Molecular Pathways in Low-Grade Serous Ovarian Cancer

Abstract

Low-grade serous cancer (LGSC) is a distinct subtype of ovarian cancer (OC), characterised by younger age at diagnosis and low chemotherapy response rates compared with the most common subtype, high-grade serous. Most women are diagnosed with advanced stage disease and there are few effective treatment options beyond surgery. We aimed to increase the understanding of the clinical and molecular features of LGSC and shed light on new treatment options. Applying stringent criteria, LGSC cases (n=99) were identified from >4,000 women being investigated for OC, representing one of the largest LGSC cohorts described to date. Tumour mutations were found in KRAS (26/99, 26.3%), BRAF (13/99, 13.1%) and NRAS (10/99, 10.1%). Few clinical differences were associated with RAS/RAF mutations, although, RAS/RAF-wildtype (WT) cases were more commonly primary peritoneal, and had worse survival compared with RAS/RAF-mutated cases. LGSC were resistant to carboplatin, in patients and in cell lines, and women who received neoadjuvant chemotherapy rather than upfront surgical debulking, had worse outcomes. Responses to paclitaxel, gemcitabine and liposomal doxorubicin were variable in LGSC cell lines, and although case numbers were small, there were more responses to these agents compared with carboplatin. This suggests that these agents could be used in preference to carboplatin in some women with LGSC. Targeting the RAS-MAPK pathway in LGSC shows promise. Sustained responses to BRAF inhibitors were seen in two women with BRAFV600 LGSC, and a second-generation RAF inhibitor decreased proliferation in KRAS-mutant cell lines suggesting activity beyond BRAFV600E LGSC. The effect of MEK inhibition differed markedly between LGSC cell lines, and RAS/RAF mutations alone did not predict response. In women, responses were seen in KRAS- and NRAS-mutation positive cases and interestingly, in RAS/RAF-WT LGSC. Rational combination approaches were explored and MEK in combination with PI3K/mTOR, CDK4/6 or RAF inhibitors were synergistic in some LGSC cell lines. In summary, the work presented advances the understanding of LGSC and highlights heterogeneous responses to treatment. Molecular characterisation, novel clinical trial designs and rationally targeted treatments are needed to improve outcomes for women with LGSC