Publications
328 results found
Li C, Course MM, McNeish IA, et al., 2023, Data from Prophylactic <i>In Vivo</i> Hematopoietic Stem Cell Gene Therapy with an Immune Checkpoint Inhibitor Reverses Tumor Growth in Syngeneic Mouse Tumor Models
<jats:p><div>Abstract<p>Population-wide testing for cancer-associated mutations has established that more than one-fifth of ovarian and breast carcinomas are associated with inherited risk. Salpingo-oophorectomy and/or mastectomy are currently the only effective options offered to women with high-risk germline mutations. Our goal here is to develop a long-lasting approach that provides immunoprophylaxis for mutation carriers. Our approach leverages the fact that at early stages, tumors recruit hematopoietic stem/progenitor cells (HSPC) from the bone marrow and differentiate them into tumor-supporting cells. We developed a technically simple technology to genetically modify HSPCs <i>in vivo</i>. The technology involves HSPC mobilization and intravenous injection of an integrating HDAd5/35++ vector. <i>In vivo</i> HSPC transduction with a GFP-expressing vector and subsequent implantation of syngeneic tumor cells showed >80% GFP marking in tumor-infiltrating leukocytes. To control expression of transgenes, we developed a miRNA regulation system that is activated only when HSPCs are recruited to and differentiated by the tumor. We tested our approach using the immune checkpoint inhibitor anti-PD-L1-γ1 as an effector gene. In <i>in vivo</i> HSPC-transduced mice with implanted mouse mammary carcinoma (MMC) tumors, after initial tumor growth, tumors regressed and did not recur. Conventional treatment with an anti-PD-L1 mAb had no significant antitumor effect, indicating that early, self-activating expression of anti-PD-L1-γ1 can overcome the immunosuppressive environment in MMC tumors. The efficacy and safety of this approach was further validated in an ovarian cancer model with typical germline mutations (ID8 p53<sup>−/−</sup> brca2<sup>−/−</sup>), both in a
Li C, Course MM, McNeish IA, et al., 2023, Data from Prophylactic <i>In Vivo</i> Hematopoietic Stem Cell Gene Therapy with an Immune Checkpoint Inhibitor Reverses Tumor Growth in Syngeneic Mouse Tumor Models
<jats:p><div>Abstract<p>Population-wide testing for cancer-associated mutations has established that more than one-fifth of ovarian and breast carcinomas are associated with inherited risk. Salpingo-oophorectomy and/or mastectomy are currently the only effective options offered to women with high-risk germline mutations. Our goal here is to develop a long-lasting approach that provides immunoprophylaxis for mutation carriers. Our approach leverages the fact that at early stages, tumors recruit hematopoietic stem/progenitor cells (HSPC) from the bone marrow and differentiate them into tumor-supporting cells. We developed a technically simple technology to genetically modify HSPCs <i>in vivo</i>. The technology involves HSPC mobilization and intravenous injection of an integrating HDAd5/35++ vector. <i>In vivo</i> HSPC transduction with a GFP-expressing vector and subsequent implantation of syngeneic tumor cells showed >80% GFP marking in tumor-infiltrating leukocytes. To control expression of transgenes, we developed a miRNA regulation system that is activated only when HSPCs are recruited to and differentiated by the tumor. We tested our approach using the immune checkpoint inhibitor anti-PD-L1-γ1 as an effector gene. In <i>in vivo</i> HSPC-transduced mice with implanted mouse mammary carcinoma (MMC) tumors, after initial tumor growth, tumors regressed and did not recur. Conventional treatment with an anti-PD-L1 mAb had no significant antitumor effect, indicating that early, self-activating expression of anti-PD-L1-γ1 can overcome the immunosuppressive environment in MMC tumors. The efficacy and safety of this approach was further validated in an ovarian cancer model with typical germline mutations (ID8 p53<sup>−/−</sup> brca2<sup>−/−</sup>), both in a
Li C, Course MM, McNeish IA, et al., 2023, Supplementary Data from Prophylactic <i>In Vivo</i> Hematopoietic Stem Cell Gene Therapy with an Immune Checkpoint Inhibitor Reverses Tumor Growth in Syngeneic Mouse Tumor Models
<jats:p><p>Supplementary Fig. S1. Rat Neu is expressed in MMC cells. Supplementary Fig. S2. Gating strategy used for immunophenotyping. Supplementary Fig. S3. Immunophenotyping of GFP+ cells in the bone marrow and spleen (MMC model). Supplementary Fig.S4. GFP expression in tumor-infiltrating leukocytes after in vivo HSPC transduction (TC-1 model). Supplementary Fig. S5. Validation of miR-423-5p expression by Northern blot. Supplementary Fig.S6. miRNA423-5p expression in humans. Supplementary Fig. S7. Autoimmune reactions in animals sacrificed at day 17 at the peak of aPDL1-gamma1, before reversal of tumor growth. Supplementary Fig. S8. Effect of anti-PDL1 monoclonal antibody therapy in neu-transgenic mice with MMC tumors. Supplementary Fig. S9. Effect of in vivo HSC transduction on hemopoiesis. Suppl. Methods</p></jats:p>
Li C, Course MM, McNeish IA, et al., 2023, Supplementary Data from Prophylactic <i>In Vivo</i> Hematopoietic Stem Cell Gene Therapy with an Immune Checkpoint Inhibitor Reverses Tumor Growth in Syngeneic Mouse Tumor Models
<jats:p><p>Supplementary Fig. S1. Rat Neu is expressed in MMC cells. Supplementary Fig. S2. Gating strategy used for immunophenotyping. Supplementary Fig. S3. Immunophenotyping of GFP+ cells in the bone marrow and spleen (MMC model). Supplementary Fig.S4. GFP expression in tumor-infiltrating leukocytes after in vivo HSPC transduction (TC-1 model). Supplementary Fig. S5. Validation of miR-423-5p expression by Northern blot. Supplementary Fig.S6. miRNA423-5p expression in humans. Supplementary Fig. S7. Autoimmune reactions in animals sacrificed at day 17 at the peak of aPDL1-gamma1, before reversal of tumor growth. Supplementary Fig. S8. Effect of anti-PDL1 monoclonal antibody therapy in neu-transgenic mice with MMC tumors. Supplementary Fig. S9. Effect of in vivo HSC transduction on hemopoiesis. Suppl. Methods</p></jats:p>
Banerjee S, Giannone G, Clamp AR, et al., 2023, Efficacy and safety of weekly paclitaxel plus vistusertib vs paclitaxel alone in patients with platinum-resistant ovarian high-grade serous carcinoma: the octopus multicenter, phase 2, randomized clinical trial., JAMA Oncology, Vol: 9, Pages: 675-682, ISSN: 2374-2437
IMPORTANCE: Patients with platinum-resistant or refractory ovarian high-grade serous carcinoma (PR-HGSC) have a poor prognosis and few therapeutic options. Preclinical studies support targeting PI3K/AKT/mTOR signaling in this setting, and a phase 1 study of the dual mTORC1/mTORC2 inhibitor vistusertib with weekly paclitaxel showed activity. OBJECTIVE: To evaluate whether the addition of vistusertib to weekly paclitaxel improves clinical outcomes in patients with PR-HGSC. DESIGN, SETTING, AND PARTICIPANTS: This phase 2, double-blind, placebo-controlled multicenter randomized clinical trial recruited patients from UK cancer centers between January 2016 and March 2018. Patients with PR-HGSC of ovarian, fallopian tube, or primary peritoneal origin and with measurable or evaluable disease (Response Evaluation Criteria in Solid Tumors version 1.1 and/or Gynecological Cancer Intergroup cancer antigen 125 criteria) were eligible. There were no restrictions on number of lines of prior therapy. Data analysis was performed from May 2019 to January 2022. INTERVENTIONS: Patients were randomized (1:1) to weekly paclitaxel (80 mg/m2 days 1, 8, and 15 of a 28-day cycle) plus oral vistusertib (50 mg twice daily) or placebo. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival in the intention-to-treat population. Secondary end points included response rate, overall survival, and quality of life. RESULTS: A total of 140 patients (median [range] age, 63 [36-86] years; 17.9% with platinum-refractory disease; 53.6% with ≥3 prior therapies) were randomized. In the paclitaxel plus vistusertib vs paclitaxel plus placebo groups, there was no difference in progression-free survival (median, 4.5 vs 4.1 months; hazard ratio [HR], 0.84; 80% CI, 0.67-1.07; 1-sided P = .18), overall survival (median, 9.7 vs 11.1 months; HR, 1.21; 80% CI, 0.91-1.60) or response rate (odds ratio, 0.86; 80% CI, 0.55-1.36). Grade 3 to 4 adverse events were 41.2% (wee
Colomban O, Swisher EM, Kristeleit R, et al., 2023, Mathematical modeling of the early modeled CA-125 longitudinal kinetics (KELIM-PARP) as a pragmatic indicator of rucaparib efficacy in patients with recurrent ovarian carcinoma in ARIEL2 & STUDY 10, EBIOMEDICINE, Vol: 89, ISSN: 2352-3964
Monk BJ, Fujiwara K, O'Malley DM, et al., 2023, The long-lasting challenge of predicting response to poly (ADP-ribose) polymerase inhibitors Reply, JOURNAL OF CLINICAL ONCOLOGY, Vol: 41, Pages: 936-938, ISSN: 0732-183X
Sundar S, Nordin A, Morrison J, et al., 2023, British Gynaecological Cancer Society Recommendations for Evidence Based, Population Data Derived Quality Performance Indicators for Ovarian Cancer, CANCERS, Vol: 15
Monk BJ, Parkinson C, Lim MC, et 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, Vol: 40, Pages: 3592-3964, 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
Ho G-Y, Kyran EL, Bedo J, et al., 2022, Epithelial-to-mesenchymal transition supports ovarian carcinosarcoma tumorigenesis and confers sensitivity to microtubule-targeting with eribulin, Cancer Research, Vol: 82, Pages: 4457-4473, ISSN: 0008-5472
Ovarian carcinosarcoma (OCS) is an aggressive and rare tumour type with limited treatment options. OCS is hypothesised to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analysed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumours. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts (PDX). Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a down-regulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8+ T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate EMT plays a key role in OCS tumourigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes.
Giannone G, Giuliano AR, Bandini M, et al., 2022, HPV vaccination and HPV-related malignancies: impact, strategies and optimizations toward global immunization coverage, CANCER TREATMENT REVIEWS, Vol: 111, ISSN: 0305-7372
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Fujiwara K, Kristeleit R, Ghamande S, et al., 2022, Rucaparib maintenance treatment in patients (pts) with newly diagnosed ovarian cancer (OC): Defining benefit according to disease risk subgroups within the phase III ATHENAeMONO study, ESMO Asia Congress, Publisher: ELSEVIER, Pages: S1505-S1506, ISSN: 0923-7534
Martins FC, Couturier D-L, de Santiago I, et al., 2022, Clonal somatic copy number altered driver events inform drug sensitivity in high-grade serous ovarian cancer, Nature Communications, Vol: 13, ISSN: 2041-1723
Chromosomal instability is a major challenge to patient stratification and targeted drug development for high-grade serous ovarian carcinoma (HGSOC). Here we show that somatic copy number alterations (SCNAs) in frequently amplified HGSOC cancer genes significantly correlate with gene expression and methylation status. We identify five prevalent clonal driver SCNAs (chromosomal amplifications encompassing MYC, PIK3CA, CCNE1, KRAS and TERT) from multi-regional HGSOC data and reason that their strong selection should prioritise them as key biomarkers for targeted therapies. We use primary HGSOC spheroid models to test interactions between in vitro targeted therapy and SCNAs. MYC chromosomal copy number is associated with in-vitro and clinical response to paclitaxel and in-vitro response to mTORC1/2 inhibition. Activation of the mTOR survival pathway in the context of MYC-amplified HGSOC is statistically associated with increased prevalence of SCNAs in genes from the PI3K pathway. Co-occurrence of amplifications in MYC and genes from the PI3K pathway is independently observed in squamous lung cancer and triple negative breast cancer. In this work, we show that identifying co-occurrence of clonal driver SCNA genes could be used to tailor therapeutics for precision medicine.
Hoare JI, Hockings H, Saxena J, et al., 2022, A novel cell line panel reveals non-genetic mediators of platinum resistance and phenotypic diversity in high grade serous ovarian cancer, Gynecologic Oncology, Vol: 167, Pages: 96-106, 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.
Samani A, Krell J, McNeish I, et al., 2022, Response to the letter entitled "Glomerular filtration rate estimation for carboplatin dosing in patients with gynaecological cancers", ESMO Open, Vol: 7, Pages: 1-1, ISSN: 2059-7029
Vergote I, Gonzalez-Martin A, Lorusso D, et al., 2022, Sixth ovarian cancer consensus conference on clinical research of the gynecologic cancer InterGroup, The Lancet Oncology, Vol: 23, Pages: e374-e384, 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.
Clamp AR, James EC, McNeish IA, et 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
Cheng Z, Mirza HB, Ennis DP, et al., 2022, The copy number landscape of early stage ovarian high grade serous carcinoma, Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Colombo N, Coleman RL, Wu X, et al., 2022, ENGOT-ov65/KEYNOTE-B96: Phase 3, randomized, double-blind study of pembrolizumab versus placebo plus paclitaxel with optional bevacizumab for platinum-resistant recurrent ovarian cancer., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
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Whelan E, Kalliala I, Semertzidou A, et 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>
Cheng Z, Mirza H, Ennis DP, et 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.
Dareng EO, Tyrer JP, Barnes DR, et 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
Dareng EO, Tyrer JP, Barnes DR, et 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.
Vergote I, Gonzalez-Martin A, Ray-Coquard I, et 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
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Samani A, Bennett R, Eremeishvili K, et 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
McNeish I, Spiliopoulou P, Spear S, et 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.
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
Kwan TT, Oza AM, Tinker A, et al., 2021, Preexisting <i>TP53</i>-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
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Monk BJ, Coleman RL, Fujiwara K, et 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
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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.
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