The molecular biology of epithelial ovarian cancer.

Dec 2012

Leary A, Pautier P, Tazi Y, Morice P, Duvillard P, Gouy S, Uzan C, Gauthier H, Balleyguier C, Lhommé C.

Source

Institut Gustave-Roussy, département de médecine, comité pluridisciplinaire de gynécologie, 114, rue Édouard-Vaillant, 94800 Villejuif, France.

Abstract

Epithelial ovarian cancer frequently presents at an advanced stage where the cornerstone of management remains surgery and platinum-based chemotherapy. Unfortunately, despite sometimes dramatic initial responses, advanced ovarian cancer almost invariably relapses. Little progress has been made in the identification of effective targeted-therapies for ovarian cancer. The majority of clinical trials investigating novel agents have been negative and the only approved targeted-therapy is bevacizumab, for which reliable predictive biomarkers still elude us. Ovarian cancer is treated as a uniform disease. Yet, biological studies have highlighted the heterogeneity of this malignancy with marked differences in histology, oncogenesis, prognosis, chemo-responsiveness, and molecular profile. Recent high throughput molecular analyses have identified a huge number of genomic/phenotypic alterations. Broadly speaking, high grade serous carcinomas (type II) display significant genomic instability and numerous amplifications and losses; low grade (type I) tumors are genomically stable but display frequent mutations. Importantly, many of these genomic alterations relate to known oncogenes for which targeted-therapies are available or in development. There is today a real potential for personalized medicine in ovarian cancer. We will review the current literature regarding the molecular characterization of epithelial ovarian cancer and discuss the biological rationale for a number of targeted strategies. In order to translate these biological advances into meaningful clinical improvements for our patients, it is imperative to incorporate translational research in ovarian cancer trials, a number of strategies will be proposed such as the acquisition of quality tumor samples, including sequential pre- and post-treatment biopsies, the potential of liquid biopsies, and novel trial designs more adapted to the molecular era of ovarian cancer research.

PubMed

Immune Response Evaluation Through Determination of Type 1, Type 2, and Type 17 Patterns in Patients With Epithelial Ovarian Cancer.

Dec 2012

Cândido EB, Silva LM, Carvalho AT, Lamaita RM, Filho RM, Cota BD, Silva-Filho AL.

Source

1Department of Obstetrics and Gynecology, Federal University of Minas Gerais, Belo Horizonte, Brazil.

Abstract

Innate and adaptive immune cells secrete different cytokines, which participate through distinct mechanisms in cell-mediated immunity and humoral immune responses. The aim of this study was to evaluate the immune response through analysis of type 1 (Th1), Th2, and Th17 cells in patients with epithelial ovarian cancer (EOC). Our study included 44 patients with EOC (study group) and 32 gynecological patients with no ovarian disease (control group). Fragments of ovarian tissue and blood samples were collected in both groups and aliquots of intracystic fluid and peritoneal fluid were recovered from the EOC patient group. Interleukin (IL)-2/IL-4/IL-6/IL-10/IL-17/tumor necrosis factor (TNF)-α/interferon (IFN)-γ levels were measured by cytometric bead array. Statistical analysis included chi-squared, Student t, Mann-Whitney, Kruskal-Wallis tests, and Cox regression model. Patients with EOC were associated with higher levels of TNF-α/IL-4/IL-6/IL-10 compared to the control group. Both IL-10 and TNF-α concentrations were higher in patients with stage III/IV EOC and also associated with higher levels of cancer antigen 125. Higher Th1-mediated immune response was observed when the cytoreduction was considered optimal. 

However, patients with EOC with unsatisfactory cytoreductive surgery and undifferentiated tumors were associated with higher concentrations of Th2 cytokines in the 4 sites studied. Higher IL-6/IL-10 and lower IFN-γ concentrations were also associated with a lower overall survival rate in patients with EOC. The EOC group presented a predominantly Th2 response and an immunosuppressant standard and had association between IL-6/IL-10/IFN-γ and prognosis.

PubMed

Antiangiogenic agents as a maintenance strategy for advanced epithelial ovarian cancer.

Nov 2012

Monk BJ, Dalton H, Farley JH, Chase DM, Benjamin I.

Source

Department of Obstetrics and Gynecology, Creighton University School of Medicine at St. Joseph's Hospital and Medical Center, United States. Electronic address: Bradley.Monk@DignityHealth.org.

Abstract

Bevacizumab is the first antiangiogenic agent to have demonstrated benefit as first-line and maintenance therapy in epithelial ovarian cancer (EOC), with the Gynecologic Oncology Group 218 and ICON 7 phase III trials revealing significantly prolonged progression-free survival (PFS) for carboplatin/paclitaxel plus bevacizumab followed by bevacizumab maintenance versus carboplatin/paclitaxel alone. Results are forthcoming from several phase III maintenance trials of investigational antiangiogenic agents, each evaluating PFS as the primary endpoint: AGO-OVAR12/LUME-Ovar1 (nintedanib [BIBF 1120]), AGO-OVAR16 (pazopanib), and TRINOVA-1, -2, and -3 (AMG 386). Here we review available data and ongoing clinical trials of investigational antiangiogenic agents as maintenance therapy for EOC. Current controversies, including uncertainties regarding the (1) most appropriate clinical trial endpoints, (2) optimal dosing, duration, and timing of therapy (e.g., with first-line chemotherapy and/or as maintenance monotherapy), and (3) feasibility, tolerability, and cost of adding these agents to platinum/taxane regimens are also highlighted.

Oncology Hematology