Tania Moujaber1, Dariush Etemadmoghadam1, Catherine J Kennedy1, Yoke-Eng Chiew1, Rosemary L Balleine1, Catherine Saunders1, Gerard V Wain1, Bo Gao1, Russell Hogg1, Sivatharsny Srirangan1, Casina Kan1, Sian Fereday1, Nadia Traficante1, Ann-Marie Patch1, John V Pearson1, Nicola Waddell1, Sean M Grimmond1, Alexander Dobrovic1, David D L Bowtell1, Paul R Harnett1, Anna deFazio1. 1. Tania 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.
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.
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.
Authors: R Silva; B Moran; S Das; N Mulligan; M Doughty; A Treacy; K Sheahan; C M Kelly; A G Duffy; A S Perry; D J Brennan Journal: Case Rep Womens Health Date: 2022-02-06