scholarly journals EXTH-65. USING METHYLATION PROFILES TO GUIDE THE REPURPOSING OF CHEMOTHERAPIES AGAINST HIGH-RISK MENINGIOMAS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii101-ii101
Author(s):  
Anh Tran ◽  
Denise Scholtens ◽  
Lyndsee Zhang ◽  
Jenny Pokorny ◽  
Aneta Baran ◽  
...  
Keyword(s):  
Apoptotic Cell ◽  
Progression Free Survival ◽  
Brain Structures ◽  
Primary Brain Tumor ◽  
Molecular Characteristics ◽  
Cpg Sites ◽  
Hazard Ratios ◽  
The Us ◽  
Patient Prognosis ◽  
Raloxifene Hydrochloride

Abstract Meningioma is the most common primary brain tumor with nearly thirty thousand new cases in the US every year. While most meningiomas grow slowly, hence categorized as benign, they can still impact brain structures and result in disability or lethality. Currently, there is no widely accepted chemotherapy for meningioma, and our understanding of the disease’s molecular characteristics is very limited. In this study, we aimed to identify druggable molecular targets for repurposing of chemotherapies against meningiomas. We analyzed previously published dataset of 493 meningioma patients by Felix Sahm et al (Lancet Oncology, 2017) for association with progression-free survival (PFS) and identified associations of methylation at individual CpG sites as detected by the Illumina 450k platform with PFS. Subsequently, we searched for candidate drugs targeting the pathways linked to poor patient prognosis. Our analyses indicated 981 genes for which methylation of mapped CpG sites was found to be consistently associated with shorter PFS (positive hazard ratios (HRs)) and with longer PFS (negative HRs) at FDR-adjusted p < 0.05. Using Cytoscape/Reactome FI app, we cross-referenced current cancer drugs that target these and identified docetaxel and raloxifene hydrochloride as potential candidates. In our vitro study, docetaxel caused apoptotic cell death in established and primary patient meningioma lines of various grades. IC50s of docetaxel in the sixteen meningioma cell lines tested ranged from 0.8nM to 4.4mM, which partially corresponded to the growth rates of these cells. Our study will advance our understanding of molecular pathways driving meningioma and identify potential targeted therapies to bridge the current gap in treatment of the disease.

DDRE-39. REPURPOSING CHEMOTHERAPIES AGAINST HIGH-RISK MENINGIOMAS WITH GUIDANCE BY METHYLATION PROFILES

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi82-vi83
Author(s):  
Anh Tran ◽  
Wenxia Wang ◽  
Denise Scholtens ◽  
Lyndsee Zhang ◽  
Jenny Pokorny ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Synergistic Effects ◽  
Progression Free Survival ◽  
Brain Structures ◽  
Primary Brain Tumor ◽  
Molecular Characteristics ◽  
Cytochrome P450 1B1 ◽  
Patient Prognosis

Abstract Meningioma is the most common primary brain tumor with nearly thirty thousand new cases in the US every year. While most meningiomas are categorized as benign, they can still impact brain structures and result in disability or lethality. Currently, there is no widely accepted chemotherapy, and our understanding of the disease’s molecular characteristics is very limited. In this study, we aimed to identify druggable molecular targets for repurposing of chemotherapies against meningiomas. We analyzed previously published dataset of 493 meningioma patients by Felix Sahm et al (Lancet Oncology, 2017) for association with progression-free survival (PFS) and searched for candidate drugs targeting the pathways linked to poor patient prognosis. Our analyses indicated 981 genes for which methylation of mapped CpG sites was found to be consistently associated with shorter or longer PFS at FDR-adjusted p < 0.05. Using Cytoscape/Reactome FI software, we cross-referenced current cancer drugs that target these and identified docetaxel and raloxifene hydrochloride as potential candidates. In our vitro study, docetaxel caused apoptotic cell death in established and primary patient meningioma lines of various grades. IC50s of docetaxel in the seventeen meningioma cell lines tested ranged from 0.8nM to 4.4mM, which partially corresponded to the growth rates of these cells. As monotherapy, the effects of docetaxel on meningioma were attenuated by multidrug resistance protein 1 (ABCB1) and Cytochrome P450 1B1 (CYP1B1). Docetaxel at 2µM augment double-stranded DNA damage caused by irradiation in vitro, leading to increased cell death. In animal model, low doses of docetaxel and radiation therapy had synergistic effects, increasing survival of mice intracranially implanted with human meningioma cells. Our study will advance our understanding of molecular pathways driving meningioma and identify potential targeted therapies to bridge the current gap in treatment of the disease.

scholarly journals DDIS-07. IDENTIFICATION OF DRUGGABLE MOLECULAR TARGETS IN MENINGIOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi66-vi66
Author(s):  
Anh Tran ◽  
Lyndsee Zhang ◽  
Felix Sahm ◽  
Denise Scholtens ◽  
Craig Horbinski
Keyword(s):  
Aggressive Behavior ◽  
Signaling Pathways ◽  
Progression Free Survival ◽  
Cpg Methylation ◽  
Published Data ◽  
Cpg Sites ◽  
Genes Encoding ◽  
Prognostic Stratification ◽  
Raloxifene Hydrochloride ◽  
Primary Intracranial Tumor

Abstract BACKGROUND Meningioma is the most common primary intracranial tumor, with nearly 30,000 new cases in the US every year. Many meningiomas invade the brain, recur, and become radioresistant, causing severe disability and lethality. Prior work by Sahm et al. showed that meningiomas have consistent patterns of global CpG methylation, and that those patterns are better at prognostic stratification than traditional WHO grading (Lancet Oncol. 2017 May;18(5):682–694). In this study, we hypothesized that specific methylation events could provide further insights as to the signaling pathways driving more aggressive behavior, and identify druggable targets. METHODS We analyzed the Illumina 450k CpG methylation profiles of 493 meningiomas that were published in Lancet Oncology, searching for associations between methylation at individual CpG sites and progression-free survival (PFS). Pathway enrichment analyses were performed using gProfiler and Reactome for genes closest to significant CpG sites, followed by screening for candidate drugs targeting the pathways that were linked with malignant behavior using the ReactomeFIViz Cytoscape Plugin. RESULTS Our analyses revealed 981 genes in which methylation of mapped CpG sites was consistently associated with either shorter PFS (positive hazard ratios (HRs)) or longer PFS (negative HRs) at FDR-adjusted p< 0.05. Methylation of genes encoding proteins involved in G-protein coupled receptor (GPCR) signaling pathways, especially G-alpha (s) and olfactory signaling pathways, showed pronounced association with PFS. We identified 134 anticancer drugs that target the GPCR pathway, including docetaxel and raloxifene hydrochloride, which specifically target G alpha (s) subcomponents. Both are FDA-approved, but no published data exist on their use in meningiomas. CONCLUSIONS This project is advancing our understanding of the molecular pathways driving aggressive behavior in meningioma, and is identifying existing drugs that can be repurposed to treat this tumor.

scholarly journals MGMT promoter methylation testing to predict overall survival in people with glioblastoma treated with temozolomide: a comprehensive meta-analysis based on a Cochrane Review

2021 ◽  
Author(s):  
Sebastian Brandner ◽  
Alexandra McAleenan ◽  
Claire Kelly ◽  
Francesca Spiga ◽  
Hung-Yuan Cheng ◽  
...  
Keyword(s):  
Overall Survival ◽  
Dna Methyltransferase ◽  
Meta Analysis ◽  
Alkylating Agents ◽  
Cochrane Review ◽  
Predictive Biomarker ◽  
Test Method ◽  
Sufficient Information ◽  
Cpg Sites ◽  
Hazard Ratios

Abstract BACKGROUND The DNA repair protein O6 methylguanine-DNA methyltransferase (MGMT) causes resistance of tumour cells to alkylating agents. It is a predictive biomarker in high grade gliomas treated with temozolomide, however there is no consensus on which test method, methylation sites, and cut-off values to use. METHODS We performed a Cochrane Review to examine studies using different techniques to measure MGMT and predict survival in glioblastoma patients treated with temozolomide. Eligible longitudinal studies included adults with glioblastoma treated with temozolomide with or without radiotherapy, or surgery; where MGMT status was determined in tumour tissue, and assessed by one or more technique; and where overall survival was an outcome parameter, with sufficient information to estimate hazard ratios. Two or more methods were compared in 32 independent cohorts with 3474 patients. RESULTS Methylation-specific PCR (MSP) and pyrosequencing (PSQ) techniques were more prognostic than immunohistochemistry for MGMT protein, and PSQ is a slightly better predictor than MSP. CONCLUSIONS We cannot draw strong conclusions about use of frozen tissue versus formalin-fixed paraffin embedded in MSP and PSQ. Also, our meta-analysis does not provide strong evidence about the best CpG sites or threshold. MSP has been studied mainly for CpG sites 76-80 and 84-87 and Pyrosequencing at CpG sites ranging from 72 to 95. A cut-off threshold of 9% for CpG sites 74-78 performed better than higher thresholds of 28% or 29% in two of three good-quality studies. 190 studies were identified presenting hazard ratios from survival analysis in patients in which MGMT methylation was measured by one technique only.

scholarly journals Screening the genome for HCC-specific CpG methylation signatures as biomarkers for diagnosis and prognosis evaluation

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Rui-kun Zhang ◽  
Jia-lin Liu
Keyword(s):  
Cox Regression ◽  
Malignant Tumors ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Survival Prediction ◽  
Training Set ◽  
Cpg Sites ◽  
Diagnosis And Prognosis ◽  
Patient Prognosis ◽  
Prognosis Evaluation

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common and invasive malignant tumors in the world. The change in DNA methylation is a key event in HCC. Methods Methylation datasets for HCC and 17 other types of cancer were downloaded from The Cancer Genome Atlas (TCGA). The CpG sites with large differences in methylation between tumor tissues and paracancerous tissues were identified. We used the HCC methylation dataset downloaded from the TCGA as the training set and removed the overlapping sites among all cancer datasets to ensure that only CpG sites specific to HCC remained. Logistic regression analysis was performed to select specific biomarkers that can be used to diagnose HCC, and two datasets—GSE157341 and GSE54503—downloaded from GEO as validation sets were used to validate our model. We also used a Cox regression model to select CpG sites related to patient prognosis. Results We identified 6 HCC-specific methylated CpG sites as biomarkers for HCC diagnosis. In the training set, the area under the receiver operating characteristic (ROC) curve (AUC) for the model containing all these sites was 0.971. The AUCs were 0.8802 and 0.9711 for the two validation sets from the GEO database. In addition, 3 other CpG sites were analyzed and used to create a risk scoring model for patient prognosis and survival prediction. Conclusions Through the analysis of HCC methylation datasets from the TCGA and Gene Expression Omnibus (GEO) databases, potential biomarkers for HCC diagnosis and prognosis evaluation were ascertained.

scholarly journals Comprehensive single-cell sequencing reveals the stromal dynamics and tumor-specific characteristics in the microenvironment of nasopharyngeal carcinoma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lanqi Gong ◽  
Dora Lai-Wan Kwong ◽  
Wei Dai ◽  
Pingan Wu ◽  
Shanshan Li ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Single Cell ◽  
Rna Sequencing ◽  
Progression Free Survival ◽  
Developmental Trajectory ◽  
Free Survival ◽  
Genetic Profiling ◽  
Single Cell Rna Sequencing ◽  
Infiltrating Cells ◽  
Patient Prognosis

AbstractThe tumor microenvironment (TME) of nasopharyngeal carcinoma (NPC) harbors a heterogeneous and dynamic stromal population. A comprehensive understanding of this tumor-specific ecosystem is necessary to enhance cancer diagnosis, therapeutics, and prognosis. However, recent advances based on bulk RNA sequencing remain insufficient to construct an in-depth landscape of infiltrating stromal cells in NPC. Here we apply single-cell RNA sequencing to 66,627 cells from 14 patients, integrated with clonotype identification on T and B cells. We identify and characterize five major stromal clusters and 36 distinct subpopulations based on genetic profiling. By comparing with the infiltrating cells in the non-malignant microenvironment, we report highly representative features in the TME, including phenotypic abundance, genetic alternations, immune dynamics, clonal expansion, developmental trajectory, and molecular interactions that profoundly influence patient prognosis and therapeutic outcome. The key findings are further independently validated in two single-cell RNA sequencing cohorts and two bulk RNA-sequencing cohorts. In the present study, we reveal the correlation between NPC-specific characteristics and progression-free survival. Together, these data facilitate the understanding of the stromal landscape and immune dynamics in NPC patients and provides deeper insights into the development of prognostic biomarkers and therapeutic targets in the TME.

671 Update of a systematic review and meta-analysis studying the association between antibiotic use and clinical outcomes of non-small-cell lung cancer patients treated with immune checkpoint inhibitors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A708-A708
Author(s):  
Pierre-Alain Bandinelli ◽  
Julie Cervesi ◽  
Clément Le Bescop ◽  
Renaud Buffet ◽  
Jean De Gunzburg ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Outcomes ◽  
Time Window ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Antibiotic Use ◽  
Forest Plot ◽  
Antibiotic Exposure ◽  
Hazard Ratios

BackgroundImmune checkpoint inhibitors (ICIs) have been shown to improve patients‘ clinical outcomes in a variety of cancers, but with variable efficacy. Prior research has also suggested that systemic antibiotic (ABX) exposure may impact the intestinal microbiota and result in suboptimal ICI treatment outcomes. Our team published a systematic review and meta-analysis showing that ABX use could indeed decrease the survival of patients diagnosed with non-small-cell lung cancer (NSCLC) and treated with ICIs.1 The present abstract aims at updating this meta-analysis by incorporating new studies that have been published in the period ranging from September 2019 to August 2020.MethodsMedline (through PubMed), the Cochrane Library and major oncology conferences proceedings were systematically searched to identify studies assessing the impact of ABX use on the clinical outcomes of NSCLC patients treated with ICIs. Studies were found eligible for inclusion when they mentioned a hazard ratio (HR) or Kaplan–Meier curves for overall survival (OS) or progression-free survival (PFS) based on antibiotic exposure. Pooled HRs for OS and PFS and HRs for OS and PFS according to different time windows for ABX exposure were calculated.Results6 eligible new studies were identified between September 2019 and August 2020 while 3 other studies were updated with new information. Altogether, 27 studies reported data for OS (6,436 patients, 826 of whom coming from new studies) and 24 for PFS (3,751 patients, 786 of whom coming from new studies). The pooled HR was 1.75 (95% confidence interval [CI]: 1.38–2.23) for OS and 1.57 (95% CI: 1.28–1.92) for PFS, confirming a significantly reduced survival in patients with NSCLC exposed to ABX. The detailed analysis in subgroups based on the time window of exposure (figure 1, figure 2) suggests that the deleterious effect of ABX is stronger when the exposition happens shortly before and after the initiation of the ICI treatment.Abstract 671 Figure 1Forest plot of hazard ratios for overall survival of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibiotics, according to the time window of antibiotic exposureAbstract 671 Figure 2Forest plot of hazard ratios for progression-free survival of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibiotics, according to the time window of antibiotic exposureConclusionsThe update of the meta-analysis confirms the previously reported deleterious effect of ABX on ICI treatment outcomes, taking into account the latest publications in the field. The topic deserves further research to uncover if the effect will stand with 1st line use of ICI together with chemotherapies and/or other approved combinations, elucidate the mechanisms at stake and improve care of patients.ReferencesLurienne L, Cervesi J, Duhalde L, de Gunzburg J, Andremont A, Zalcman G, et al. NSCLC immunotherapy efficacy and antibiotic use: a systematic review and meta-analysis. J Thorac Oncol 2020;15:1147–1159.

scholarly journals Molecular Mechanisms of Drug Resistance in Glioblastoma

2021 ◽  
Vol 22 (12) ◽  
pp. 6385
Author(s):  
Maya A. Dymova ◽  
Elena V. Kuligina ◽  
Vladimir A. Richter
Keyword(s):  
Drug Resistance ◽  
Brain Tumor ◽  
Molecular Mechanisms ◽  
Primary Brain Tumor ◽  
Therapeutic Resistance ◽  
Molecular Characteristics ◽  
Blood Brain ◽  
Conventional Radiation ◽  
The Brain ◽  
Made In

Glioblastoma multiforme (GBM) is the most common and fatal primary brain tumor, is highly resistant to conventional radiation and chemotherapy, and is not amenable to effective surgical resection. The present review summarizes recent advances in our understanding of the molecular mechanisms of therapeutic resistance of GBM to already known drugs, the molecular characteristics of glioblastoma cells, and the barriers in the brain that underlie drug resistance. We also discuss the progress that has been made in the development of new targeted drugs for glioblastoma, as well as advances in drug delivery across the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB).

Association between selenium intake, diabetes, and mortality in adults: findings from National Health and Nutrition Examination Survey (NHANES) 2003-2014

2021 ◽  
pp. 1-24
Author(s):  
Bushra Hoque ◽  
Zumin Shi
Keyword(s):  
National Health ◽  
Cox Regression ◽  
Inverse Association ◽  
Nutrition Examination Survey ◽  
Health And Nutrition ◽  
Hazard Ratios ◽  
The Us ◽  
All Cause Mortality ◽  
Cvd Mortality

Abstract Selenium (Se) is a trace mineral that has antioxidant and anti-inflammatory properties. This study aimed to investigate the association between Se intake, diabetes, all-cause and cause-specific mortality in a representative sample of US adults. Data from 18,932 adults who attended the 2003-2014 National Health and Nutrition Examination Survey (NHANES) were analysed. Information on mortality was obtained from the US mortality registry updated to 2015. Multivariable logistic regression and Cox regression were used. Cross-sectionally, Se intake was positively associated with diabetes. Comparing extreme quartiles of Se intake, the odds ratio (OR) for diabetes was 1.44 (95% CI: 1.09–1.89). During a mean of 6.6 years follow-up, there were 1627 death (312 CVD, 386 cancer). High intake of Se was associated with a lower risk of all-cause mortality. When comparing the highest with the lowest quartiles of Se intake, the hazard ratios (HRs) for all-cause, CVD mortality, cancer mortality and other mortality were: 0.77 (95% CI 0.59-1.01), 0.62 (95% CI, 0.35-1.13), 1.42 (95% CI, 0.78-2.58) and 0.60 (95% CI,0.40-0.80), respectively. The inverse association between Se intake and all-cause mortality was only found among white participants. In conclusion, Se intake was positively associated with diabetes but inversely associated with all-cause mortality. There was no interaction between Se intake and diabetes in relation to all-cause mortality.

Sequential monitoring of PD-L1 on circulating stromal cells in blood predicts PFS in NSCLC patients undergoing immunotherapy after definitive chemoradiation.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8534-8534
Author(s):  
Daniel L Adams ◽  
Alexander Augustyn ◽  
Jianzhong He ◽  
Yawei Qiao ◽  
Ting Xu ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Progression Free Survival ◽  
Free Survival ◽  
Hazard Ratios ◽  
Fda Approval ◽  
Inflammatory State ◽  
Nsclc Patients ◽  
Tumor Biopsies ◽  
Relationship Of ◽  
The Relationship

8534 Background: Cancer Associated Macrophage-Like cells (CAMLs) are circulating stromal cells in the blood of patients (pts) with solid tumors that are phagocytic macrophages that may represent the inflammatory state of the tumor microenvironment. Previously, we demonstrated CAMLs ≥50µm after chemo-radiation therapy (CRT) in NSCLC is associated with worse progression free survival (PFS) and overall survival (OS). We also showed that PDL1 expression in CAMLs is dynamic & can change with CRT, difficult to assess with repeat biopsies, but possible with liquid biopsy. For this study we evaluated whether CAML properties can predict response to CRT with/without immunotherapy (IMT) agents in unresectable NSCLC. Methods: A single blind multi-year prospective study was undertaken to test the relationship of PDL1 expression and ≥50µm CAML size to PFS/OS in NSCLC, pre and post CRT with (n = 96) and without (n = 72) anti-PDL1/PD1 IMT. This included atezolizumab (prospective single arm NCT02525757) n = 39, durvalumab n = 52 or pembrolizumab n = 5 both after 2018 FDA approval. We recruited 168 pts with pathologically confirmed unresectable NSCLC prior to CRT. Blood samples 15 mL were taken at baseline (BL), CRT completion (T1), and ̃1 month after CRT (T2) (with n = 96 or without n = 72 IMT). Blood was filtered by CellSieve filtration and CAMLs quantified for size ( < 49 µm or ≥50 µm) and PDL1 expression to evaluate PFS and OS hazard ratios (HRs) by censored univariate and multivariate analysis at 24 months. Results: CAMLs were found in 90% of all samples, average 5.8 CAMLs/15mL. At BL, ≥50µm CAMLs did not predict PFS in CRT/IMT pts (HR 1.6, p = 0.220) nor CRT alone (HR 1.3, p = 0.593). However, after completion of CRT (T1) ≥50µm CAMLs predicted PFS in CRT/IMT pts (HR 2.7, p = 0.003) and CRT alone (HR 2.5, p = 0.015). In primary tumor biopsies, PDL1 expression > 1% did not predict CRT/IMT response (PFS HR 1.8, p = 0.262 & OS HR 2.3, p = 0.158). At BL, high CAML PDL1 did not predict PFS in CRT/IMT pts (HR 1.4, p = 0.427) nor CRT alone (HR 1.1, p = 0.982). Further, at CRT completion (T1), high CAML PDL1 only trended for better PFS in CRT/IMT pts (HR 1.7, p = 0.137), but not CRT alone (HR 1.1, p = 0.972). At T2, however, pts with continuously high CAML PDL1 had significantly better PFS with IMT (HR 3.2, p = 0.002) vs CRT alone (HR 1.4, p = 0.616). While ≥50µm CAMLs at BL did not predict 24 month progression, ≥50 µm CAMLs after CRT (with or without 1 cycle of anti-PDL1 IMT) was 84% accurate at predicting progression. Further subtyping and analysis is ongoing to evaluate OS and PDL1 in the CAML populations. Conclusions: Our data suggests that in unresectable NSCLC, ≥50 µm CAMLs after completion of CRT is prognostic regardless of IMT use. PDL1 expression in CAMLs also appears to predict for response to consolidated IMT after CRT. Additional studies are needed to validate these findings.

Clinical and molecular characteristics of ARIEL3 patients who derived exceptional benefit from rucaparib maintenance treatment for high-grade ovarian cancer (HGOC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5537-5537
Author(s):  
Tanya Kwan ◽  
Amit M. Oza ◽  
Domenica Lorusso ◽  
Carol Aghajanian ◽  
Ana Oaknin ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Maintenance Treatment ◽  
Parp Inhibitor ◽  
Progression Free Survival ◽  
Molecular Characteristics ◽  
Brca Mutations ◽  
Molecular Features ◽  
Brca1 Promoter Methylation ◽  
Genome Wide ◽  
To Receive

5537 Background: ARIEL3 is a placebo-controlled randomized trial of the PARP inhibitor (PARPi) rucaparib as maintenance treatment in HGOC patients (pts) who responded to the latest line of platinum therapy (NCT01968213). Rucaparib improved progression-free survival (PFS) across all predefined subgroups. Here, we present an exploratory analysis of clinical and molecular characteristics associated with exceptional benefit from rucaparib. Methods: Pts were randomized 2:1 to receive rucaparib 600 mg BID or placebo. At the data cutoff of Dec 31, 2019, 33/375 (9%) and 1/189 (0.5%) pts were still ongoing and receiving rucaparib or placebo, respectively. Molecular features (genomic alterations, BRCA1 promoter methylation) and baseline clinical characteristics were compared between pts who derived exceptional benefit (PFS ≥2 yrs), and those with disease progression on first scan (≈12 wks; the short-term [ST] subgroup) within each treatment arm. Results: Of 564 pts, 83 (15%) showed exceptional benefit: 79/375 (21%) in the rucaparib arm and 4/189 (2%) in the placebo arm. Within the rucaparib arm, exceptional benefit pts had more favorable clinical prognostic factors at baseline compared with the ST subgroup (Table). While BRCA mutations were enriched in the rucaparib exceptional benefit subgroup, 34/79 (43%) of these pts were BRCA wild type. Among other biomarkers, RAD51C/D mutations were associated with exceptional benefit; low genome-wide loss of heterozygosity was enriched within the ST subgroup; and high BRCA1 methylation was present at similar fractions. Trends were similar in the placebo arm (Table). Conclusions: Exceptional benefit in ARIEL3 was more common in, but not exclusive to, pts with favorable clinical characteristics and known mechanisms of PARPi sensitivity. Our results suggest that rucaparib can deliver exceptional benefit to a diverse set of HGOC pts. Clinical trial information: NCT01968213. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document