scholarly journals Study design and data analysis considerations for the discovery of prognostic molecular biomarkers: a case study of progression free survival in advanced serous ovarian cancer

2016 ◽  
Vol 9 (1) ◽  
Author(s):  
Li-Xuan Qin ◽  
Douglas A. Levine
Keyword(s):  
Ovarian Cancer ◽  
Data Analysis ◽  
Study Design ◽  
Progression Free Survival ◽  
Molecular Biomarkers ◽  
Serous Ovarian Cancer ◽  
Free Survival

scholarly journals Somatic Mutations in BRCA2 BRC Repeat Associated with Outcome in Patients with High Grade Serous Ovarian Cancer

2020 ◽  
Author(s):  
Guonan Zhang ◽  
Jie Zhang ◽  
Yi Zhu ◽  
Hong Liu ◽  
Yu Shi ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Somatic Mutations ◽  
Progression Free Survival ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Blood Leukocytes ◽  
Free Survival ◽  
Chemotherapy Sensitivity ◽  
Factors Affecting ◽  
Platinum Based Chemotherapy

Abstract BackgroundThe interaction between BRCA2 BRC repeats and RAD51 is one of the great important factors affecting the homologous recombination in DNA damage repair of tumor cells. We investigated the effect of BRCA2 BRC repeat mutations on outcome in patients with high grade serous ovarian cancer (HGSOC) who received platinum-based chemotherapy.MethodsWe identified the type and location of BRCA2 BRC repeat mutations by PCR and DNA sequencing in tumor and peripheral blood leukocytes (PBL) samples of 113 patients with stage IIIC/IV high grade serous ovarian cancer (HGSOC), and assessed chemotherapy-free interval (CFI), progression-free survival (PFS) and overall survival (OS).Results24 (21.23%) cases with somatic mutation were identified in 113 HGSOC patients. Among them, 8 (7.1%) cases with nonsense mutation resulting in BRCA2 truncation significantly prolonged median CFI (37 vs 8 months,P=0.000), PFS (43 vs 14 months, p=0.000) and OS (56 vs 31 months, P=0.002); Interestingly, 16 (14.13%) cases with missense mutation also prolonged median CFI (15 vs 8 months, P=0.044), PFS (21 vs 14 months, P=0.049) and OS ( 38 vs 31 months, P=0.037). ConclusionsSomatic mutations in BRCA2 BRC5-8 repeat motifs are associated with platinum-based chemotherapy sensitivity and a better outcome in patients with HGSOC.

scholarly journals A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Panagiotis A. Konstantinopoulos ◽  
Alexandre André B. A. da Costa ◽  
Doga Gulhan ◽  
Elizabeth K. Lee ◽  
Su-Chun Cheng ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Progression Free Survival ◽  
Replication Stress ◽  
Inhibitor Therapy ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Free Survival ◽  
Rb Pathway ◽  
Pathway Regulation ◽  
Stress Biomarker

AbstractIn a trial of patients with high grade serous ovarian cancer (HGSOC), addition of the ATR inhibitor berzosertib to gemcitabine improved progression free survival (PFS) compared to gemcitabine alone but biomarkers predictive of treatment are lacking. Here we report a candidate biomarker of response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in HGSOC ovarian cancer. Patients with replication stress (RS)-high tumors (n = 27), defined as harboring at least one genomic RS alteration related to loss of RB pathway regulation and/or oncogene-induced replication stress achieve significantly prolonged PFS (HR = 0.38, 90% CI, 0.17–0.86) on gemcitabine monotherapy compared to those with tumors without such alterations (defined as RS-low, n = 30). However, addition of berzosertib to gemcitabine benefits only patients with RS-low tumors (gemcitabine/berzosertib HR 0.34, 90% CI, 0.13–0.86) and not patients with RS-high tumors (HR 1.11, 90% CI, 0.47–2.62). Our findings support the notion that the exacerbation of RS by gemcitabine monotherapy is adequate for lethality in RS-high tumors. Conversely, for RS-low tumors addition of berzosertib-mediated ATR inhibition to gemcitabine is necessary for lethality to occur. Independent prospective validation of this biomarker is required.

scholarly journals Frizzled class 7 receptor is differentially expressed in high-grade serous ovarian cancer and based on patient survival.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Ovarian Cancer ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Progression Free Survival ◽  
Global Gene Expression ◽  
Differentially Expressed ◽  
Published Data ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Free Survival

High-grade serous ovarian cancer (HGSC) is the most common type of the most lethal gynecologic malignancy (1). To identify genes whose expression was associated with survival outcomes in HGSC, we used published data from patients enrolled in the ICON7 trial to compare the global gene expression profiles of primary HGSC tumors from women with the best and worst progression-free survival (PFS) (2). We found that the Frizzled class 7 (Fzd7) receptor was among the genes most differentially expressed in HGSC tumors when comparing tumor transcriptomes based on superior or inferior PFS. In two independent datasets, Fzd7 was among the genes most differentially expressed in HGSC tumors when comparing primary tumor to the normal ovary (3, 4). Wnt pathway signaling through Fzd7 may be relevant to the biology of high-grade serous ovarian cancers.

Phase Ib with expansion study of olaparib plus weekly (Metronomic) carboplatin and paclitaxel in relapsed ovarian cancer patients

2019 ◽  
Vol 29 (2) ◽  
pp. 325-333 ◽  
Author(s):  
Saul Eugene Rivkin ◽  
James Moon ◽  
Desiree S Iriarte ◽  
Erik Bailey ◽  
Heather L Sloan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Complete Remission ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Free Survival ◽  
Phase Ib ◽  
Experienced Grade

ObjectiveOur goals were to: establish the maximum-tolerated dose of olaparib tablets combined with metronomic carboplatin and paclitaxel in patients with relapsed high-grade serous ovarian cancer; evaluate dose-limiting toxicities; and evaluate efficacy at the maximum tolerated dose.MethodsIn this open-label, single-arm, investigator-initiated trial (ClinicalTrials.gov NCT01650376), patients with high-grade serous ovarian cancer who failed primary platinum and taxane therapy received oral olaparib tablets twice daily days 1–3 each week combined with fixed-dose metronomic carboplatin AUC2 and paclitaxel 60 mg/m2 weekly for 3 out of 4 weeks. A 3 × 3 design was used to determine the olaparib maximum tolerated dose. Combination therapy continued until disease progression, but patients with partial or complete response were transitioned to olaparib maintenance therapy. All patients were included in the analysis.ResultsThe maximum tolerated dose of olaparib tablets was 150 mg twice daily with metronomic carboplatin and paclitaxel. 54 women were enrolled, 14 in phase Ib and 40 in the expansion phase. The median number of prior therapeutic regimens was 3. Response included 13 complete remission (24%) and 16 partial remission (30%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for an overall response rate of 54% (95% CI 40% to 67%). Of 47 patients who underwent BRCA testing, 23 were BRCA mutation (BRCAm) and 24 BRCA wild type (BRCAwt). Progression-free survival for BRCAm was 12.1 months versus 4.8 for BRCAwt (p=0.0001). Median overall survival for BRCAm was 24.1 months versus 10.4 months for BRCAwt (p=0.02). 42 patients (78%) experienced grade 3–4 toxicities with combination therapy; the most common were hematologic. There were no treatment related deaths. Among 14 patients who received maintenance therapy, 7 experienced grade 1–2 non-hematologic toxicities.ConclusionsOlaparib 150 mg tablet twice daily can be safely administered in combination with metronomic carboplatin and paclitaxel in pre-treated relapsed ovarian cancer with 24% complete remission. BRCAm patients had statistically significant longer progression-free survival and overall survival than BRCAwt.Trial registration numberNCT01650376.

scholarly journals Management of the Elderly Patients with High-Grade Serous Ovarian Cancer in the REAL-WORLD Setting

2021 ◽  
Vol 28 (2) ◽  
pp. 1143-1152
Author(s):  
Michalis Liontos ◽  
Alkistis Papatheodoridi ◽  
Angeliki Andrikopoulou ◽  
Nikolaos Thomakos ◽  
Dimitrios Haidopoulos ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Elderly Patients ◽  
Cancer Patients ◽  
Progression Free Survival ◽  
Optimal Treatment ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Debulking Surgery ◽  
Free Survival

Treatment of elderly patients with neoplasia is challenging. Age is a known prognostic factor in ovarian cancer but the optimal treatment of elderly patients has not been determined. We undertook a retrospective analysis to determine clinical practice in advanced-stage ovarian cancer patients older than 70 years of age. Methods: Medical records of women with high-grade serous ovarian cancer, stage III and IV were retrospectively analyzed. Results: A total of 735 patients were identified with a median age of 61.5 years. 22.4% among them were older than 70 years of age at diagnosis. First-line Progression-Free Survival (PFS) and Overall Survival (OS) were significantly worse in elderly patients in comparison to the younger ones [mPFS 11.3 months vs. 14.8 months, (p < 0.001) and mOS 30.2 months vs. 45.6 months (p < 0.001)]. However, elderly patients were characterized by worse ECOG-Performance Status and they were more frequently treated with Neoadjuvant Chemotherapy followed by Interval Debulking Surgery, while often they were more frequently denied debulking surgery compared to patients under 70 years of age. Moreover, elderly patients received more frequently monotherapy with platinum as frontline treatment. In contrast, there was no significant difference in the outcome of the debulking surgery in comparison to the younger patients or the frequency that gBRCA test was performed. Age over 70 years did not retain its significance for either Progression-Free Survival or Overall Survival when adjusted for all other reported prognostic factors. Conclusions: Elderly ovarian cancer patients have a worse prognosis. Comprehensive geriatric assessment should be performed for the optimal treatment of these patients.

VEGF-A and i-NOS expression are prognostic factors in serous epithelial ovarian carcinomas after complete surgical resection

2009 ◽  
Vol 62 (5) ◽  
pp. 448-454 ◽  
Author(s):  
K Engels ◽  
A du Bois ◽  
P Harter ◽  
A Fisseler-Eckhoff ◽  
F Kommoss ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Prognostic Factors ◽  
Progression Free Survival ◽  
Figo Stage ◽  
Tumour Resection ◽  
Residual Tumour ◽  
Serous Ovarian Cancer ◽  
Free Survival ◽  
Complete Tumour Resection ◽  
Complete Tumour

Aims:Clinical stage at the time of diagnosis and achievement of complete macroscopic resection during initial surgery are key factors determining the outcome of ovarian cancer. However, prediction of outcome lacks accuracy and more reliable prognostic factors are required. Therefore, an analysis and evaluation of key angiogenic factors was carried out to determine their diagnostic and prognostic value in serous ovarian cancer.Methods:Expression levels of vascular endothelial growth factor (VEGF)-A, hypoxia-inducible factor (HIF)1-α and inducible nitric oxide synthase (i-NOS) were analysed by immunohistochemistry in a homogenous group of 112 patients with serous adenocarcinoma of the ovary. Vascular density as an indicator of angiogenesis was assessed using the Chalkley eyepiece method after staining for CD34. The correlation of these data with survival and established prognostic factors such as histological grade, Federation of Gynecology and Obstetrics (FIGO) stage, and residual tumour after surgery, was evaluated. Survival analyses, multivariate analyses and correlation tests were performed.Results:In the patient group with macroscopic complete tumour resection (R0) there was a significant correlation between VEGF-A and i-NOS expression. Kaplan–Meier analysis further revealed improved progression-free survival for R0 patients with VEGF-A-positive and i-NOS-negative tumours. The predictive relevance of VEGF-A regarding progression-free survival was sustained in multivariate analysis using FIGO stage, grading and resection status as fixed variables.Conclusion:VEGF-A and i-NOS are prognostic markers for clinical outcome in serous ovarian cancer patients with macroscopic complete tumour resection (R0). Hence, pre-therapeutic assessment of VEGF-A as predictive factor for an antiangiogenic therapy might be of clinical value.

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