Molecular Profiling and Commercial Predication Assays in Ovarian Cancer: Still Not Ready for Prime Time?

2014 ◽  
pp. 139-147 ◽  
Author(s):  
Elise C. Kohn
Keyword(s):  
Ovarian Cancer ◽  
Germ Line ◽  
Molecular Profiling ◽  
Added Value ◽  
Prime Time ◽  
Cancer Type ◽  
Brca1 And Brca2 ◽  
Major Barrier ◽  
The Individual

Short of early detection to allow curative primary intervention, the other major barrier to further success in treatment of ovarian cancers is matching the best treatment to the proper ovarian cancer type and to the individual patient. There are several decades of experience applying in vitro chemoresponse testing for solid tumors including ovarian cancer. This concept, first described in 1979, has yet to receive level one evidence supporting its application, despite the testing of numerous assays commercially as well as in academic centers and its use for tens of thousands of patients at a significant cost. The approach—rather than undergoing rigorous scientific examination—is now being muddied by the development of commercial molecular profiling assays from which treatment suggestions are provided. Molecular profiling as a research tool has added value to our understanding and treatment of patients with ovarian cancer. Morphologic and histochemical characterizations coupled now with increasing knowledge of ovarian cancer type-specific molecular patterns is improving our ability to properly diagnosis ovarian cancer type and thus guide therapy. With the exception of the role of germ-line and possibly somatic BRCA1 and BRCA2 mutations and their true predictiveness for probable response to poly(ADP-ribose) polymerase inhibition, molecular typing and profiling has yet to identify druggable molecular targets in ovarian cancer. Its use should be continued as a research and learning tool, and its results should be subjected to clinical trial validation. For very different reasons, neither chemoresponse assays nor molecular profiling are ready for prime time, yet.

scholarly journals Chimeric Antigen Receptor Design and Efficacy in Ovarian Cancer Treatment

2021 ◽  
Vol 22 (7) ◽  
pp. 3495
Author(s):  
Katarzyna M. Terlikowska ◽  
Bożena Dobrzycka ◽  
Sławomir J. Terlikowski
Keyword(s):  
Ovarian Cancer ◽  
In Vivo Studies ◽  
Specific Cell ◽  
Cancer Syndrome ◽  
Brca1 And Brca2 ◽  
Cell Surface Antigens ◽  
Extrinsic Factors ◽  
Molecular Therapies ◽  
Targeted Molecular Therapies

Our increased understanding of tumour biology gained over the last few years has led to the development of targeted molecular therapies, e.g., vascular endothelial growth factor A (VEGF-A) antagonists, poly[ADP-ribose] polymerase 1 (PARP1) inhibitors in hereditary breast and ovarian cancer syndrome (BRCA1 and BRCA2 mutants), increasing survival and improving the quality of life. However, the majority of ovarian cancer (OC) patients still do not have access to targeted molecular therapies that would be capable of controlling their disease, especially resistant or relapsed. Chimeric antigen receptors (CARs) are recombinant receptor constructs located on T lymphocytes or other immune cells that change its specificity and functions. Therefore, in a search for a successful solid tumour therapy using CARs the specific cell surface antigens identification is crucial. Numerous in vitro and in vivo studies, as well as studies on humans, prove that targeting overexpressed molecules, such as mucin 16 (MUC16), annexin 2 (ANXA2), receptor tyrosine-protein kinase erbB-2 (HER2/neu) causes high tumour cells toxicity and decreased tumour burden. CARs are well tolerated, side effects are minimal and they inhibit disease progression. However, as OC is heterogenic in its nature with high mutation diversity and overexpression of different receptors, there is a need to consider an individual approach to treat this type of cancer. In this publication, we would like to present the history and status of therapies involving the CAR T cells in treatment of OC tumours, suggest potential T cell-intrinsic determinants of response and resistance as well as present extrinsic factors impacting the success of this approach.

Determinants of serum adiponectin levels: a cross-sectional study

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Azar Sattarinezhad ◽  
Akbar Rasekhi Kazerouni ◽  
Gholamhossein Ranjbar Omrani ◽  
Mesbah Shams
Keyword(s):  
Ovarian Cancer ◽  
Germ Line ◽  
Brca Mutation ◽  
Bilateral Mastectomy ◽  
Ovarian Cancer Risk ◽  
Breast And Ovarian Cancer ◽  
Double Blind ◽  
Cross Sectional ◽  
Mutation Carriers

Abstract Objectives To review non-surgical prevention strategies in women with hereditary breast and ovarian cancer syndromes. Content Women with a gBRCA1 or 2 mutations face a high cumulative breast and ovarian cancer risk. While bilateral mastectomy (PBM) and bilateral salpingo-oophrectomy (PBSO) profoundly reduce the respective cancer risks, they are also associated with considerable side effects. There is therefore an urgent need for alternative and non-surgical risk reduction options. Tamoxifen and aromatase inhibitors have both been evaluated in secondary prevention, but their benefit in primary prevention is currently unknown in BRCA mutation carriers. In addition, their use is compromised by their side effect profile which makes them less appealing for a use in chemoprevention. Summary and outlook Denosumab is a well-tolerated osteoprotective drug, which has been demonstrated to have a potential preventive effect particularly in BRCA1-deficient models in vitro. The prospectively randomized double-blind BRCA-P trial is currently investigating the preventative effect of denosumab in healthy BRCA1 germ line mutation carriers.

scholarly journals Immunohistochemistry for the detection of BRCA1 and BRCA2 proteins in patients with ovarian cancer: a systematic review

2019 ◽  
Vol 73 (4) ◽  
pp. 191-196 ◽  
Author(s):  
Lorena Alves Teixeira ◽  
Francisco Jose Candido dos Reis
Keyword(s):  
Breast Cancer ◽  
Systematic Review ◽  
Ovarian Cancer ◽  
Cancer Type ◽  
Loss Of Function ◽  
Brca1 And Brca2 ◽  
Brca1 Protein ◽  
Current Usage ◽  
Breast Cancer Type

BackgroundLoss of function in either breast cancer type 1 susceptibility protein (BRCA1) or breast cancer type 2 susceptibility protein (BRCA2) is a major risk factor for epithelial ovarian cancer (EOC) development. BRCA1 or BRCA2 deficiencies are associated with short-term prognosis and might have importance for the treatment of women with the disease. However, the screening of all possible mechanisms of dysfunction is expensive, time-consuming and difficult to apply in clinical practice. On the other hand, immunohistochemistry (IHC) is a simple and reliable method to access the expression of several proteins in tumour tissues.Materials and methodsThis systematic review aims to evaluate the current usage of IHC to detect BRCA1 and BRCA2 deficiencies in EOC. We searched and evaluated all primary literature on the use of IHC for evaluating BRCA1 and BRCA2 proteins expression in EOC. The main concepts for the search were: ovarian neoplasms, IHC, BRCA1 and BRCA2.ResultsForty-four studies from 925 unique titles were included. A total of 4206 tumour samples were evaluated for BRCA1 and 1041 for BRCA2 expression. Twelve BRCA1 primary antibodies were used in 41 studies, and the most common was the MS110 clone (75.6%). Seven BRCA2 primary antibodies were used in ten studies. Using the cut-off of 10%, 47.0% of EOCs are associated with loss of BRCA1 and 34.5% with the loss of BRCA2 expression.ConclusionIHC was effective to detect loss of BRCA1 protein expression in EOC; however, data on BRCA2 expression were heterogeneous and difficult to interpret.

A comprehensive literature review and meta-analysis on prognostic value of BRCAm, HRRm and HRD+ across tumor types.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3125-3125
Author(s):  
Changxia Shao ◽  
Andrew Marley ◽  
Huilin Tang ◽  
Jun Wan ◽  
Chelsey Miller ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Literature Review ◽  
Meta Analysis ◽  
Positive Association ◽  
Cochrane Central Register ◽  
Cancer Type ◽  
Brca1 And Brca2 ◽  
Summary Estimate ◽  
Cochrane Reviews ◽  
Tumor Types

3125 Background: Poly (ADP-ribose) polymerase inhibitor (PARPi) may have broad application in the treatment of cancer patients with mutations of BRCA (BRCAm) or other homologous recombination repair genes (HRRm) or HR deficiency positive (HRD+). A literature review and meta-analysis were conducted to evaluate the clinical prognostic outcomes by total BRCAm, HRRm, and HRD+ status across tumor types among patients treated with non-PARPi treatment. Methods: Comprehensive searches for eligible studies in Ovid MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane reviews were performed in May 2020 to capture studies published in English within 10 years for manuscripts and 3 years for abstracts across geographic regions. A summary estimate with corresponding 95% CI was calculated using random-effects models due to varying effects sizes across studies. Results: A total of 135 eligible studies were included. Breast cancer (BC) patients with either BRCA1m or BRCA2m (BRCA1/2m) had a similar overall survival (OS) to those with wild-type BRCA1 and BRCA2 (BRCA1/2wt) across 18 studies reporting data on BRCA1m and BRCA2m. The pooled estimates of hazard ratio (HR) was 1.0 (95% CI: 0.8-1.3) overall and was 1.0 (0.7-1.5) for triple-negative BC (TNBC, 7 studies). Similarly, the HR was 1.1 (0.9-1.3) across all 10 studies reporting BRCA1m data and 1.1 (0.8-1.3) across all 7 studies reporting BRCA2m data. Ovarian cancer (OC) patients with BRCA1/2m had a significantly longer OS than those with BRCA1/2wt across 24 studies reporting BRCA1m and BRCA2m, with a HR of 0.7 (0.6-0.8). The HR was 0.6 (0.4, 0.8) across 4 studies on stage III-IV ovarian cancer. The HR was 0.8 (0.6-1.1) across 13 studies reporting BRCA1m and 0.5 (0.3-0.9) across 8 studies reporting BRCA2m. Less OS data were reported for other tumors, 6 studies for BRCA2m in prostate cancer with a HR of 1.9 (1.1-3.2) and 2 studies for BRCA1/2m in pancreatic cancer with a HR of 1.5 (0.8-3.1). Only 4 studies reported HRD+ by either BRCAm or genomic instability score (GIS) ≥ 42 and OS by HRD status; 3 on TNBC and 1 on high-grade serous ovarian cancer. The HR was 0.67 (0.43-1.02) for OS with HRD+ vs. HRD-. A total of 15 studies reported the association between HRRm and OS of cancers (5 on prostate, 4 on pancreas, 3 on ovary, 2 on breast and 1 on urothelial cancer), in which one or more HRR genes were examined. The HR was 1.0 (0.7-1.4) comparing patients with HRRm to those with HRRwt across tumor types. Due to the limited study number and inconsistent methodology/definitions of HRRm and HRD+, these results should be interpreted with caution. Conclusions: The effects of BRCA1/2m on OS in patients treated with chemotherapy varies by cancer type with no effect in BC and a positive association in OC. More study is required in other cancer types. There was no significant association found between HRD+ or HRRm with OS. These findings could help inform evidence-based treatment decisions.

scholarly journals Virtual clinical trials identify effective combination therapies in ovarian cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Emilia Kozłowska ◽  
Tuulia Vallius ◽  
Johanna Hynninen ◽  
Sakari Hietanen ◽  
Anniina Färkkilä ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Resistance Mechanisms ◽  
Added Value ◽  
Platinum Resistance ◽  
Mathematical Framework ◽  
Effective Combination

AbstractA major issue in oncology is the high failure rate of translating preclinical results in successful clinical trials. Using a virtual clinical trial simulations approach, we present a mathematical framework to estimate the added value of combinatorial treatments in ovarian cancer. This approach was applied to identify effective targeted therapies that can be combined with the platinum-taxane regimen and overcome platinum resistance in high-grade serous ovarian cancer. We modeled and evaluated the effectiveness of three drugs that target the main platinum resistance mechanisms, which have shown promising efficacy in vitro, in vivo, and early clinical trials. Our results show that drugs resensitizing chemoresistant cells are superior to those aimed at triggering apoptosis or increasing the bioavailability of platinum. Our results further show that the benefit of using biomarker stratification in clinical trials is dependent on the efficacy of the drug and tumor composition. The mathematical framework presented herein is suitable for systematically testing various drug combinations and clinical trial designs in solid cancers.

scholarly journals Detection of Germline Variants in 450 Breast/Ovarian Cancer Families with a Multi-Gene Panel Including Coding and Regulatory Regions

2021 ◽  
Vol 22 (14) ◽  
pp. 7693
Author(s):  
Chiara Guglielmi ◽  
Rosa Scarpitta ◽  
Gaetana Gambino ◽  
Eleonora Conti ◽  
Francesca Bellè ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Disease Onset ◽  
Cancer Type ◽  
Cancer Syndrome ◽  
Brca1 And Brca2 ◽  
Illumina Platform ◽  
Regulatory Regions ◽  
Tumor Onset ◽  
Significant Difference ◽  
Coding Variants

With the progress of sequencing technologies, an ever-increasing number of variants of unknown functional and clinical significance (VUS) have been identified in both coding and non-coding regions of the main Breast Cancer (BC) predisposition genes. The aim of this study is to identify a mutational profile of coding and intron-exon junction regions of 12 moderate penetrance genes (ATM, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53) in a cohort of 450 Italian patients with Hereditary Breast/Ovarian Cancer Syndrome, wild type for germline mutation in BRCA1/2 genes. The analysis was extended to 5′UTR and 3′UTR of all the genes listed above and to the BRCA1 and BRCA2 known regulatory regions in a subset of 120 patients. The screening was performed through NGS target resequencing on the Illumina platform MiSeq. 8.7% of the patients analyzed is carriers of class 5/4 coding variants in the ATM (3.6%), BRIP1 (1.6%), CHEK2 (1.8%), PALB2 (0.7%), RAD51C (0.4%), RAD51D (0.4%), and TP53 (0.2%) genes, while variants of uncertain pathological significance (VUSs)/class 3 were identified in 9.1% of the samples. In intron-exon junctions and in regulatory regions, variants were detected respectively in 5.1% and in 32.5% of the cases analyzed. The average age of disease onset of 44.4 in non-coding variant carriers is absolutely similar to the average age of disease onset in coding variant carriers for each proband’s group with the same cancer type. Furthermore, there is not a statistically significant difference in the proportion of cases with a tumor onset under age of 40 between the two groups, but the presence of multiple non-coding variants in the same patient may affect the aggressiveness of the tumor and it is worth underlining that 25% of patients with an aggressive tumor are carriers of a PTEN 3′UTR-variant. This data provides initial information on how important it might be to extend mutational screening to the regulatory regions in clinical practice.

Treatment of chemoresistant ovarian cancer with sigma2/SMAC and cisplatin.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e16508-e16508
Author(s):  
Ivy Wilkinson-Ryan ◽  
Dirk Spitzer ◽  
Robert Mach ◽  
Suwanna Vangveravong ◽  
Peter S Goedegebuure ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Combination Therapy ◽  
Cancer Cells ◽  
Caspase 3 ◽  
Platinum Resistance ◽  
Apoptotic Pathway ◽  
Major Barrier ◽  
Skov3 Cells

e16508 Background: Platinum resistance continues to be a major barrier to the successful treatment of ovarian cancer. Overexpression of the X-linked inhibitor of apoptosis proteins (XIAP) contribute to platinum resistance in ovarian cancer through inhibition of caspases and up regulation of Akt activity. Second mitochondrial-derived activators of caspases (SMAC) is an endogenous protein that binds to and reverses XIAP-mediated inhibition of caspases. In order to exploit the SMAC-mediated pro-apoptotic pathway pharmacologically, SMAC mimetics have been developed and shown to induce apoptosis in cancer cells in vitro and in vivo. Untargeted cytotoxic cancer drugs bind to both malignant and normal tissue leading to significant toxicity. We have shown previously that solid tumors upregulate the sigma-2 receptor. We have also shown that sigma-2 ligands are internalized into cancer cells and are therefore an appealing vehicle for tumor targeted therapy. The goal of this study is to test if a conjugate drug of sigma-2 ligand and a SMAC mimetic (sigma-2/SMAC) in combination with chemotherapy is capable of overcoming chemoresistance in ovarian cancer. Methods: SKOV3 and OVCAR3 ovarian cancer cell lines were treated with sigma2/SMAC (1-16μM) and/or cisplatin (.5-10μg/mL). Viability assays were used to detect cell death. Luminescence-based caspase assays were used to compare the activity of caspase-3, -7, and -9 between treatment groups to document involvement of the XIAP survival pathway. Results: We found that sigma2-SMAC is synergistic when used in combination with cisplatin. Compared to untreated cells, SKOV3 cells treated with sigma/2SMAC (4uM), cisplatin .5ug/mL, or combination therapy showed 52.6%, 117.7%, and 34.8% viability respectively (p<.05). Cisplatin and sigma2/SMAC remained synergistic at increasing doses. Similar results were observed in OVCAR3 cells. Caspase-3 and -7 increased in combination therapy 1.2-fold over Sigma/2SMAC alone (4uM) and 7-fold over cisplatin alone (.5ug/mL) in SKOV3 cells (p<.05). Conclusions: This study suggests that the sigma2/SMAC conjugate provides a targeted means for overcoming chemoresistance in ovarian cancer through inhibition of XIAP and activation of caspases.

Cytotoxic effects of disulfiram and synergism with cisplatin on ovarian cancer cells in vitro

2018 ◽  
Author(s):  
F Guo ◽  
Z Yang ◽  
J Xu ◽  
J Sehouli ◽  
AE Albers ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
Cytotoxic Effects
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