Abstract IA24: Low-grade serous ovarian cancer: Recent advances and future directions
Authors: Grisham Rachel N. 
Published: September 2020

Abstract
Low-grade serous ovarian cancer accounts for approximately 10% of epithelial ovarian cancer cases and is histologically, clinically, and molecularly distinct from high-grade serous ovarian cancer. Patients often present at a younger age and can have a protracted clinical course with median survival approaching 10 years. Prior retrospective studies have shown lower response rates to chemotherapy than are typically seen for patients with high-grade serous ovarian cancer in both the upfront and recurrent setting. However, patients with low-grade serous ovarian cancer also tend to be hormone receptor positive, with approximately 90% of patients being estrogen receptor and/or progesterone receptor positive. This has led to considerable interest in the use of hormonal therapies such as aromatase inhibitors and tamoxifen. Based on prior retrospective studies showing response, hormonal therapies are now routinely used for treatment of recurrent low-grade serous ovarian cancer. Given the generally well-tolerated side effect profile of hormonal therapies, the limited response rates to chemotherapy, and the high prevalence of hormone receptor positivity in low-grade serous ovarian cancer, there has also been considerable interest in the use of hormonal therapies in the first-line treatment of this disease. Dr. Gershenson and colleagues presented a large retrospective study showing a significant improvement in progression-free survival for patients with advanced low-grade serous ovarian cancer treated with maintenance hormonal therapy following upfront surgery and adjuvant chemotherapy. Hormonal therapy is now a standard-of-care management option following surgery and chemotherapy. These findings have led others to question if chemotherapy could potentially be omitted from upfront treatment altogether. The upcoming randomized phase III study, NRG-GY019, seeks to answer this question by randomizing patients with stage II-IV low-grade serous ovarian cancer treated with primary debulking surgery to either 6 cycles of carboplatin and paclitaxel chemotherapy followed by letrozole maintenance therapy or to letrozole maintenance therapy alone. With the recent FDA approval of bevacizumab in the front-line setting for treatment of all patients with advanced ovarian cancer, triplet therapy with carboplatin, paclitaxel, and bevacizumab has recently also become an option for selected patients with advanced low-grade serous ovarian cancer, a strategy specifically supported in low-grade serous ovarian cancer based on retrospective studies showing activity of bevacizumab in combination with chemotherapy in the recurrent setting. There has also been considerable interest in the use of targeted therapies for the treatment of recurrent low-grade serous ovarian cancer, with most efforts thus far targeting the MAP kinase pathway. Thirty-five to 45% of patients with advanced disease harbor a hotspot KRAS mutation and a smaller percentage a BRAF V600E mutation. Following promising results seen in a phase II study of selumetinib, two large phase III studies randomized patients with recurrent disease to treatment with single-agent MEK inhibitor vs. either standard-of-care chemotherapy or hormonal therapy, with results of both studies expected to be reported soon. Additional early-stage studies have shown promising results with targeted therapy combinations, but further development has been limited by toxicity and associated compliance issues. Newer strategies and trials currently in development concentrate on novel hormonal therapies such as the progesterone antagonist onapristone, and hormonal combination strategies such as CDK 4/6 inhibitors in combination with letrozole or fulvestrant.
Citation Format: Rachel N. Grisham. Low-grade serous ovarian cancer: Recent advances and future directions [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA24.