Ovarian cancer is the most lethal gynecological malignancy, frequently diagnosed at an advanced stage and with poor long-term survival rates. At first relapse, approximately 25% of patients have platinum-resistant/refractory ovarian cancer and almost all patients with recurrent disease ultimately develop platinum resistance. Development of platinum resistance is associated with worse PFS and OS.
Optimal management of recurrent platinum-resistant/refractory ovarian cancer remains an area of uncertainty. This subgroup of patients constitutes, indeed, a heterogeneous spectrum of disease with a low response rate to therapy (10%-25%), generally of short duration. For this reason, in this setting of patients, research is focusing on identifying new molecular targets with the final aims of better understanding the mechanisms leading OC to platinum-resistance and introducing targeted agents able to overcome resistance to platinum, thus impacting patients' survival.
Aim of the present study is to evaluate, in both platinum-resistant/refractory paired primary and recurrent OC tissue samples, the modulation of a panel of 14 intratumoral immune-related proteins expression, thus tracing an intratumoral immunological signature possibly able to predict patients' treatment response and survival outcome. The study will be carried out in collaboration with the international research group of "TOC Network" (www.toc-network.de), which currently holds the largest European collection of paired primary and recurrent ovarian cancer tissue samples. TOC samples are stored at the "Tumor Bank Ovarian Cancer Laboratory" (TOC-Lab), at the Department of Gynecology, Charité Medical University of Berlin, Germany (Head Prof. Jalid Sehouli, TOC Coordinator Prof. Elena Ioana Braicu).
Ovarian cancer(OC) is currently the most lethal malignancy among gynecological neoplasms (1). It has a large tumor burden which has been shown to elicit a strong immune response polarized towards immunesuppression(2).In neoplastic tissue intratumoral regulatory CD3+FoxP3+Tcells(Tregs) negatively influence response to therapies and patients' prognosis(3).The Tcell immunoinfiltrate can be rescued from exhaustion or anergy for a potent immune activation that has the potential to induce a clinical response in advanced or metastatic tumors (4).
In ovarian cancer, the high expression of immunosuppressive molecules and the recruitment of regulatory T cells (Treg) are the mechanisms of immune evasion. The blockade of PD-1 and CTLA-4 has been shown to restore antitumor activity of dysfunctional T cells and to limit activity of Tregs (8-10).
Optimal management of recurrent platinum-resistant/refractory ovarian cancer remains an area of uncertainty. This subgroup of patients constitutes, indeed, a heterogeneous spectrum of disease with a low response rate to therapy (10%-25%), generally of short duration.
In this context there is a urgent need of better understanding how the intratumoral immune system behaves during the course of the platinum-resistant disease and whether the analysis of primary compared to recurrent tumor is able to predict, through an immunological signature, the development of platinum resistance.
The present project, thanks to the TOC Network collaboration and to its unique and precious population of primary and recurrent platinum-resistant ovarian cancer samples available, belonging to the same patients, will be able to assess if there's a role exerted by the immune-related ovarian cancer intratumoral proteins in predicting OC patients' platinum-response during the natural course of the disease history.