Abstract IA18: Progress and future directions in the management of low-grade serous cancer of the ovary
Authors: Gershenson David M. 
Published: August 2018

Abstract
Low-grade serous carcinoma of the ovary or peritoneum is a rare histologic subtype that may originate de novo or following a diagnosis of a serous borderline tumor. It accounts for approximately 10% of all serous carcinomas. It is distinguished from high-grade serous carcinoma based on the degree of nuclear atypia (mild to moderate versus marked) and mitotic index (&lt; 12 mitoses/10 HPF versus &gt; 12 mitoses/10 HPF). Rarely, low-grade and high-grade serous carcinoma may coexist in the same tumor. Compared to high-grade serous carcinoma, it is characterized by younger age at diagnosis, prolonged survival, and relative chemoresistance. In unsupervised clustering analysis of expression profiles, it tends to cluster with serous borderline tumor. The MAP kinase pathway appears to play a role in the pathogenesis of low-grade serous carcinoma; BRAF mutations occur in approximately 5% of cases, and KRAS mutations occur in 20-40% of cases. NRAS and HRAS mutations also occur less frequently. Preliminary findings suggest that tumors with a mutation in the MAP kinase pathway are associated with improved survival compared to tumors without mutations. Multiple studies have demonstrated relative resistance to conventional chemotherapy in the neoadjuvant, adjuvant, and salvage settings. Thus, a search for more effective therapies has dominated the clinical research of this subtype over the past decade. Bevacizumab has demonstrated objective responses in approximately 40-50% of patients in the salvage setting. The initial trial of a single-agent MEK inhibitor for recurrent low-grade serous carcinoma found a response rate of 15%, but there was no correlation of clinical response with mutational status. Three second-generation randomized MEK inhibitor trials have been conducted: one (in combination with a PI3K inhibitor) closed prematurely for toxicity, one closed prematurely for futility, and a third (GOG 0281) is completing accrual in the next few months. Detailed results of all three trials are not yet available. There have also been reports of objective responses to BRAF inhibitors in patients whose tumor harbors a BRAF mutation. In addition, hormonal therapies are of interest in this subtype given the fact that there are several similarities between low-grade serous carcinoma and ER+ breast cancer: 1) at least 80% of these tumors are ER+, 2) women &lt; 35 years of age have a worse prognosis, 3) anti-estrogen hormonal therapies have activity in the salvage setting, and 4) following primary surgery and chemotherapy, hormonal maintenance therapy appears to be associated with superior outcomes compared to observation. Future directions include understanding further the molecular biology of this subtype through preclinical investigations and additional prospective clinical trials of novel agents, including targeted therapies, combinations of targeted therapies, and hormonal therapies in the neoadjuvant, adjuvant, and salvage settings.
Citation Format: David M. Gershenson. Progress and future directions in the management of low-grade serous cancer of the ovary. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA18.