BRAF mutations in low-grade serous ovarian cancer and response to BRAF inhibition

Tania Moujaber, Dariush Etemadmoghadam, Catherine J. Kennedy, Yoke Eng Chiew, Rosemary L. Balleine, Catherine Saunders, Gerard V. Wain, Bo Gao, Russell Hogg, Sivatharsny Srirangan, Casina Kan, Sian Fereday, Nadia Traficante, Australian Ovarian Cancer Study, Ann Marie Patch, John V. Pearson, Nicola Waddell, Sean M. Grimmond, Alexander Dobrovic, David D.L. BowtellPaul R. Harnett, Anna deFazio*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

Abstract

Purpose 

Low-grade serous ovarian carcinoma (LGSC) responds poorly to chemotherapy and is characterized by activating mutations in the Ras sarcoma-mitogen-activated protein kinase (RAS-MAPK) pathway, including oncogenic BRAF. However, response to BRAF inhibitors is tumor-type specific. Significant improvement in survival is seen in patients with BRAF-mutant melanoma, but other cancer types, such as colorectal cancers, are generally less sensitive. We examined the frequency and characteristics of BRAF-mutated LGSC and described the response to treatment with BRAF inhibitors. 

Patients and Methods 

Mutations were assessed in LGSC (N = 65) by using targeted, exome, and whole-genome sequencing. Patient characteristics, treatment, and clinical outcome were assessed, and the median follow-up time was more than 5 years. BRAF inhibitors were trialed in two patients with a somatic BRAF V600E mutation: one patient received dabrafenib monotherapy and was monitored clinically, biochemically (cancer antigen [CA]-125 levels), and with positron emission tomography (PET) imaging. Expression of the BRAF V600E protein in this patient was assessed by immunohistochemistry. 

Results 

Among patients with LGSC, nine (13.8%) of 65 had a somatic BRAF mutation. Of the nine patients with BRAF mutation-positive LGSC, four experienced progressive disease that did not respond to conventional chemotherapy. Two of the patients experienced progression quickly and died as a result of disease progression, and two received targeted treatment. Two patients with BRAF V600E mutation received BRAF inhibitors at relapse and both achieved durable responses. 

Conclusion 

BRAF mutations are not uncommon in patients with LGSC and should be routinely tested, because BRAF inhibitors can be an effective treatment for these patients. The results highlight the need for targeted treatment in this rare tumor type, and a prospective study is needed to formally assess the response rate and clinical benefit.

Original languageEnglish
Pages (from-to)1-14
Number of pages14
JournalJCO Precision Oncology
Volume2
DOIs
Publication statusPublished - 1 Jan 2018
Externally publishedYes

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