215 results found
McNeish I, Ennis D, Stronach E, Development and validation of the gene-expression Predictor of high-grade-serous Ovarian carcinoma molecular subTYPE (PrOTYPE), Clinical Cancer Research, ISSN: 1078-0432
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.
Millstein J, Budden T, Goode EL, et al., 2020, Prognostic gene expression signature for high-grade serous ovarian cancer, Annals of Oncology, 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.
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.
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, 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, 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.
Rumford M, Lythgoe M, McNeish I, et al., 2020, Oncologist-led BRCA ‘mainstreaming’ in the ovarian cancer clinic: A study of 255 patients and its impact on their management, Scientific Reports, Vol: 10, ISSN: 2045-2322
Although guidelines recommend BRCA testing for all women with non-mucinous epithelial ovarian cancer, there is significant variability in access to testing across the UK. A germline BRCA mutation (BRCAm) in ovarian cancer patients provides prognostic and predictive information and influences clinical management, such as the use of PARP inhibitors, which have demonstrated a progression-free survival benefit in the BRCAm cohort. Additionally, the finding of a BRCAm has significant implications for patients and their families in terms of cancer risk and prevention. We studied the impact of a newly-formed, oncologist-led ‘mainstreaming’ germline BRCA testing pathway in 255 ovarian cancer patients at Imperial College NHS Trust. Prior to the establishment of ‘mainstreaming’, uptake of germline BRCA testing was 14% with a mean turnaround time of 148.2 calendar days. The ‘mainstreaming’ approach led to a 95% uptake of germline BRCA testing and a mean turnaround time of 20.6 days. Thirty-four (13.33%) BRCAm patients were identified. At the time of data collection nine BRCAm patients had received a PARP inhibitor off-trial, three had entered a PARP inhibitor trial and 5 were receiving platinum-based chemotherapy with a plan to receive PARP inhibitor maintenance. This study provides further evidence of the impact of oncologist-led ‘mainstreaming’ programs.
Cohen PA, Powell A, Böhm S, et al., 2020, Corrigendum to "Pathological chemotherapy response score is prognostic in tubo-ovarian high-grade serous carcinoma: A systematic review and meta-analysis of individual patient data" [Gynecol. Oncol. 154 (2019) 441-448]., Gynecol Oncol
Li C, Course MM, McNeish IA, et al., 2020, Prophylactic In Vivo Hematopoietic Stem Cell Gene Therapy with an Immune Checkpoint Inhibitor Reverses Tumor Growth in Syngeneic Mouse Tumor Models, CANCER RESEARCH, Vol: 80, Pages: 549-560, ISSN: 0008-5472
Blagih J, Zani F, Chakravarty P, et al., 2020, Cancer-specific loss of p53 leads to a modulation of myeloid and T cell responses, Cell Reports, Vol: 30, Pages: 481-196.e6, ISSN: 2211-1247
Loss of p53 function contributes to the development of many cancers. While cell-autonomous consequences of p53 mutation have been studied extensively, the role of p53 in regulating the anti-tumor immune response is still poorly understood. Here, we show that loss of p53 in cancer cells modulates the tumor-immune landscape to circumvent immune destruction. Deletion of p53 promotes the recruitment and instruction of suppressive myeloid CD11b+ cells, in part through increased expression of CXCR3/CCR2-associated chemokines and macrophage colony-stimulating factor (M-CSF), and attenuates the CD4+ T helper 1 (Th1) and CD8+ T cell responses in vivo. p53-null tumors also show an accumulation of suppressive regulatory T (Treg) cells. Finally, we show that two key drivers of tumorigenesis, activation of KRAS and deletion of p53, cooperate to promote immune tolerance.
Clamp AR, James EC, McNeish IA, et al., 2019, Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment (ICON8): primary progression free survival analysis results from a GCIG phase 3 randomised controlled trial, The Lancet, Vol: 394, Pages: 2084-2095, ISSN: 0140-6736
BACKGROUND: Carboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer. METHODS: In this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC-IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m2 paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0·75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3). FINDINGS: Between June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (med
Spear S, McNeish IA, Capasso M, 2019, Generation of orthotopic pancreatic tumors and ex vivo characterization of tumor-infiltrating T cell cytotoxicity., Journal of Visualized Experiments, Vol: 154, Pages: 1-11, ISSN: 1940-087X
In vivo models of pancreatic cancer provide invaluable tools for studying disease dynamics, immune infiltration and new therapeutic strategies. The orthotopic murine model can be performed on large cohorts of immunocompetent mice simultaneously, is relatively inexpensive and preserves the cognate tissue microenvironment. The quantification of T cell infiltration and cytotoxic activity within orthotopic tumors provides a useful indicator of an antitumoral response. This protocol describes the methodology for surgical generation of orthotopic pancreatic tumors by injection of a low number of syngeneic tumor cells resuspended in 5 µL basement membrane directly into the pancreas. Mice bearing orthotopic tumors take approximately 30 days to reach endpoint, at which point tumors can be harvested and processed for characterization of tumor-infiltrating T cell activity. Rapid enzymatic digestion using collagenase and DNase allows a single-cell suspension to be extracted from tumors. The viability and cell surface markers of immune cells extracted from the tumor are preserved; therefore, it is appropriate for multiple downstream applications, including flow-assisted cell sorting of immune cells for culture or RNA extraction, flow cytometry analysis of immune cell populations. Here, we describe the ex vivo stimulation of T cell populations for intracellular cytokine quantification (IFNγ and TNFα) and degranulation activity (CD107a) as a measure of overall cytotoxicity. Whole-tumor digests were stimulated with phorbol myristate acetate and ionomycin for 5 h, in the presence of anti-CD107a antibody in order to upregulate cytokine production and degranulation. The addition of brefeldin A and monensin for the final 4 h was performed to block extracellular transport and maximize cytokine detection. Extra- and intra-cellular staining of cells was then performed for flow cytometry analysis, where the proportion of IFNγ+, TNFα+ and CD107a+ CD4+ and CD8+
Macintyre G, Goranova TE, De Silva D, et al., 2019, COPY-NUMBER SIGNATURES AND MUTATIONAL PROCESSES IN HIGH GRADE SEROUS OVARIAN CARCINOMA, 12th Rivkin-Centre Biennial Ovarian Cancer Research Symposium, Publisher: AMER ASSOC CANCER RESEARCH, Pages: 64-64, ISSN: 1078-0432
Kristeleit RS, Oaknin A, Ray-Coquard I, et al., 2019, Antitumor activity of the poly(ADP-ribose) polymerase inhibitor rucaparib as monotherapy in patients with platinum-sensitive, relapsed, BRCA-mutated, high-grade ovarian cancer, and an update on safety, International Journal of Gynecologic Cancer, Vol: 29, Pages: 1396-1404, ISSN: 1048-891X
Objective To report results from an integrated efficacy and safety analysis supporting the European Commission's approval of the poly(ADP-ribose) polymerase inhibitor rucaparib as monotherapy treatment for relapsed, platinum-sensitive, BRCA-mutated ovarian cancer.Methods Efficacy was analyzed in platinum-sensitive patients from Study 10 (NCT01482715) and ARIEL2 (NCT01891344) who had high-grade serous or endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer and a deleterious BRCA1 or BRCA2 mutation and received two or more prior chemotherapies (including two or more platinum-based therapies). The primary end point was investigator-assessed, confirmed objective response rate (visit cut-off: April 10, 2017). Safety was analyzed in patients with ovarian cancer, regardless of BRCA mutation status or lines of prior chemotherapies, who received at least one dose of rucaparib 600 mg in either study (visit cut-off: December 31, 2017).Results In the integrated platinum-sensitive efficacy population (n=79), objective response rate was 64.6% (95% CI, 53.0 to 75.0); 10.1% (8/79) of patients had a complete response and 54.4% (43/79) had a partial response. Median duration of response was 294 days (95% CI, 224 to 393). In the integrated safety population (n=565), the most common any-grade treatment-emergent adverse events were nausea (77.7%, 439/565), asthenia/fatigue (74.7%, 422/565), vomiting (45.8%, 259/565), and hemoglobin decreased (44.2%, 250/565). Treatment-emergent adverse events led to treatment interruption, dose reduction, or discontinuation in 60.2% (340/565), 46.0% (260/565), and 16.8% (95/565) of patients.Conclusions In patients with platinum-sensitive, BRCA-mutated ovarian cancer, rucaparib demonstrated antitumor activity and is the first and currently the only poly(ADP-ribose) polymerase inhibitor approved by the European Commission as treatment for this population. The safety analysis used a more recent visit cut-off date and
Spiliopoulou P, Spear S, Dowson S, et al., 2019, Inhibiting Ehmt2 and Ezh2 histone methyltransferases alters the immune microenvironment in a Trp53-/- murine ovarian cancer model, 44th Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: OXFORD UNIV PRESS, Pages: 784-784, ISSN: 0923-7534
Banerjee S, Lewsley L-A, Clamp AR, et al., 2019, OCTOPUS: A randomised, multi-centre phase II umbrella trial of weekly paclitaxel plus /- novel agents in platinum-resistant ovarian cancer: Vistusertib, 44th Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: OXFORD UNIV PRESS, Pages: 403-+, ISSN: 0923-7534
McNeish IA, Moreno V, Jayson G, et al., 2019, OCTAVE: A phase I study of enadenotucirev, an oncolytic group B adenovirus, in combination with weekly paclitaxel in platinum-resistant epithelial ovarian cancer, 44th Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: OXFORD UNIV PRESS, Pages: 421-421, ISSN: 0923-7534
Kristeleit RS, Oza AM, Oaknin A, et al., 2019, Integrated safety analysis of the poly (ADP-ribose) polymerase (PARP) inhibitor rucaparib in patients (pts) with ovarian cancer in the treatment and maintenance settings, 44th Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: OXFORD UNIV PRESS, Pages: 409-+, ISSN: 0923-7534
McNeish I, Gabra H, ICON8: A GCIG phase III randomised controlled trial evaluating weekly dose- dense chemotherapy in first-line epithelial ovarian/fallopian tube/primary peritoneal carcinoma (EOC) treatment: primary progression free survival analysis results, The Lancet, ISSN: 0140-6736
Background Carboplatin and paclitaxel administered every three weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer (EOC). The Japanese JGOG3016 trial demonstrated a significant improvement in progression-free (PFS) and overall survival (OS) with dose-dense weekly paclitaxel and three-weekly carboplatin. We compared efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European EOC population. Methods In this phase 3 trial, women with newly diagnosed FIGO stage Ic-IV EOC were randomised 1:1:1 toArm 1 (carboplatin (AUC5/6) and paclitaxel (175mg/m2) every 3 weeks), Arm 2 (carboplatin (AUC5/6)every 3 weeks and paclitaxel (80mg/m2) weekly) or Arm 3 (carboplatin (AUC2) and paclitaxel (80mg/m2) weekly). Patients entered after immediate primary surgery, or prior to neo-adjuvant chemotherapy before planned delayed primary surgery. An intention-to-treat primary PFS efficacy analysis compared Arm 2 vs 1 and Arm 3 vs 1. Findings 1566 women were randomised. 72%, 60% and 63% completed 6 protocol-defined treatment cycles in Arms 1, 2 and 3 respectively, although 90%, 89% and 85% completed 6 platinum-based chemotherapy cycles. Paclitaxel dose-intensification was achieved with weekly treatment (mediantotal paclitaxel dose 1011; 1234; 1274 mg/m2). Although Grade 3/4 toxicity increased with weekly treatment, this was predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across arms. By February 2017, 64% patients had experienced disease progression. No significant PFS increase was observed with either weekly regimen (log-rank Arm 2vs1 p=0.3532; Arm 3vs1 p=0.5130, non-proportionality p=0.0297, restricted mean survival time = 24.4; 24.9; 25.3 months in Arms 1, 2, 3 with 97.5% CI: 23.0 to 26.0; 24.0 to 25.9; 23.9 to 26.9 months respectively). Interpretation Weekly dose-dense chemotherapy can be delivered successfully as first-line EOC treatment but does not significa
Cohen PA, Powell A, Böhm S, et al., 2019, Pathological chemotherapy response score is prognostic in tubo-ovarian high-grade serous carcinoma: a systematic review and meta-analysis of individual patient data, Gynecologic Oncology, Vol: 154, Pages: 441-448, ISSN: 0090-8258
ObjectiveThere is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT.MethodsWe established an international collaboration to conduct a systematic review and meta-analysis, pooling individual patient data from 16 sites in 11 countries. Patients had stage IIIC/IV HGSC, 3–4 NACT cycles and >6-months follow-up. Random effects models were used to derive combined odds ratios in the pooled population to investigate associations between CRS and progression free and overall survival (PFS and OS).Results877 patients were included from published and unpublished studies. Median PFS and OS were 15 months (IQR 5–65) and 28 months (IQR 7–92) respectively. CRS3 was seen in 249 patients (28%). The pooled hazard ratios (HR) for PFS and OS for CRS3 versus CRS1/CRS2 were 0·55 (95% CI, 0·45–0·66; P < 0·001) and 0·65 (95% CI 0·50–0·85, P = 0·002) respectively; no heterogeneity was identified (PFS: Q = 6·42, P = 0·698, I2 = 0·0%; OS: Q = 6·89, P = 0·648, I2 = 0·0%). CRS was significantly associated with PFS and OS in multivariate models adjusting for age and stage. Of 306 patients with known germline BRCA1/2 status, those with BRCA1/2 mutations (n = 80) were more likely to achieve CRS3 (P = 0·027).ConclusionsCRS3 was significantly associated with improved PFS and OS compared to CRS1/2. This validation of CRS in a real-world setting demonstrates it to be a robust and reproducible biomarker with potential to be incorporated into therapeutic decision-making and clinical
Colombo N, Sessa C, du Bois A, et al., 2019, ESMO-ESGO consensus conference recommendations on ovarian cancer: Pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease, International Journal of Gynecological Cancer, Vol: 29, Pages: 728-760, ISSN: 1048-891X
The development of guidelines is one of the core activities of the European Society for Medical Oncology (ESMO) and European Society of Gynaecologial Oncology (ESGO), as part of the mission of both societies to improve the quality of care for patients with cancer across Europe. ESMO and ESGO jointly developed clinically-relevant and evidence-based guidelines in several selected areas in order to improve the quality of care for women with ovarian cancer. The ESMO-ESGO consensus conference on ovarian cancer was held on 12-14 April 2018 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of ovarian cancer. Before the conference, the expert panel worked on five clinically relevant questions regarding ovarian cancer relating to each of the following four areas: pathology and molecular biology, early-stage and borderline tumours, advanced stage disease and recurrent disease. Relevant scientific literature, as identified using a systematic search, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. The recommendations presented here are thus based on the best available evidence and expert agreement. This article presents the recommendations of this ESMO-ESGO consensus conference, together with a summary of evidence supporting each recommendation.
Colombo N, Sessa C, du Bois A, et al., 2019, ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease, ANNALS OF ONCOLOGY, Vol: 30, Pages: 672-705, ISSN: 0923-7534
Goranova T, Ennis D, Piskorz AM, et al., 2019, Correction: Safety and utility of image-guided research biopsies in relapsed high-grade serous ovarian carcinoma-experience of the BriTROC consortium., British Journal of Cancer, Vol: 120, ISSN: 0007-0920
This article was originally published under a CC BY NC SA License, but has now been made available under a CC BY 4.0 License.
Bagnoli M, Shi TY, Gourley C, et al., 2019, Gynecological cancers translational, research implementation, and harmonization: Gynecologic Cancer InterGroup consensus and still open questions, Cells, Vol: 8, ISSN: 2073-4409
In the era of personalized medicine, the introduction of translational studies in clinical trials has substantially increased their costs, but provides the possibility of improving the productivity of trials with a better selection of recruited patients. With the overall goal of creating a roadmap to improve translational design for future gynecological cancer trials and of defining translational goals, a main discussion was held during a brainstorming day of the Gynecologic Cancer InterGroup (GCIG) Translational Research Committee and overall conclusions are here reported. A particular emphasis was dedicated to the new frontier of the immunoprofiling of gynecological cancers. The discussion pointed out that to maximize patients’ benefit, translational studies should be integral to clinical trial design with standardization and optimization of procedures including a harmonization program of Standard Operating Procedures. Pathology-reviewed sample collection should be mandatory and ensured by dedicated funding. Biomarker validation and development should be made public and transparent to ensure rapid progresses with positive outcomes for patients. Guidelines/templates for patients’ informed consent are needed. Importantly for the public, recognized goals are to increase the involvement of advocates and to improve the reporting of translational data in a forum accessible to patients.
Buckley MA, Woods NT, Tyrer JP, et al., 2019, Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus, CANCER RESEARCH, Vol: 79, Pages: 467-481, ISSN: 0008-5472
Yang Y, Wu L, Shu X, et al., 2019, Genetic data from nearly 63,000 women of European descent predicts DNA methylation biomarkers and epithelial ovarian cancer risk, Cancer Research, Vol: 79, Pages: 505-517, ISSN: 1538-7445
DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N=1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P<7.94×10-7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27 and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression.
Lin KK, Harrell MI, Oza AM, et al., 2019, BRCA reversion mutations in circulating tumor DNA predict primary and acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma, Cancer Discovery, Vol: 9, Pages: 210-219, ISSN: 2159-8274
A key resistance mechanism to platinum-based chemotherapies and PARP inhibitors in BRCA-mutant cancers is the acquisition of BRCA reversion mutations that restore protein function. To estimate the prevalence of BRCA reversion mutations in high-grade ovarian carcinoma (HGOC), we performed targeted next-generation sequencing of circulating cell-free DNA (cfDNA) extracted from pretreatment and postprogression plasma in patients with deleterious germline or somatic BRCA mutations treated with the PARP inhibitor rucaparib. BRCA reversion mutations were identified in pretreatment cfDNA from 18% (2/11) of platinum-refractory and 13% (5/38) of platinum-resistant cancers, compared to 2% (1/48) of platinum-sensitive cancers (P = 0.049). Patients without BRCA reversion mutations detected in pretreatment cfDNA had significantly longer rucaparib progression-free survival than those with reversion mutations (median, 9.0 vs. 1.8 months; HR, 0.12; P < 0.0001). To study acquired resistance, we sequenced 78 postprogression cfDNA, identifying eight additional patients with BRCA reversion mutations not found in pretreatment cfDNA.
Macintyre G, Piskorz A, Ross E, et al., 2018, frenchFISH: Poisson models for quantifying DNA copy-number from fluorescence in situ hybridisation of tissue sections
Chromosomal aberration and DNA copy number change are robust hallmarks of cancer. Imaging of spots generated using fluorescence in situ hybridisation (FISH) of locus specific probes is routinely used to detect copy number changes in tumour nuclei. However, it often does not perform well on solid tumour tissue sections, where partially represented or overlapping nuclei are common. To 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 homogenous Poisson Point Process model for automated spot counting. We benchmarked the performance of FrenchFISH against previous approaches in a controlled simulation scenario and exemplify its use in 12 ovarian cancer FFPE-tissue sections, for which we assess copy number alterations in three loci (c-Myc, hTERC and SE7). We show that FrenchFISH outperforms standard spot counting approaches and that the automated spot counting is significantly faster than manual without loss of performance. FrenchFISH is a general approach that can be used to enhance clinical diagnosis on sections of any tissue.
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