Abstract A25: BRAFV600E mutations in serous ovarian cancer and response to the BRAF inhibitor, dabrafenib.
Authors: DeFazio Anna , Moujaber Tania , Etemadmoghadam Dariush , Kennedy Catherine , Chiew Yoke-Eng , Balleine Rosemary L. , Saunders Catherine , Wain Gerard V. , Dobrovic Alexander ,   Australian Ovarian Cancer Study Group (AOCS), Bowtell David DL , Harnett Paul R. 
Published: May 2016

Abstract
Low-grade serous ovarian cancer (LGSC) is a challenging disease to treat effectively. It often occurs in young women and it is well-recognized to be resistant to standard chemotherapy. The underlying molecular driver mutations are now beginning to be understood and they are distinctly different from the more common counterpart, high-grade serous ovarian cancer. LGSC are characterized by somatic mutations in RAS/RAF genes and a number of new agents have been developed that target these mutations, and related activated pathways. However, it is not yet known which pathway-targeted drugs, or combination of drugs, will be effective in the treatment of LGSC. BRAFV600E mutations have been reported in LGSC and BRAF inhibitors have demonstrated significant improvement in progression-free survival in patients with BRAF-mutant melanoma. However, limited response is seen in other cancer types, such as colorectal cancers harboring the same mutation, suggesting that clinical benefit is tumor-type specific. In this study we aimed to characterize BRAF mutations in LGSC and to determine whether BRAF inhibitors could demonstrate a clinical benefit in ovarian cancer patients.
Patients with LGSC were identified through the Australian Ovarian Cancer Study and the Westmead GynBiobank, Sydney, Australia. Tumor mutations were assessed using targeted and exome sequencing, and gene copy number was measured by whole genome SNP arrays. Tumor expression of BRAFV600E protein was also assessed by immunohistochemistry. Dabrafenib monotherapy was trialed in a patient with a somatic BRAFV600E mutation and progress was monitored clinically, biochemically using CA125 tumor marker levels and radiologically with PET imaging.
Amongst Grade 1 serous ovarian carcinoma cases, 5/40 (12.5%) were shown to have a BRAFV600E mutation. Tumors with a BRAFV600E mutation had a relatively low degree of gene copy number change and were TP53 wild-type. The BRAF-inhibitor, dabrafenib was trialed in a heavily pre-treated BRAFV600E mutation-positive LGSC patient with progressive chemotherapy-resistant disease (n=1). Whole exome sequencing confirmed the BRAFV600E mutation was the highest frequency variant allele present and also identified deleterious mutations in other cancer-associated genes including CSMD1, BMP1 and DNM1 at lower frequencies, suggestive of sub-clonal events. The patient received dabrafenib monotherapy for 11 months, and demonstrated a substantial clinical, radiological and biochemical response, with complete normalization of her CA125 levels for the first time in six years.
These results demonstrate that molecular analysis of low-grade serous ovarian carcinoma can identify targetable mutations and provide effective treatment options. The substantial response to dabrafenib suggests that BRAF inhibition represents a potential therapeutic option for ovarian cancer patients with somatic BRAFV600E mutations and should be tested in future trials. However, the results also highlight the need for novel clinical trial design, as traditional clinical trials are unlikely to be effective in such rare ovarian cancer sub-groups.
Citation Format: Anna DeFazio, Tania Moujaber, Dariush Etemadmoghadam, Catherine Kennedy, Yoke-Eng Chiew, Rosemary L. Balleine, Catherine Saunders, Gerard V. Wain, Alexander Dobrovic, Australian Ovarian Cancer Study Group (AOCS), David DL Bowtell, Paul R. Harnett. BRAFV600E mutations in serous ovarian cancer and response to the BRAF inhibitor, dabrafenib. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A25.