Pembrolizumab plus chemotherapy in frontline treatment of advanced epithelial ovarian cancer: clinical and translational results from a phase II trial
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE271757 | GEO | 2025/01/22
REPOSITORIES: GEO
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Project description:A phase I trial of a SRC kinase Inhibitor, dasatinib, in combination with paclitaxel and carboplatin in patients with advanced or recurrent ovarian cancer. Background: We conducted a phase I study of dasatinib, an oral SRC tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in advanced and recurrent epithelial ovarian cancer (EOC). Methods: The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included toxicity, response rate (RR), pharmacokinetics and pharmacodynamics. Based on the 3+3 design, cohorts of 3-6 pts received paclitaxel 175 mg/m2 and carboplatin AUC 6 every three weeks with escalating doses of dasatinib (100, 120, 150 mg daily), followed by an 8 patient expansion cohort. Results: Twenty patients were enrolled between 06/07 and 12/09. The median age was 61 yrs (42-82) with a median of 2 prior regimens (0-6), and 71% had platinum-sensitive disease. There were 3-6 pts in each cohort, and 8 in the expansion cohort. Pharmacokinetics were observed over the first 2 cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia. Other toxicities in all cycles included neutropenia (95% grade 3-4), thrombocytopenia (35% grade 3-4), and fatigue (10% grade 3). The RR was 45% (complete responses, 3/18(17%); partial responses, 5/18(28%)) and 56% (10/18) had stable disease. The PFS6-month actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively. Conclusions: Due to the high incidence of myelosuppression with subsequent cycles the recommended phase II dose is 150 mg daily of dasatinib in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity in advanced EOC. Global profiles of expression were characterized using unsupervised clustering methods and gene- and pathway-analyses of differential expression.
2012-04-11 | E-GEOD-37180 | biostudies-arrayexpress
Project description:A phase I trial of a SRC kinase Inhibitor, dasatinib, in combination with paclitaxel and carboplatin in patients with advanced or recurrent ovarian cancer. Background: We conducted a phase I study of dasatinib, an oral SRC tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in advanced and recurrent epithelial ovarian cancer (EOC). Methods: The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included toxicity, response rate (RR), pharmacokinetics and pharmacodynamics. Based on the 3+3 design, cohorts of 3-6 pts received paclitaxel 175 mg/m2 and carboplatin AUC 6 every three weeks with escalating doses of dasatinib (100, 120, 150 mg daily), followed by an 8 patient expansion cohort. Results: Twenty patients were enrolled between 06/07 and 12/09. The median age was 61 yrs (42-82) with a median of 2 prior regimens (0-6), and 71% had platinum-sensitive disease. There were 3-6 pts in each cohort, and 8 in the expansion cohort. Pharmacokinetics were observed over the first 2 cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia. Other toxicities in all cycles included neutropenia (95% grade 3-4), thrombocytopenia (35% grade 3-4), and fatigue (10% grade 3). The RR was 45% (complete responses, 3/18(17%); partial responses, 5/18(28%)) and 56% (10/18) had stable disease. The PFS6-month actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively. Conclusions: Due to the high incidence of myelosuppression with subsequent cycles the recommended phase II dose is 150 mg daily of dasatinib in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity in advanced EOC.
2012-04-12 | GSE37180 | GEO
Project description:Identification of differently methylated regions of CpG islands in epithelial ovarian cancer (EOC) tissue from patients with progression free survival <3 years (worse outcome) vs. patients with PFS >3 years (good outcome, relapse free until last follow up). Patients were homogenous in regard to clinical (FIGO III/IV, serous histology, optimally resected (macroscopically tumor free), platin-taxan chemotherapy) and molecular properties (immunohistochemistry for p16, BRCA1, Ki67 and p53)).
2015-11-16 | GSE62851 | GEO
Project description:Background. To develop a radiomics signature for predicting overall survival (OS) and progression-free survival (PFS) in patients with medulloblastoma (MB), and to investigate the incremental prognostic value and underlying biological pathways of the radiomics signature.Methods. A radiomics signature was constructed based on five magnetic resonance (MR) sequences (T1, T1c, T2, FLAIR and ADC) from a training cohort (n = 83) using LASSO-Cox model. Association between the signature and survival was evaluated on a testing cohort (n = 83). Incremental prognostic value of the signature beyond clinicomolecular factors was assessed with respect to calibration, discrimination, reclassification and clinical usefulness by a radiomics-clinicomolecular nomogram. Key pathways associated with the signature were identified. Prognostic value of pathway genes was assessed in a public TCGA cohort.Results. The radiomics signature was significantly associated with OS/PFS, independent from clinicomolecular factors. The radiomics-clinicomolecular nomogram predicted OS (C-index 0.762) and PFS (C-index 0.697) better than either the radiomics signature (C-index: OS: 0.649; PFS: 0.593) or the clinicomolecular nomogram (C-index: OS: 0.725; PFS: 0.691) only, with a better calibration and classification accuracy (net reclassification improvement: OS: 0.298, P = 0.022; PFS: 0.252, P = 0.026). Nine pathways were significantly correlated with the radiomics signature. Average expression value of pathway genes achieved significant risk stratification in public cohort (log-rank P = 0.016). Conclusion. This study demonstrated radiomics signature was an independent prognostic marker and offered incremental value over clinicomolecular factors in OS/PFS predictions for MB patients. The signature was associated with dysregulated pathways affecting patient prognosis in MB.
2020-06-01 | GSE151519 | GEO
Project description:The Piedmont study is a prospectively designed retrospective evaluation of a new 48-gene antifolate response signature (AF-PRS) in patients with locally advanced/metastatic NS-NSCLC treated with pemetrexed-containing platinum doublet chemotherapy (PMX-PDC). The study tested the hypothesis that the AF-PRS selects for patients with NS-NSCLC that preferentially respond to PMX-PDC, with a goal of providing clinical support for AF-PRS as potential diagnostic test. Overall, 53% of patients were AF-PRS(+), which was associated with extended PFS, but not OS, vs. AF-PRS(-) (16.6 vs. 6.6 mo; p = 0.025). In patients who were Stage I-III patients at time of treatment, PFS, but not OS, was further extended in AF-PRS(+) vs. AF-PRS(-) (36.2 vs. 9.3 mo; p = 0.03). A complete response (CR) to therapy was noted in 14 of 95 patients. AF-PRS(+) preferentially selected a majority (79%) of CRs, which were evenly split between patients Stage I-III (6 of 7) and Stage IV (5 of 7) at time of treatment. AF-PRS identified a significant population of patients with extended survival and/or clinical response following PMX-PDC treatment. AF-PRS may be a useful diagnostic test for patients indicated for systemic chemotherapy, especially when determining the optimal PDC regimen for locally advanced disease.
2023-05-23 | GSE232569 | GEO
Project description:We performed Array CGH on 25 patients with high grade serous epithelial ovarian cancer (HGS-EOC): each of this had multiple biopsies taken at the moment of the surgery in different anatomical sites, and 18 had also temporal biopsies taken after several cycles of chemotherapy. Blood was used as control. The experiment was performed to identify genomic alterations that can be used to classify the disease, going beyond the individual tumor heterogeneity.
2019-12-19 | E-MTAB-6900 | biostudies-arrayexpress
Project description:Metastatic renal cell carcinoma (mRCC) patients treated with anti-vascular endothelial growth factor (VEGF) therapies demonstrate promising outcomes but not all patients benefit. Factors that predict response remain to be elucidated. Nephrectomy material from 37 patients with mRCC receiving bevacizumab 6 erlotinib was used for protein and gene expression assessment. Protein lysates were subjected to reverse-phase protein array profiling. RNA extracts were used to carry out gene expression microarray-based profiling. Normalized protein and gene expression data were correlated with overall survival (OS) and progression-free survival (PFS) using univariate Cox hazard model and linear regression. Immunoblotting was carried out to validate the results. High protein levels of AMP-activated protein kinase and low levels of cyclin B1 (CCNB1) were associated with longer OS and PFS. Further validation revealed reduced expression and activation of phosphoinositide 3-kinase (PI3K) pathway components and cell cycle factors in patients with prolonged survival after therapy. Gene expression analysis revealed up-regulation of PI3K- and cell cycle-related pathways in patients with shorter PFS. The OS and PFS of bevacizumab 6 erlotinib-treated patients with renal cell carcinoma were associated with changes in expression of protein and gene expression markers related to PI3K pathway and cell cycle signaling. Expression profiling of ccRCC samples post-treatment (bevacizumab plus erlotinib, or bevacizumab alone). Note: sample 'Jonasch_R06_Tumor_3-27-08_CMM' was not used in the publication (PMID: 20089566).
2011-01-07 | E-GEOD-25698 | biostudies-arrayexpress
Project description:Nowadays, risk stratification for oropharyngeal squamous cell carcinoma (OPSCC) is based on HPV status, tobacco smoking, and tumor stage. Although HPV positivity represents a strong prognostic factor for both reduced risk of relapse, and improved survival, there is a subset of HPV-positive OPSCC patients who still experience poor outcomes. Furthermore, HPV-negative OPSCC patients, who have an even higher risk of relapse within two years from the end of the treatment, are still lacking suitable prognostic biomarkers for clinical outcome. In this scenario, inclusion of new biomarkers that differentiate OPSCC patients with a diverse prognosis is urgently needed. Since genes encoding for epigenetic regulators have been frequently found mutated in several tumors, including OPSCC, it is expected that epigenetic changes may play a major role in OPSCC pathogenesis and response to therapy. Consistently, HPV oncoproteins have been also demonstrated to impact on epigenetic pattern by interacting with different epigenetic regulators, thus affecting the chromatin landscape of OPSCC HPV-positive cells. Along this line, we have recently demonstrated the methylation levels of the “Long interspersed nucleotide element-1” (LINE-1) repetitive elements, a widely accepted surrogate of overall genomic DNA methylation content, was different between HPV16-positive and -negative OPSCC patients. In particular, the lowest level of LINE-1 element methylation was observed in HPV16-negative OPSCC patients who relapsed within 24 months, thus indicating the overall level of genomic DNA methylation may have an impact on early OPSCC relapse risk. Despite these promising initial data, the influence of LINE1 methylation levels on OPSCC survival is not yet well defined. We retrospectively reviewed a cohort of 156 patients with stage III–IVB (AJCC TNM 7th Ed.) OPSCC. Forty patients were diagnosed and treated at Treviso Regional Hospital, and 116 at National Cancer Institute of Aviano and/or Pordenone Hospital. All patients were managed with curative intent with elective radiotherapy ± chemotherapy or surgery ± adjuvant (chemo)radiotherapy, in accordance with current clinical practice. Genomic DNA was extracted from OPSCC formalin-fixed paraffin-embedded tissues. The quantification of HPV16 DNA was performed by real-time quantitative PCR by using specific primers for the amplification of a region spanning the E6 genes of the HPV16 genome, whereas the methylation status of LINE1 repetitive sequences was evaluated by real-time quantitative Methylation-Specific PCR. The impact of genome-wide methylation patterns on progression-free survival (PFS) and overall survival (OS) was assessed using Kaplan-Meier analyses. Optimal cut-points for LINE-1 were search through a recursive algorithm which estimates the predictive value for PFS (Harrell's c-index) for each possible couple of LINE-1 values; optimal cut-points were defined as those which maximized Harrell's c-index. Multivariate hazard risk (HR) and corresponding confidence intervals (CI) were calculated according to Cox proportional hazard model adjusting for gender, age, TNM stage, and HPV status.The median follow up was 30 months (interquartile range: 17-72 months) Considering all cases, PFS and OS were respectively 64.6% and 71.8% at 2 years, and 49.5% and 53.7% at 5 years. HPV DNA prevalence was 28.8% (45/156). Compared to HPV-negative patients, HPV-positive ones had a better outcome in terms of PFS at 2 (81.0% vs. 58.2%) and 5 years (70.9% vs 41.6%; p=0.003), as well as in terms of OS (5-year OS: 74.1 vs. 45.9%, respectively; p=0.003). LINE-1 methylation level was significantly higher in HPV-positive OPSCC patients than in HPV-negative ones (median, 66.9% and 48.7% respectively; p<0.001). Three patterns of LINE-1 methylation status were indentified according to PFS: high ≥55%, medium 35-54%, low <35%. The same cut-points were identified from the analysis on OS. Analyzing all patients, PFS at 2 years was 75.9% in the high methylation group, 62.0% in the intermediate group, and 41.6% in the low methylation group (p≤0.001). Compared to LINE-1≥55%, multivariate HR were 1.66 (95% CI: 0.92-2.99) for LINE-1 35-54% and 2.84 (95% CI: 1.51-5.37) for LINE-1<35%. Moreover, OS at 2 and 5 years was significantly better in the high methylation group (p<0.001), with HRs of death similar to those for PFS. It is worth noting that the level of LINE-1 remained a prognostic factor for both PFS (p= 0.004) and of OS (p=0.011) when we restricted the analysis to HPV-negative patients. Among these patients, the multivariate HRs for LINE-1<35% were 2.87 (95% CI: 1.49-5.52) for PFS and 2.86 (1.43-5.74) for OS. In HPV-positive group, respect to patients with LINE-1 <55%, cases with a LINE-1≥55% have had better trend in terms of PFS and OS, but this difference was not statistically significant (p=0.112; p= 0.113), mainly due to small sample size. Between HPV-positive patients, only one had a methylation of LINE-1 < 35%. LINE-1 methylation has been identified as a molecular marker of prognosis for stage III-IV OPSCC patients, becoming a promising biomarker to be integrated in current prognostic factors (e.g., stage, HPV status, tobacco smoking) to refine the comprehensive clinical management of OPSCC. This is of particular clinical relevance for HPV-positive OPSCC patients, since this marker may help in indentify the subset of these patients with bad prognosis. However, further validation in a prospective study is needed for its application in daily clinical practice.
2022-07-14 | E-MTAB-11152 | biostudies-arrayexpress
Project description:Nowadays, risk stratification for oropharyngeal squamous cell carcinoma (OPSCC) is based on HPV status, tobacco smoking, and tumor stage. Although HPV positivity represents a strong prognostic factor for both reduced risk of relapse, and improved survival, there is a subset of HPV-positive OPSCC patients who still experience poor outcomes. Furthermore, HPV-negative OPSCC patients, who have an even higher risk of relapse within two years from the end of the treatment, are still lacking suitable prognostic biomarkers for clinical outcome. In this scenario, inclusion of new biomarkers that differentiate OPSCC patients with a diverse prognosis is urgently needed. Since genes encoding for epigenetic regulators have been frequently found mutated in several tumors, including OPSCC, it is expected that epigenetic changes may play a major role in OPSCC pathogenesis and response to therapy. Consistently, HPV oncoproteins have been also demonstrated to impact on epigenetic pattern by interacting with different epigenetic regulators, thus affecting the chromatin landscape of OPSCC HPV-positive cells. Along this line, we have recently demonstrated the methylation levels of the “Long interspersed nucleotide element-1” (LINE-1) repetitive elements, a widely accepted surrogate of overall genomic DNA methylation content, was different between HPV16-positive and -negative OPSCC patients. In particular, the lowest level of LINE-1 element methylation was observed in HPV16-negative OPSCC patients who relapsed within 24 months, thus indicating the overall level of genomic DNA methylation may have an impact on early OPSCC relapse risk. Despite these promising initial data, the influence of LINE1 methylation levels on OPSCC survival is not yet well defined. We retrospectively reviewed a cohort of 156 patients with stage III–IVB (AJCC TNM 7th Ed.) OPSCC. Forty patients were diagnosed and treated at Treviso Regional Hospital, and 116 at National Cancer Institute of Aviano and/or Pordenone Hospital. All patients were managed with curative intent with elective radiotherapy ± chemotherapy or surgery ± adjuvant (chemo)radiotherapy, in accordance with current clinical practice. Genomic DNA was extracted from OPSCC formalin-fixed paraffin-embedded tissues. The quantification of HPV16 DNA was performed by real-time quantitative PCR by using specific primers for the amplification of a region spanning the E6 genes of the HPV16 genome, whereas the methylation status of LINE1 repetitive sequences was evaluated by real-time quantitative Methylation-Specific PCR. The impact of genome-wide methylation patterns on progression-free survival (PFS) and overall survival (OS) was assessed using Kaplan-Meier analyses. Optimal cut-points for LINE-1 were search through a recursive algorithm which estimates the predictive value for PFS (Harrell's c-index) for each possible couple of LINE-1 values; optimal cut-points were defined as those which maximized Harrell's c-index. Multivariate hazard risk (HR) and corresponding confidence intervals (CI) were calculated according to Cox proportional hazard model adjusting for gender, age, TNM stage, and HPV status.The median follow up was 30 months (interquartile range: 17-72 months) Considering all cases, PFS and OS were respectively 64.6% and 71.8% at 2 years, and 49.5% and 53.7% at 5 years. HPV DNA prevalence was 28.8% (45/156). Compared to HPV-negative patients, HPV-positive ones had a better outcome in terms of PFS at 2 (81.0% vs. 58.2%) and 5 years (70.9% vs 41.6%; p=0.003), as well as in terms of OS (5-year OS: 74.1 vs. 45.9%, respectively; p=0.003). LINE-1 methylation level was significantly higher in HPV-positive OPSCC patients than in HPV-negative ones (median, 66.9% and 48.7% respectively; p<0.001). Three patterns of LINE-1 methylation status were indentified according to PFS: high ≥55%, medium 35-54%, low <35%. The same cut-points were identified from the analysis on OS. Analyzing all patients, PFS at 2 years was 75.9% in the high methylation group, 62.0% in the intermediate group, and 41.6% in the low methylation group (p≤0.001). Compared to LINE-1≥55%, multivariate HR were 1.66 (95% CI: 0.92-2.99) for LINE-1 35-54% and 2.84 (95% CI: 1.51-5.37) for LINE-1<35%. Moreover, OS at 2 and 5 years was significantly better in the high methylation group (p<0.001), with HRs of death similar to those for PFS. It is worth noting that the level of LINE-1 remained a prognostic factor for both PFS (p= 0.004) and of OS (p=0.011) when we restricted the analysis to HPV-negative patients. Among these patients, the multivariate HRs for LINE-1<35% were 2.87 (95% CI: 1.49-5.52) for PFS and 2.86 (1.43-5.74) for OS. In HPV-positive group, respect to patients with LINE-1 <55%, cases with a LINE-1≥55% have had better trend in terms of PFS and OS, but this difference was not statistically significant (p=0.112; p= 0.113), mainly due to small sample size. Between HPV-positive patients, only one had a methylation of LINE-1 < 35%. LINE-1 methylation has been identified as a molecular marker of prognosis for stage III-IV OPSCC patients, becoming a promising biomarker to be integrated in current prognostic factors (e.g., stage, HPV status, tobacco smoking) to refine the comprehensive clinical management of OPSCC. This is of particular clinical relevance for HPV-positive OPSCC patients, since this marker may help in indentify the subset of these patients with bad prognosis. However, further validation in a prospective study is needed for its application in daily clinical practice.
2023-02-21 | E-MTAB-12032 | biostudies-arrayexpress
Project description:The AVAglio and RTOG-0825 randomized, placebo-controlled phase III trials in newly diagnosed glioblastoma reported prolonged progression-free survival (PFS), but not overall survival (OS), with the addition of bevacizumab to radiotherapy/temozolomide. To establish whether certain patient subgroups derived OS benefit from the addition of bevacizumab to first-line standard-of-care therapy, AVAglio patients were retrospectively evaluated for molecular subtype, and bevacizumab efficacy assessed for each patient subgroup. A multivariate analysis accounting for prognostic covariates revealed that bevacizumab conferred a significant OS advantage versus placebo for patients with Proneural IDH1 wild-type tumors (17.1 v 12.8 months, respectively; hazard ratio, 0.43; 95% CI, 0.26 to 0.73; P = .002). This analysis also revealed an interaction between the Proneural subtype biomarker and treatment arm (P = .023). The group of patients with Mesenchymal and Proneural tumors derived a PFS benefit from bevacizumab, compared with placebo; however, this translated to an OS benefit in the Proneural subset only. Retrospective analysis of AVAglio data suggests that patients with IDH1 wild-type Proneural glioblastoma may derive OS benefit from first-line bevacizumab treatment. The predictive value of the Proneural subtype observed in AVAglio should be validated in an independent dataset. A total of 349 (bevacizumab arm, n = 171; placebo arm, n = 178) pretreatment specimens from AVAglio patients (total n = 921) were available for biomarker analysis. Samples were profiled for gene expression and isocitrate dehydrogenase 1 (IDH1) mutation status and classified into previously identified molecular subtypes. PFS and OS were assessed within each subtype.
2016-07-06 | E-GEOD-84010 | biostudies-arrayexpress