TY - JOUR
T1 - BRAF mutations in low-grade serous ovarian cancer and response to BRAF inhibition
AU - Moujaber, Tania
AU - Etemadmoghadam, Dariush
AU - Kennedy, Catherine J.
AU - Chiew, Yoke Eng
AU - Balleine, Rosemary L.
AU - Saunders, Catherine
AU - Wain, Gerard V.
AU - Gao, Bo
AU - Hogg, Russell
AU - Srirangan, Sivatharsny
AU - Kan, Casina
AU - Fereday, Sian
AU - Traficante, Nadia
AU - Australian Ovarian Cancer Study
AU - Patch, Ann Marie
AU - Pearson, John V.
AU - Waddell, Nicola
AU - Grimmond, Sean M.
AU - Dobrovic, Alexander
AU - Bowtell, David D.L.
AU - Harnett, Paul R.
AU - deFazio, Anna
AU - Chenevix-Trench, G.
AU - Green, A.
AU - Webb, P.
AU - Gertig, D.
AU - Moore, S.
AU - Harrap, K.
AU - Sadkowsky, T.
AU - Pandeya, N.
AU - Hung, J.
AU - Malt, M.
AU - Alexander, B.
AU - Ashover, P.
AU - Brown, S.
AU - Corrish, T.
AU - Green, L.
AU - Jackman, L.
AU - Ferguson, K.
AU - Martin, K.
AU - Martyn, A.
AU - Ranieri, B.
AU - Mellon, A.
AU - Robertson, R.
AU - Vanden Bergh, T.
AU - Jones, M.
AU - Mackenzie, P.
AU - Maidens, J.
AU - Nattress, K.
AU - Stenlake, A.
AU - Sullivan, H.
AU - White, J.
AU - Jayde, V.
AU - Mamers, P.
AU - Bowes, L.
AU - Galletta, L.
AU - Giles, D.
AU - Hendley, J.
AU - Alsop, K.
AU - Ball, C.
AU - Young, C.
AU - Schmidt, T.
AU - Shirley, H.
AU - Viduka, S.
AU - Tran, Hoa
AU - Bilic, Sanela
AU - Glavinas, Lydia
AU - Brooks, Julia
AU - Stuart-Harris, R.
AU - Kirsten, F.
AU - Rutovitz, J.
AU - Clingan, P.
AU - Glasgow, A.
AU - Proietto, A.
AU - Braye, S.
AU - Otton, G.
AU - Shannon, J.
AU - Bonaventura, T.
AU - Stewart, J.
AU - Begbie, S.
AU - Bell, D.
AU - Baron-Hay, S.
AU - Ferrier, A.
AU - Gard, G.
AU - Nevell, D.
AU - Pavlakis, N.
AU - Valmadre, S.
AU - Young, B.
AU - Camaris, C.
AU - Crouch, R.
AU - Edwards, L.
AU - Hacker, N.
AU - Marsden, D.
AU - Robertson, G.
AU - Beale, P.
AU - Beith, J.
AU - Carter, J.
AU - Dalrymple, C.
AU - Houghton, R.
AU - Russell, P.
AU - Links, M.
AU - Grygiel, J.
AU - Hill, J.
AU - Brand, A.
AU - Byth, K.
AU - Jaworski, R.
AU - Sharma, R.
AU - Harnett, P.
AU - Wain, G.
AU - Friedlander, M.
AU - Ward, B.
AU - Papadimos, D.
AU - Crandon, A.
AU - Cummings, M.
AU - Horwood, K.
AU - Obermair, A.
AU - Perrin, L.
AU - Wyld, D.
AU - Nicklin, J.
AU - Davy, M.
AU - Oehler, M. K.
AU - Hall, C.
AU - Dodd, T.
AU - Healy, T.
AU - Pittman, K.
AU - Henderson, D.
AU - Miller, J.
AU - Pierdes, J.
AU - Blomfield, P.
AU - Challis, D.
AU - McIntosh, R.
AU - Parker, A.
AU - Brown, B.
AU - Rome, R.
AU - Allen, D.
AU - Grant, P.
AU - Hyde, S.
AU - Laurie, R.
AU - Robbie, M.
AU - Healy, D.
AU - Jobling, T.
AU - Manolitsas, T.
AU - McNealage, J.
AU - Rogers, P.
AU - Susil, B.
AU - Sumithran, E.
AU - Simpson, I.
AU - Phillips, K.
AU - Rischin, D.
AU - Fox, S.
AU - Johnson, D.
AU - Lade, S.
AU - Loughrey, M.
AU - O'Callaghan, N.
AU - Murray, W.
AU - Waring, P.
AU - Billson, V.
AU - Pyman, J.
AU - Neesham, D.
AU - Quinn, M.
AU - Underhill, C.
AU - Bell, R.
AU - Ng, L. F.
AU - Blum, R.
AU - Ganju, V.
AU - Hammond, I.
AU - Leung, Y.
AU - McCartney, A.
AU - Buck, M.
AU - Haviv, I.
AU - Purdie, D.
AU - Whiteman, D.
AU - Zeps, N.
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85065768354&partnerID=8YFLogxK
U2 - 10.1200/PO.17.00221
DO - 10.1200/PO.17.00221
M3 - Article
AN - SCOPUS:85065768354
SN - 2473-4284
VL - 2
SP - 1
EP - 14
JO - JCO Precision Oncology
JF - JCO Precision Oncology
ER -
