scholarly journals Clinical Utility of Real-Time Targeted Molecular Profiling in the Clinical Management of Ovarian Cancer: The ALLOCATE Study

2019 ◽  
pp. 1-18
Author(s):  
Olga Kondrashova ◽  
Gwo-Yaw Ho ◽  
George Au-Yeung ◽  
Leakhena Leas ◽  
Tiffany Boughtwood ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Real Time ◽  
Targeted Therapies ◽  
Clinical Management ◽  
Clinical Utility ◽  
Advanced Ovarian Cancer ◽  
Molecular Profiling ◽  
Molecular Testing ◽  
Low Grade ◽  
Ovarian Carcinomas

PURPOSE The ALLOCATE study was designed as a pilot to demonstrate the feasibility and clinical utility of real-time targeted molecular profiling of patients with recurrent or advanced ovarian cancer for identification of potential targeted therapies. PATIENTS AND METHODS A total of 113 patients with ovarian cancer of varying histologies were recruited from two tertiary hospitals, with 99 patient cases suitable for prospective analysis. Targeted molecular and methylation profiling of fresh biopsy and archived tumor samples were performed by screening for mutations or copy-number variations in 44 genes and for promoter methylation of BRCA1 and RAD51C. RESULTS Somatic genomic or methylation events were identified in 85% of all patient cases, with potentially actionable events with defined targeted therapies (including four resistance events) detected in 60% of all patient cases. On the basis of these findings, six patients received molecularly guided therapy, three patients had unsuspected germline cancer–associated BRCA1/ 2 mutations and were referred for genetic counseling, and two intermediate differentiated (grade 2) serous ovarian carcinomas were reclassified as low grade, leading to changes in clinical management. Additionally, secondary reversion mutations in BRCA1/ 2 were identified in fresh biopsy samples of two patients, consistent with clinical platinum/poly (ADP-ribose) polymerase inhibitor resistance. Timely reporting of results if molecular testing is done at disease recurrence, as well as early referral for patients with platinum-resistant cancers, were identified as factors that could improve the clinical utility of molecular profiling. CONCLUSION ALLOCATE molecular profiling identified known genomic and methylation alterations of the different ovarian cancer subtypes and was deemed feasible and useful in routine clinical practice. Better patient selection and access to a wider range of targeted therapies or clinical trials will further enhance the clinical utility of molecular profiling.

MOLECULAR AND GENETIC SUBTYPES OF OVARIAN CANCER: PROSPECTS FOR FURTHER STUDIES

2019 ◽  
Vol 65 (1) ◽  
pp. 56-62
Author(s):  
Alisa Villert ◽  
Larisa Kolomiets ◽  
Natalya Yunusova ◽  
Yevgeniya Fesik
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
Molecular Subtypes ◽  
Survival Rates ◽  
Consensus Algorithm ◽  
Histopathological Diagnosis ◽  
Low Grade ◽  
High Grade ◽  
Ovarian Carcinomas ◽  
Genetic Subtypes

High-grade ovarian carcinoma is a histopathological diagnosis, however, at the molecular level, ovarian cancer represents a heterogeneous group of diseases. Studies aimed at identifying molecular genetic subtypes of ovarian cancer are conducted in order to find the answer to the question: can different molecular subgroups influence the choice of treatment? One of the achievements in this trend is the recognition of the dualistic model that categorizes various types of ovarian cancer into two groups designated high-grade (HG) and low-grade (LG) tumors. However, the tumor genome sequencing data suggest the existence of 6 ovarian carcinoma subtypes, including two LG and four HG subtypes. Subtype C1 exhibits a high stromal response and the lowest survival. Subtypes C2 and C4 demonstrate higher number of intratumoral CD3 + cells, lower stromal gene expression and better survival than sybtype C1. Subtype C5 (mesenchymal) is characterized by mesenchymal cells, over-expression of N-cadherin and P-cadherin, low expression of differentiation markers, and lower survival rates than C2 and C4. The use of a consensus algorithm to determine the subtype allows identification of only a minority of ovarian carcinomas (approximately 25%) therefore, the practical importance of this classification requires additional research. There is evidence that it makes sense to randomize tumors into groups with altered expression of angiogenic genes and groups with overexpression of the immune response genes, as in the angiogenic group there is a comparative superiority in terms of survival. The administration of bevacizumab in the angiogenic group improves survival, while the administration of bevacizumab in the immune group even worsens the outcome. Molecular subtypes with worse survival rates (proliferative and mesenchymal) also benefit most from bevacizumab treatment. This review focuses on some of the advances in understanding molecular, cellular, and genetic changes in ovarian carcinomas with the results achieved so far regarding the formulation of molecular subtypes of ovarian cancer, however further studies are needed.

Paradigm Shift in the Management Strategy for Epithelial Ovarian Cancer

2016 ◽  
pp. e247-e257 ◽  
Author(s):  
Keiichi Fujiwara ◽  
Jessica N. McAlpine ◽  
Stephanie Lheureux ◽  
Noriomi Matsumura ◽  
Amit M. Oza
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Paradigm Shift ◽  
Management Strategy ◽  
Clear Cell ◽  
Treatment Strategies ◽  
Low Grade ◽  
Ovarian Carcinomas ◽  
Coelomic Epithelium ◽  
Histologic Types

The hypothesis on the pathogenesis of epithelial ovarian cancer continues to evolve. Although epithelial ovarian cancer had been assumed to arise from the coelomic epithelium of the ovarian surface, it is now becoming clearer that the majority of serous carcinomas arise from epithelium of the distal fallopian tube, whereas clear cell and endometrioid cancers arise from endometriosis. Molecular and genomic characteristics of epithelial ovarian cancer have been extensively investigated. Our understanding of pathogenesis of the various histologic types of ovarian cancer have begun to inform changes to the strategies for management of epithelial ovarian cancer, which represent a paradigm shift not only for treatment but also for prevention, which previously had not been considered achievable. In this article, we will discuss novel attempts at the prevention of high-grade serous ovarian cancer and treatment strategies for two distinct entities in epithelial ovarian cancer: low-grade serous and clear cell ovarian carcinomas, which are relatively rare and resistant to conventional chemotherapy.

Letrozole in the management of advanced ovarian cancer: an old drug as a new targeted therapy

2020 ◽  
Vol 30 (7) ◽  
pp. 1058-1064
Author(s):  
Claudia Marchetti ◽  
Francesca De Felice ◽  
Raffaella Ergasti ◽  
Giovanni Scambia ◽  
Anna Fagotti
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Treatment ◽  
Advanced Ovarian Cancer ◽  
Standard Of Care ◽  
Low Grade ◽  
Toxicity Profile ◽  
Biologically Relevant ◽  
Cancer Management ◽  
Free Interval ◽  
Optimal Setting

At present, there is no standard of care on the use of letrozole in ovarian cancer management. We performed a systematic review of the available literature addressing this issue. Data demonstrated a role for letrozole in ovarian cancer, in both the primary and recurrent setting. Letrozole, which has a favorable toxicity profile, seems to assure a prolonged recurrence-free interval, particularly when used as maintenance treatment, in low grade serous ovarian cancer; in recurrent cases it had also led to prolonged disease control. However, the optimal setting and biologically relevant patient population needs to be defined in larger trials.

Total Infragastric Omentectomy Including the Vascular Perigastric Arcade in Patients With Advanced Serous Ovarian Tumors

2017 ◽  
Vol 27 (2) ◽  
pp. 252-257
Author(s):  
Gloria Cordeiro Vidal ◽  
Sabrina Croce ◽  
Frédéric Guyon ◽  
Guillaume Babin ◽  
Denis Querleu
Keyword(s):  
Ovarian Cancer ◽  
Advanced Ovarian Cancer ◽  
Ovarian Tumors ◽  
Serous Carcinoma ◽  
Pathological Examination ◽  
Low Grade ◽  
Debulking Surgery ◽  
Macroscopic Appearance ◽  
Primary Debulking Surgery ◽  
Interval Debulking Surgery

ObjectiveThe aim of this study was to document the need of including the perigastric area when performing omentectomy in patients with stage III to IV serous epithelial ovarian tumors.Patients and MethodsPatients undergoing omentectomy in the setting of surgery for advanced epithelial serous ovarian cancer between February and September 2015 were included. Patients with macroscopic involvement of the perigastric area, nonepithelial serous tumors, and recurrences of ovarian cancer were excluded. The perigastric area was isolated and comprehensively processed for pathological examination.ResultsTwenty-four patients were included. Six patients underwent primary debulking surgery, and 18 patients underwent an interval debulking surgery. The mean number of pathologic blocks in the perigastric area was 24 (range, 8–41). Microscopic involvement of the perigastric omentum area was found in 62.5% of the cases. One patient had a low-grade serous carcinoma, with microscopic involvement of the perigastric area. Among the 23 patients with a high-grade serous carcinoma, 10 (83%) of 12 patients with a gross involvement of the rest of the omentum had a microscopic involvement of the perigastric area. The presence of microscopic disease in the perigastric arcade was found in 4 (36.3%) of 11 patients with a macroscopically normal omentum.ConclusionsIn this study, evidence is given that total omentectomy including the perigastric area is a necessary component of complete cytoreductive surgery in advanced ovarian cancer, whatever the macroscopic appearance of the omentum.

scholarly journals Is it possible to improve primary therapy of advanced ovarian cancer?

2020 ◽  
pp. 128-135
Author(s):  
S. V. Khokhlova
Keyword(s):  
Ovarian Cancer ◽  
Life Expectancy ◽  
Brca1 Mutation ◽  
Advanced Ovarian Cancer ◽  
Subsequent Treatment ◽  
Low Grade ◽  
Primary Therapy ◽  
Average Life Expectancy ◽  
Ovarian Adenocarcinoma ◽  
Specific Patient

In 2011, a standard approach to the treatment of primary ovarian cancer (OC) included a cytoreductive surgery, which could be performed after 2–3 cycles of neoadjuvant chemotherapy, and chemotherapy consisting of platinum and taxanes. Such approach was provided for all patients, regardless of tumour histology and any molecular biological and genetic factors. The most complete picture of management and therapy of patients can be made using the treatment of a specific patient as an example. After application to the N.N. Blokhin National Medical Research Center of Oncology in 2011, the patient with OC received standard primary therapy and subsequent treatment of the recurrent disease, which was accompanied by various types of adverse events resulting in the poor quality of life for the patient. The data that some patients with OC have a BRCA1/2 mutation that is significant for prognosis and treatment came to hand later and, unfortunately, the awareness of a significant germinal BRCA1 mutation was of no use to the woman any longer. The life expectancy of this patient was 47 months. This is the average life expectancy for patients with stage IIIC OC. Major changes have been brought in the primary therapy of OC. If a diagnosis of low-grade IIIC ovarian adenocarcinoma was established in this patient today, needless to say that the BRCA1 mutation would be identified during the first-line chemotherapy, and in case of full or partial treatment effect, we would prescribe olaparib as maintenance therapy to the patient. Considering the fact that the median progression-free survival has not yet been achieved in the patients of SOLO-1 study, who received olaparib therapy, and is only approaching 54 months, it can be assumed that even the first relapse could not have developed in this patient.

Functional profiling of clear cell ovarian cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5035-5035
Author(s):  
Rowan Miller ◽  
Rachel Brough ◽  
Ilirjana Bajrami ◽  
Stanley B. Kaye ◽  
Christopher J. Lord ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
High Throughput Screening ◽  
Clear Cell ◽  
Integral Functional ◽  
Therapeutic Targets ◽  
Molecular Profiling ◽  
Loss Of Function ◽  
Ovarian Carcinomas ◽  
Ovarian Cancers ◽  
Platinum Based Chemotherapy

5035 Background: Clear cell ovarian cancer represents up to 15% of epithelial ovarian cancers. In comparison to other subtypes, clear cell ovarian carcinomas have a poorer prognosis and are relatively resistant to standard platinum based chemotherapy. Recently, loss of function mutations in the tumour suppressor gene ARID1A were identified in up to 50% of ovarian clear cell carcinomas. We have adopted an integral functional and molecular profiling approach as a route to identify new genetic dependencies and therapeutic targets for this disease. Methods: Clear cell ovarian cancer cell lines were functionally profiled using high throughput screening with chemical and siRNA libraries. This has been integrated with molecular profiling data generated from exome and transcriptome sequencing to aid the discovery of novel targets. Results: Using functional screens we have now identified critical gene dependencies and potential therapeutics in a series of clear cell ovarian cancer models. The comparison of functional viability profiles for models characterized by ARID1A loss of function mutations is now enabling an analysis of synthetic lethal effects that could be used to target clear cell ovarian cancers carrying these mutations. Conclusions: The work undertaken so far provides the framework for the discovery of therapeutic targets for clear cell ovarian cancer using an integrated approach. Revalidation of these preliminary results is now underway to characterize new genetic dependencies for this disease.

scholarly journals Current ideas about molecular genetic subtypes of ovarian cancer: a personalized approach and a new platform for further research

2021 ◽  
Vol 11 (11) ◽  
pp. 157-168
Author(s):  
A. Rybin
Keyword(s):  
Ovarian Cancer ◽  
Molecular Subtypes ◽  
Molecular Genetic ◽  
Consensus Algorithm ◽  
Histopathological Diagnosis ◽  
Low Grade ◽  
Ovarian Carcinomas ◽  
Altered Expression ◽  
Ovarian Cancers ◽  
Genetic Subtypes

Highly malignant ovarian cancers are a histopathological diagnosis, but can be multiple diseases at the molecular level. Research aimed at identifying molecular genetic subtypes of ovarian cancer is being conducted to find an answer to the question: can different molecular subgroups influence the choice of treatment? One of the achievements of this direction is the recognition of the dualistic theory of the origin of ovarian carcinomas with their division into High-grade and Low-grade subtypes. However, the data of sequencing of the tumor genome suggest the existence of 6 subtypes of carcinoma, including two LG and four HG subtypes. Patients of subtype C1 are characterized by a high stromal response and have the lowest survival, tumors of C2 and C4 subtypes have a higher rate of intratumoral CD3 + cells, lower stroma gene expression and better survival than C1. The mesenchymal subtype C5 is widely represented by mesenchymal cells, characterized by overexpression of N-cadherins and P-cadherins, low expression of differentiation markers and lower survival than C2 and C4. The use of a consensus algorithm to determine the subtype allows the identification of only a minority of ovarian cancers (approximately 25%). In this regard, the practical significance of this classification still requires additional research, and today it is permissible to talk about the existence of only 2-3 reproducible subtypes. It is thought that it makes sense to randomize tumors into groups with altered expression of angiogenic genes and with overexpression of immune response genes, as in the angiogenic group there is a comparison of the advantage in survival (prescribing bevacizumab improves it, and in the immune group even increases bevacizumab). Molecular subtypes with poorer survival rates (proliferative and mesenchymal) also benefit most from bevacizumab treatment. The review focuses on some advances in understanding molecular, cellular, and genetic changes related to ovarian cancers with the results achieved so far in describing molecular subtypes of ovarian cancer. The available information is the basis for planning further research.

Utility of circulating tumor DNA in the clinical management of patients with BRAFV600E metastatic colorectal cancer.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 119-119
Author(s):  
Van K. Morris ◽  
Kanwal Pratap Singh Raghav ◽  
Arvind Dasari ◽  
Michael J. Overman ◽  
Bryan K. Kee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Targeted Therapies ◽  
Clinical Management ◽  
Tumor Tissue ◽  
Tumor Biology ◽  
Molecular Profiling ◽  
Circulating Tumor Dna ◽  
Md Anderson ◽  
Tumor Dna

119 Background: Molecular profiling is critical for oncologists in personalizing treatment decisions for patients (pts) with metastatic colorectal cancer (mCRC). In contrast to archival tumor tissue specimens classically used profiling, sequencing of circulating tumor DNA (ctDNA) is more sensitive at quantifying low mutation allele frequencies and characterize “real time” tumor biology. We assessed the relationship between detection of BRAFV600E mutations in ctDNA and the clinical management of pts with mCRC. Methods: We retrospectively analyzed mCRC patients evaluated at MD Anderson Cancer Center with BRAFV600E mutations on ctDNA. ctDNA was isolated and sequenced for somatic mutations using a 70-gene next-generation sequencing assay (MD Anderson/GuardantHealth LB70 panel). Variant allele frequency (VAF) was characterized as the ratio of mutant reads: total reads for a given gene. BRAFV600E mutations were classified as “clonal” if the relative VAF (rVAF) exceeded 50% of the maximum VAF. “Major” and “minor” subclonal mutations were called for a rVAF of 10-50% and < 10%, respectively. Associations between BRAFV600E clonality and treatment decision were performed using a Fisher’s exact test. Survival outcomes were estimated using the Kaplan-Meier method. Results: 64 patients with mCRC had a BRAFV600E mutation detected in ctDNA. Concordance between tissue and ctDNA for BRAFV600E mutation was occurred in 44/55 (80%) patients with evaluable tumor specimen. There were 9 patients with BRAFV600E mutations identified in the absence of evaluable tumor tissue. Median VAF for BRAFV600E in the ctDNA was 3.6% (interquartile range, 0.50 – 17%). The majority of patients had a clonal BRAFV600E mutation (50/64, 78%). There were 3 (5%) and 11 (17%) patients with major subclonal and minor subclonal BRAFV600E mutations, respectively. Among patients with minor subclonal BRAFV600E mutations, 91% (10/11) had developed resistance to anti-EGFR therapies for management of RASwild-type mCRC. Discordance between tissue and ctDNA BRAFV600E status was associated with minor subclones (odds ratio (OR) 56, p < .0001). Clonal BRAFV600E mutations in the ctDNA were associated with a higher likelihood for treatment with BRAF targeted therapies (OR 5.8, p = .008). Median progression-free survival among 37 evaluable patients was 6.4 months. Conclusions: Reported VAF in the ctDNA served to stratify BRAFV600E according to relative clonality. Lower VAF was linked to acquired resistance to anti-EGFR therapies, whereas higher VAF was associated with receipt of matched targeted therapies for BRAFV600E mCRC. ctDNA technologies for identifying BRAFV600E mutations are feasible and informative for conducting relevant molecular profiling for patients with mCRC.

Clinical outcome of sequential chemotherapy after immune checkpoint inhibitors in advanced ovarian cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5580-5580
Author(s):  
Luisa Bonilla ◽  
Amit M. Oza ◽  
Stephanie Lheureux ◽  
Sam Saibil ◽  
Shiyi Chen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Clinical Outcomes ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Low Grade

5580 Background: Immunomodulation through check point inhibition is an important treatment strategy in many cancers. In ovarian cancer (OC) response rates with immune checkpoint inhibitors (ICI) alone are around 10%. Chemotherapy antitumoural effect is driven by cytotoxicity and immunomodulatory effect. ICI treatment reduces tumour induced immune-tolerance improving immunocompetence, essential for chemotherapy effect. We chose to investigate clinical outcomes of chemotherapy post ICI in women with OC. Methods: The Tumor Immunotherapy Program (TIP) database at the Princess Margaret Cancer Centre identified patients with OC treated with chemotherapy after ICI from 2011 to 2018. Evaluation of clinical outcomes including response rate (RR), progression free survival (PFS) and overall survival (OS) was assessed for pre ICI, ICI and post ICI. Results: 40 women with OC were treated with chemotherapy after ICI. 90% had high grade serous histology, 7.5% carcinosarcoma and 2.5% low grade serous. Median number of pre ICI treatment lines was 3 (1-8) and 2 (1-6) in the post ICI setting. Median time of ICI initiation from diagnosis was 3 years. At ICI all patients had PS 0-1 and treated in clinical trials. 2% of the patients had platinum refractory disease, 88% had platinum resistant disease and 10% platinum sensitive disease. 50% were treated with ICI single agent, 16% were treated with ICI combined with chemotherapy, 14% ICI combo and 17% ICI in combination with other agents. Patients were treated for a median of 3 cycles (1-26). 8% experienced PR, 18% SD, no CR were seen. 67% of the patients discontinued treatment due to PD, 25% due to toxicity. Last treatment in pre ICI RR was 35%. First treatment in post ICI RR was 30%. RR for each treatment used in post ICI was 9% for liposomal doxorubicin, 25% for single agent platinum, 29% for weekly paclitaxel and 67% for chemotherapy with bevacizumab. Median PFS in the last pre ICI treatment was 6.5m and 5m in the first post ICI treatment. Median PFS and OS for all the population was 53m and 54m respectively. Conclusions: ICI are associated with modest activity in OC, planned clinical trials exploring systematic sequential therapy integrating ICI, targeted agents and chemotherapy are needed.

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