A Spreafico1, A M Oza1, B A Clarke2, H J Mackay1, P Shaw2, M Butler1, N C Dhani1, S Lheureux1, M K Wilson1, S Welch3, T Zhang2, C Yu1, T Stockley1, L L Siu1, S Kamel-Reid2, P L Bedard4. 1. Department of Medicine, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada. 2. Department of Pathology and Laboratory Medicine, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. 3. Division of Medical Oncology, Department of Oncology, London Health Sciences Centre, University of Western Ontario, London, ON, Canada. 4. Department of Medicine, Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada. Electronic address: philippe.bedard@uhn.ca.
Abstract
BACKGROUND: Genomic alterations that activate the MAPK signaling pathway frequently occur in Type I Epithelial Ovarian Cancers (EOCs). We evaluated therapeutic response outcomes in patients with type I EOC treated with genotype-matched therapy on clinical trials enrolled in a prospective molecular profiling program. MATERIAL AND METHODS: Formalin fixed paraffin embedded tumor tissues were prospectively screened for genomic alterations using MALDI-ToF mass-spectrometry platform or targeted sequencing using the Illumina MiSeq TruSeq Amplicon Cancer Panel. Treatment outcomes on genotype-matched trials were retrospectively reviewed using RECIST version 1.1 and Gynecological Cancer Intergroup CA125 related-response criteria RESULTS: 55 patients with type I EOC underwent molecular profiling, 41 (75%) low grade serous (LGS), 9 (16%) clear cell (CC), and 5 (9%) mucinous (MC) histologies. Thirty-five patients (64%) were found to have ≥1 somatic mutations: 23 KRAS, 6 NRAS, 5 PIK3CA, 2 PTEN, 1 BRAF, 1 AKT, 1 TP53, and 1 CTNNB1. Fifteen patients were subsequently enrolled in genotype-matched phase I or II trials, including 14 patients with KRAS/NRAS mutations treated with MEK inhibitor targeted combinations. Among 14 RECIST evaluable patients, there were 7 partial responses (PR), 7 stable disease (SD) and 1 disease progression (PD). CA125 responses were observed in 10/10 evaluable KRAS/NRAS mutant patients treated with MEK inhibitor combinations CONCLUSIONS: Genotyping and targeted sequencing of Type I EOCs frequently identifies actionable mutations. Matched treatment with MEK-based combination therapy in KRAS and/or NRAS mutant type I EOC patients is an active therapeutic strategy.
BACKGROUND: Genomic alterations that activate the MAPK signaling pathway frequently occur in Type I Epithelial Ovarian Cancers (EOCs). We evaluated therapeutic response outcomes in patients with type I EOC treated with genotype-matched therapy on clinical trials enrolled in a prospective molecular profiling program. MATERIAL AND METHODS:Formalin fixed paraffin embedded tumor tissues were prospectively screened for genomic alterations using MALDI-ToF mass-spectrometry platform or targeted sequencing using the Illumina MiSeq TruSeq Amplicon Cancer Panel. Treatment outcomes on genotype-matched trials were retrospectively reviewed using RECIST version 1.1 and Gynecological Cancer Intergroup CA125 related-response criteria RESULTS: 55 patients with type I EOC underwent molecular profiling, 41 (75%) low grade serous (LGS), 9 (16%) clear cell (CC), and 5 (9%) mucinous (MC) histologies. Thirty-five patients (64%) were found to have ≥1 somatic mutations: 23 KRAS, 6 NRAS, 5 PIK3CA, 2 PTEN, 1 BRAF, 1 AKT, 1TP53, and 1 CTNNB1. Fifteen patients were subsequently enrolled in genotype-matched phase I or II trials, including 14 patients with KRAS/NRAS mutations treated with MEK inhibitor targeted combinations. Among 14 RECIST evaluable patients, there were 7 partial responses (PR), 7 stable disease (SD) and 1 disease progression (PD). CA125 responses were observed in 10/10 evaluable KRAS/NRAS mutant patients treated with MEK inhibitor combinations CONCLUSIONS: Genotyping and targeted sequencing of Type I EOCs frequently identifies actionable mutations. Matched treatment with MEK-based combination therapy in KRAS and/or NRAS mutant type I EOC patients is an active therapeutic strategy.
Authors: Bradley J Monk; Rachel N Grisham; Susana Banerjee; Elsa Kalbacher; Mansoor Raza Mirza; Ignacio Romero; Peter Vuylsteke; Robert L Coleman; Felix Hilpert; Amit M Oza; Anneke Westermann; Martin K Oehler; Sandro Pignata; Carol Aghajanian; Nicoletta Colombo; Esther Drill; David Cibula; Kathleen N Moore; Janna Christy-Bittel; Josep M Del Campo; Regina Berger; Christian Marth; Jalid Sehouli; David M O'Malley; Cristina Churruca; Adam P Boyd; Gunnar Kristensen; Andrew Clamp; Isabelle Ray-Coquard; Ignace Vergote Journal: J Clin Oncol Date: 2020-08-21 Impact factor: 44.544
Authors: Irene Brana; Nhu-An Pham; Lucia Kim; Shingo Sakashita; Ming Li; Christine Ng; Yuhui Wang; Peter Loparco; Rafael Sierra; Lisa Wang; Blaise A Clarke; Benjamin G Neel; Lillian L Siu; Ming-Sound Tsao Journal: Oncotarget Date: 2017-07-08