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BRAF Mutations in Low-Grade Serous Ovarian Cancer and Response to BRAF Inhibition
Tania Moujaber1, Dariush Etemadmoghadam1, Catherine J Kennedy1
1Tania Moujaber, Catherine J. Kennedy, Yoke-Eng Chiew, Rosemary L. Balleine, Bo Gao, Sivatharsny Srirangan, Casina Kan, Paul R. Harnett, and Anna deFazio, Westmead Institute for Medical Research; Tania Moujaber, Catherine J. Kennedy, Yoke-Eng Chiew, Rosemary L. Balleine, Catherine Saunders, Russell Hogg, Paul R. Harnett, and Anna DeFazio, University of Sydney; Tania Moujaber, Catherine J. Kennedy, Yoke-Eng Chiew, Rosemary L. Balleine, Catherine Saunders, Gerard V. Wain, Bo Gao, Paul R. Harnett, and Anna DeFazio, Westmead Hospital; Rosemary L. Balleine, New South Wales Health Pathology, Westmead, New South Wales; Dariush Etemadmoghadam, Sian Fereday, Nadia Traficante, and David D.L. Bowtell, Peter MacCallum Cancer Centre; Sean M. Grimmond, David D.L. Bowtell, Dariush Etemadmoghadam, and Alexander Dobrovic, University of Melbourne; Alexander Dobrovic, Olivia Newton John Cancer Research Institute, Heidelberg (Melbourne), and La Trobe University, Bundoora, Victoria; Ann-Marie Patch, John V. Pearson, and Nicola Waddell, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; and David D.L. Bowtell, Imperial College London, London, United Kingdom.
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.
Insights
BRAF mutations occur in 13.8% of low-grade serous ovarian carcinoma (LGSC). BRAF inhibitors show promise for treating LGSC patients with BRAF mutations, offering durable responses.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Low-grade serous ovarian carcinoma (LGSC) exhibits poor response to chemotherapy.
- Activating mutations in the Ras sarcoma-mitogen-activated protein kinase (RAS-MAPK) pathway, including BRAF, are characteristic of LGSC.
- Tumor-type specificity affects response to BRAF inhibitors, as seen in melanoma versus colorectal cancers.
Purpose of the Study:
- To determine the frequency and characteristics of BRAF mutations in LGSC.
- To evaluate the response of LGSC patients with BRAF mutations to BRAF inhibitors.
Main Methods:
- Genomic sequencing (targeted, exome, whole-genome) was used to assess mutations in 65 LGSC patients.
- Clinical outcomes and patient characteristics were analyzed over a median follow-up of 5 years.
- BRAF inhibitors were administered to two patients with somatic BRAF V600E mutations, with monitoring via clinical assessment, CA-125 levels, and PET imaging.
Main Results:
- Somatic BRAF mutations were identified in 13.8% (9/65) of LGSC patients.
- Four patients with BRAF-mutated LGSC had chemotherapy-refractory progressive disease.
- Two patients with BRAF V600E mutations achieved durable responses to BRAF inhibitors at relapse.
Conclusions:
- BRAF mutations are relatively common in LGSC and warrant routine testing.
- BRAF inhibitors represent a potentially effective targeted treatment for LGSC patients with BRAF mutations.
- Further prospective studies are needed to confirm response rates and clinical benefits.
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