scholarly journals CCNE1 Amplification as a Predictive Biomarker of Chemotherapy Resistance in Epithelial Ovarian Cancer

Diagnostics ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 279
Author(s):  
Justin W. Gorski ◽  
Frederick R. Ueland ◽  
Jill M. Kolesar
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Chemotherapy Resistance ◽  
Predictive Marker ◽  
Predictive Biomarker ◽  
The United States ◽  
Genetic Alterations ◽  
Cyclin E1 ◽  
One Year ◽  
Line Setting

Ovarian cancer is the most-deadly gynecologic malignancy, with greater than 14,000 women expected to succumb to the disease this year in the United States alone. In the front-line setting, patients are treated with a platinum and taxane doublet. Although 40–60% of patients achieve complete clinical response to first-line chemotherapy, 25% are inherently platinum-resistant or refractory with a median overall survival of about one year. More than 80% of women afflicted with ovarian cancer will recur. Many attempts have been made to understand the mechanism of platinum and taxane based chemotherapy resistance. However, despite decades of research, few predictive markers of chemotherapy resistance have been identified. Here, we review the current understanding of one of the most common genetic alterations in epithelial ovarian cancer, CCNE1 (cyclin E1) amplification, and its role as a potential predictive marker of cytotoxic chemotherapy resistance. CCNE1 amplification has been identified as a primary oncogenic driver in a subset of high grade serous ovarian cancer that have an unmet clinical need. Understanding the interplay between cyclin E1 amplification and other common ovarian cancer genetic alterations provides the basis for chemotherapeutic resistance in CCNE1 amplified disease. Exploration of the effect of cyclin E1 amplification on the cellular machinery that causes dysregulated proliferation in cancer cells has allowed investigators to explore promising targeted therapies that provide the basis for emerging clinical trials.

scholarly journals Disruption of the gut microbiota attenuates epithelial ovarian cancer sensitivity to cisplatin therapy

2020 ◽  
Author(s):  
Laura M. Chambers ◽  
Emily L. Esakov ◽  
Chad Braley ◽  
Lexie Trestan ◽  
Zahraa Alali ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Antibiotic Therapy ◽  
Epithelial Ovarian Cancer ◽  
Gut Microbiome ◽  
Gynecologic Cancer ◽  
Chemotherapy Resistance ◽  
The United States ◽  
Additional Treatment ◽  
Cisplatin Therapy

AbstractBackgroundEpithelial Ovarian Cancer (EOC) is the second most common gynecologic malignancy in the United States, but the leading cause of gynecologic cancer death. Despite many achieving remission with first-line therapy, up to 80% of patients will recur and require additional treatment. Antibiotic therapy is frequently used during cancer treatments for both prophylaxis and treatment of infections, although this profoundly impacts the gut microbiome. Multiple studies suggest that an unperturbed gut microbiome may provide a protective microenvironment, and disruption may be permissive to tumor growth and chemotherapy resistance, including platinum agents.Experimental DesignWe assessed whether antibiotic therapy would impact growth of EOC and sensitivity to cisplatin in murine models. Immune competent or compromised mice were given either metronidazole, ampicillin, vancomycin, and neomycin (ABX) containing or control water for two weeks before being intraperitoneally injected with murine ID8 or ID8-VEGF EOC cells. Tumors were monitored and cisplatin therapy was administered weekly until endpoint. Stool was collected throughout the study to asses for microbial population effects over time.ResultsBoth immune competent and immune compromised ID8 and ID8 VEGF tumor-bearing mice demonstrated a decreased response to cisplatin therapy in ABX treated groups with an increase in overall tumor burden. RNAseq analysis showed enrichment of multiple cell proliferation and stem cell pathways, and stem cell genes SOX2, WNT and PAX2. The self-renewal of ABX treated tumor cells was also increased.ConclusionCollectively, these studies indicate an intact microbiome provides a tumor suppressive microenvironment and enhances sensitivity to cisplatin.

scholarly journals Disruption of the Gut Microbiota Attenuates Epithelial Ovarian Cancer Sensitivity to Cisplatin Therapy

2020 ◽  
Author(s):  
Laura Chambers ◽  
Emily Esakov ◽  
Chad Braley ◽  
Lexie Trestan ◽  
Zahraa Alali ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Antibiotic Therapy ◽  
Epithelial Ovarian Cancer ◽  
Gut Microbiome ◽  
Gynecologic Cancer ◽  
Chemotherapy Resistance ◽  
The United States ◽  
Additional Treatment ◽  
Cisplatin Therapy

Abstract Background: Epithelial Ovarian Cancer (EOC) is the second most common gynecologic malignancy in the United States, but the leading cause of gynecologic cancer death. Despite many achieving remission with first-line therapy, up to 80% of patients will recur and require additional treatment. Antibiotic therapy is frequently used during cancer treatments for both prophylaxis and treatment of infections, although this profoundly impacts the gut microbiome. Multiple studies suggest that an unperturbed gut microbiome may provide a protective microenvironment, and disruption may be permissive to tumor growth and chemotherapy resistance, including platinum agents. Experimental Design: We assessed whether antibiotic therapy would impact growth of EOC and sensitivity to cisplatin in murine models. Immune competent or compromised mice were given either metronidazole, ampicillin, vancomycin, and neomycin (ABX) containing or control water for two weeks before being intraperitoneally injected with murine ID8 or ID8-VEGF EOC cells. Tumors were monitored and cisplatin therapy was administered weekly until endpoint. Stool was collected throughout the study to asses for microbial population effects over time.Results: Both immune competent and immune compromised ID8 and ID8 VEGF tumor-bearing mice demonstrated a decreased response to cisplatin therapy in ABX treated groups with an increase in overall tumor burden. RNAseq analysis showed enrichment of multiple cell proliferation and stem cell pathways, and stem cell genes SOX2, WNT and PAX2. The self-renewal of ABX treated tumor cells was also increased.Conclusion: Collectively, these studies indicate an intact microbiome provides a tumor suppressive microenvironment and enhances sensitivity to cisplatin.

HE4 as a predictor of adjuvant chemotherapy resistance and survival in patients with epithelial ovarian cancer

Apmis ◽  
2016 ◽  
Vol 124 (12) ◽  
pp. 1038-1045 ◽  
Author(s):  
Mona Aarenstrup Karlsen ◽  
Claus Høgdall ◽  
Lotte Nedergaard ◽  
Kira Philipsen Prahm ◽  
Nikoline Marie Schou Karlsen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Adjuvant Chemotherapy ◽  
Epithelial Ovarian Cancer ◽  
Chemotherapy Resistance

BRCA1 is both a prognostic and predictive biomarker of response to chemotherapy in sporadic epithelial ovarian cancer

2011 ◽  
Vol 123 (3) ◽  
pp. 492-498 ◽  
Author(s):  
Judith E. Carser ◽  
Jennifer E. Quinn ◽  
Caroline O. Michie ◽  
Eamonn J. O'Brien ◽  
W. Glenn McCluggage ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Predictive Biomarker ◽  
Response To Chemotherapy

Ovarian Cancer

2008 ◽  
Vol 6 (8) ◽  
pp. 766 ◽  
Author(s):  
_ _
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Clinical Presentation ◽  
Advanced Disease ◽  
Gynecologic Cancer ◽  
The United States ◽  
Epidemiologic Studies ◽  
Nccn Guidelines ◽  
New Information ◽  
Recent Version

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer and the fifth most common cause of cancer mortality in women in the United States. Fewer than 40% of women with ovarian cancer are cured, and 70% of patients present with advanced disease; because of the location of the ovaries, ovarian cancer has been difficult to diagnose at earlier stages. Epidemiologic studies have identified risk factors, including family history. The NCCN guidelines discuss epithelial ovarian cancer as well as less common ovarian histopathologies, including germ cell neoplasms, carcinosarcomas (malignant mixed Müllerian tumors of the ovary), and ovarian stromal tumors. For 2008, updates include the addition of platinum-based combination therapy as a possible treatment modality for recurrence and a listing of preferred agents for acceptable recurrence modalities. New information was also added to the section on clinical presentation. For the most recent version of the guidelines, please visit NCCN.org

Integrative molecular profiling and response to chemotherapy on the COMPASS trial.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 188-188 ◽  
Author(s):  
Grainne M. O'Kane ◽  
Sandra Fischer ◽  
Rob Denroche ◽  
Gun Ho Jang ◽  
Amy Zhang ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Chemotherapy Resistance ◽  
Predictive Biomarker ◽  
Genetic Alterations ◽  
Molecular Characteristics ◽  
Strongly Correlated ◽  
First Line ◽  
Tumor Biopsy ◽  
Response To Chemotherapy

188 Background: Predictive mutational and transcriptional features in advanced PDAC are needed for improved patient stratification and treatment selection. Methods: Patients (pts) on the COMPASS trial with advanced PDAC are prospectively recruited prior to first-line chemotherapy for WGS and RNAseq. Tumor tissue undergoes enrichment by laser capture microdissection with genomic analyses available within eight wks. Tumor responses and clinical outcomes in this maturing cohort were correlated with molecular characteristics. Results: 157 pts underwent a tumor biopsy between Dec 2015 and Jul 2018 with over 95% success in achieving results. 141 genomes have been reported in pts planned to receive chemotherapy; the median time from biopsy to report was 35.5 days. In the ITT population,118 pts are summarised for first-line response. The median age was 63 yrs (29-81), 55% were male, and 16% had locally advanced disease. 66 (56%) received modified FFX as first-line treatment. 25 (21%) tumors displayed the Moffitt basal-like RNA signature which associated with chemotherapy resistance, with tumor shrinkage mainly observed in the classical RNA subtype (p = 0.002). GATA6 expression (log10 scale) clearly separated Moffitt subgroups with classical tumors exhibiting high expression (p < 0.0001). GATA6 in situ hybridization strongly correlated with RNAseq, (r = 0.89, p < 0.001) with strong correlation also seen with GATA6 IHC. The median overall survival (OS) in the classical group was 8.5 mths vs. 6.6 mths in the basal-like group (HR 0.53, 95% CI 0.32-0.89 p = 0.015). In those treated with mFFX, median OS was 10.1mths in classical versus 6.6mths in the basal-like subtypes, (HR 0.32, 95% CI 0.16-0.63, p=0.001). 30% of pts had potentially actionable genetic alterations including BRAF variants (n = 4) and an NTRK3-EML4 fusion in KRAS WT tumors (8%). Signatures of homologous recombination deficiency (HRD) were found in seven pts; two additional pts with BRCA germline variants did not exhibit somatic HRD hallmarks. Conclusions: Subsets of pts with advanced PDAC have actionable variants including those with HRD signatures and patients with KRAS WT tumors. GATA6 is a putative predictive biomarker of transcriptomic subgroups which should be incorporated in clinical trials. Clinical trial information: NCT02750657.

Sign in / Sign up

Export Citation Format

Share Document