML are reported as of April 12, 2022.Results
Median follow-up was 77.0 months as of the efficacy data cutoff. In the ITT population, death events had occurred in 410/564 (72.7%) patients. PFS2 and OS are presented in the table 1. Among placebo-arm patients, ≈45% received a PARP inhibitor as a subsequent treatment. Safety was consistent with prior reports; MDS/AML was reported in 14 (3.8%) rucaparib-arm and 6 (3.2%) placebo-arm patients (P=0.72) (reported post-study drug treatment in 8 cases in the rucaparib arm and 6 in the placebo arm).Conclusions
These data support the use of rucaparib as a maintenance treatment for recurrent ovarian carcinoma; although no OS benefit was seen, the PFS benefit for rucaparib was maintained through the subsequent line of therapy.5 citations
TL;DR: No significant difference in overall survival was observed in either comparison and evidence of non-proportional hazards was seen, with restricted mean survival time of 23·9 months, in the intention-to-treat population.
4 citations
TL;DR: The Phase IIIb, single-arm OPINION study reported a median progression-free survival (PFS) of 9.2 months (mo) with maintenance olaparib in pts with non-gBRCAm PSR OC as mentioned in this paper .
TL;DR: The Measure of Ovarian Symptoms and Treatment (MOST) concerns is a validated patient-reported symptom assessment tool for assessing symptom benefit and adverse effects of palliative chemotherapy in women with recurrent ovarian cancer (ROC) as mentioned in this paper .
TL;DR: A large number of the patients treated in this study had no prior history of cancer or prior treatment history of any kind that could have contributed to their diagnosis.
Abstract: Domenico Pagano, Philip Home, Alar Irs, Jonathan Ledermann , Giuseppe Curigliano, Tsuguo Iwatani, John Mandrola and Nick Freemantle University Hospitals Birmingham, Birmingham, B15 2GW, UK Translational and Clinical Research Institute, Newcastle University, NE1 7RU, UK Heart Clinic, Tartu University Hospital, 50406 Tartu, Estonia UCL Cancer Institute, University College London, WC1E 6BT, UK University of Milano and European Institute of Oncology, IRCCS, 20122 Milan, Italy Breast Surgery, National Cancer Center Hospital East, 277-8577 Chiba, Japan Baptist Health Louisville, Louisville, KY 40207, USA Institute of Clinical Trials and Methodology, University College London, London, WC1E 6BT, UK Corresponding author: Domenico Pagano. Email: domenicopagano@me.com
TL;DR: The Best of ESGO 2022 as mentioned in this paper includes a selection of best original research presented during the 23rd European Congress on Gynaecological Oncology between October 27 and 30, 2022 in Berlin.
Abstract: Best of ESGO 2022 includes a selection of best original research presented during the 23rd European Congress on Gynaecological Oncology between October 27 and 30, 2022 in Berlin. Out of 1107 submitted abstracts, authors of studies which obtained the highest scores in a blinded review process were invited to present their results during four oral sessions, young investigators session, and oral poster sessions. By means of this publication, we aim to provide readers with an overview of the best quality research presented at the European Society of Gynaecological Oncology (ESGO) 2022.
TL;DR: The emerging data on HRD as a predictive biomarker for PARP inhibitors is reviewed and the merits and disadvantages of different HRD assays are discussed.
Abstract: Abstract Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have revolutionised the management of patients with high-grade serous and endometrioid ovarian cancer demonstrating significant improvements in progression-free survival. Whilst the greatest benefit is seen with BRCA1/2 mutant cancers, it is clear that the benefit extends beyond this group. This sensitivity is thought to be due to homologous recombination deficiency (HRD), which is present in up to 50% of the high-grade serous cancers. Several different HRD assays exist, which fall into one of three main categories: homologous recombination repair (HRR)-related gene analysis, genomic “scars” and/or mutational signatures, and real-time HRD functional assessment. We review the emerging data on HRD as a predictive biomarker for PARP inhibitors and discuss the merits and disadvantages of different HRD assays.
TL;DR: An update on this data set for reporting of the ovarian, fallopian tube and primary peritoneal carcinomas, as a second edition, that reflects changes in the 2020 World Health Organization Classification of Female Genital Tumours as well as some other minor modifications are provided.
Abstract: The move toward consistent and comprehensive surgical pathology reports for cancer resection specimens has been a key development in supporting evidence-based patient management and consistent cancer staging. The International Collaboration on Cancer Reporting (ICCR) previously developed a data set for reporting of the ovarian, fallopian tube and primary peritoneal carcinomas which was published in 2015. In this paper, we provide an update on this data set, as a second edition, that reflects changes in the 2020 World Health Organization (WHO) Classification of Female Genital Tumours as well as some other minor modifications. The data set has been developed by a panel of internationally recognized expert pathologists and a clinician and consists of "core" and "noncore" elements to be included in surgical pathology reports, with detailed commentary to guide users, including references. This data set replaces the widely used first edition, and will facilitate consistent and accurate case reporting, data collection for quality assurance and research, and allow for comparison of epidemiological and pathologic parameters between different populations.
TL;DR: Ofra-vec in combination with weekly paclitaxel was well tolerated and associated with a CA-125 Objective Response Rate (ORR) of 58%, a trend for improved survival and induction of an immunotherapeutic effect of tumor infiltration with CD-8 T cells.
Abstract: TPS5606 Background: Ofranergene obadenovec (Ofra-vec, VB-111) is an anti-cancer gene based immune activator and targeted vascular disruptor. The dual mechanism of action triggers a broad antiangiogenic effect and induces of a tumor directed immune response. A phase II trial in patients with platinum resistant ovarian cancer (PROC) demonstrated that ofra-vec in combination with weekly paclitaxel was well tolerated and associated with a CA-125 Objective Response Rate (ORR) of 58%, a trend for improved survival and induction of an immunotherapeutic effect of tumor infiltration with CD-8 T cells. Based on these observations, a pivotal phase III study was initiated in collaboration with the GOG Foundation, Inc. Methods: Study NCT03398655 is an international, randomized, double-blind, placebo-controlled, phase III study. Eligible patients have recurrent PROC and may have been previously treated with up to 5 prior lines of therapy (but not >2 for PROC). Patient are randomized 1:1 to receive ofra-vec (1x1013 Viral Particles) with weekly paclitaxel (80mg/m2), or weekly paclitaxel with placebo. Randomization is stratified by number of prior treatment lines, prior antiangiogenic therapy and platinum refractory disease status. The dual primary endpoints are OS and PFS. A pre-planned interim analysis of CA-125 response (GCIG) performed by the DSMC met the pre-defined criteria showing that CA-125 ORR in the treatment arm was at least 10% higher than in the control arm. Study is enrolling in the US, EU, Japan and Israel, with 90% enrollment to date. Completion of accrual is anticipated in Q1 2022. Clinical trial information: NCT03398655.
TL;DR: The OPINION study as mentioned in this paper demonstrated the activity of maintenance olaparib in patients with platinum-sensitive relapsed ovarian cancer (PSR OC) without a germline mutation (non-gBRCAm), with an overall median progression-free survival (PFS) of 9.2 months.
TL;DR: SANDI as discussed by the authors is a self-supervised pipeline that learns intrinsic similarities in unlabeled cell images to mitigate the requirement for expert supervision, which is demonstrated through the analysis of three different multiplexed immunohistochemistry datasets.
Abstract: Multiplexed pathology imaging techniques allow spatially resolved analysis of cell phenotypes for interrogating disease biology. Existing methods for cell phenotyping in multiplex images require extensive annotation workload due to the need for fully supervised training. To overcome this challenge, we develop SANDI, a self-supervised-based pipeline that learns intrinsic similarities in unlabeled cell images to mitigate the requirement for expert supervision. The capability of SANDI to efficiently classify cells with minimal manual annotations is demonstrated through the analysis of 3 different multiplexed immunohistochemistry datasets. We show that in coupled with representations learnt by SANDI from unlabeled cell images, a linear Support Vector Machine classifier trained on 10 annotations per cell type yields a higher or comparable weighted F1-score to the supervised classifier trained on an average of about 300–1000 annotations per cell type. By striking a fine balance between minimal expert guidance and the power of deep learning to learn similarity within abundant data, SANDI presents new opportunities for efficient, large-scale learning for multiplexed imaging data.
TL;DR: In the last decade treatment of ovarian cancer has shifted from a 'one size fits all' approach to biologically determined treatment options as mentioned in this paper , driven by an understanding of the importance of BRCA mutations to predict the benefit of PARP inhibitor treatment.
TL;DR: The Myriad myChoice® HRD assay was used to detect pathogenic BRCA1/2 variants and a genomic instability score (GIS) in formalin-fixed paraffin-embedded tumour tissue as mentioned in this paper .
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TL;DR: The International Journal for Numerical and Analytical Methods in Geomechanics (Nag) as discussed by the authors was the first journal to publish a full-text version of this article.
Abstract: International Journal for Numerical and Analytical Methods in GeomechanicsVolume 46, Issue 6 p. 1027-1028 ISSUE INFORMATIONFree Access Issue Information First published: 05 April 2022 https://doi.org/10.1002/nag.3230AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume46, Issue625 April 2022Pages 1027-1028 RelatedInformation
TL;DR: During the 23rd Congress on Gynaecological Oncology held in Berlin in October 2022, eight interviews on relevant and up-to-date topics in gynecologic oncology with leading speakers were conducted by current and former Editorial Fellows of the IJGC endorsed by the ENYGO as discussed by the authors .
Abstract: During the 23rd Congress on Gynaecological Oncology held in Berlin in October 2022, eight interviews on relevant and up-to-date topics in gynecologic oncology with leading speakers were conducted by current and former Editorial Fellows of the IJGC endorsed by the ENYGO. Interviewee: Professor