María Dolores Fenor1,2, Sergio Ruiz-Llorente1,2,3, Juan Francisco Rodríguez-Moreno1,2,3, Eduardo Caleiras4, Juan Carlos Torrego5, Elena Sevillano-Fernández1,2,3, Paloma Navarro1,2,3, Mónica Yagüe-Fernández1,2,3, Sandra Amarilla-Quintana1,2,3, Arantzazu Barquín1,2,3, Jesús García-Donas6,7,8. 1. Laboratory of Innovation in Oncology, HM CIOCC MADRID (Centro Integral Oncológico Clara Campal), Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain. 2. Department of Genitourinary and Gynecological Tumors, Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain. 3. Institute of Applied Molecular Medicine (IMMA), Department of Basic Medical Sciences, Facultad de Medicina, Universidad San Pablo CEU, CEU Universities, Urbanización Montepríncipe, Monteprincipe Avenue, 28668, Madrid, Spain. 4. Histopathology Core Unit, Spanish National Cancer Center (CNIO), Madrid, Spain. 5. Medical Oncology Department, Campo Grande Hospital, Valladolid, Spain. 6. Laboratory of Innovation in Oncology, HM CIOCC MADRID (Centro Integral Oncológico Clara Campal), Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain. jgarciadonas@hmhospitales.com. 7. Department of Genitourinary and Gynecological Tumors, Hospital Universitario HM Sanchinarro, HM Hospitales, Madrid, Spain. jgarciadonas@hmhospitales.com. 8. Institute of Applied Molecular Medicine (IMMA), Department of Basic Medical Sciences, Facultad de Medicina, Universidad San Pablo CEU, CEU Universities, Urbanización Montepríncipe, Monteprincipe Avenue, 28668, Madrid, Spain. jgarciadonas@hmhospitales.com.
Abstract
PURPOSE: The identification of subpopulations harboring druggable targets has become a major step forward in the subclassification of solid tumors into small groups suitable for specific therapies. BRAF fusions represent a paradigm of uncommon and targetable oncogenic events and have been widely correlated to the development of specific malignancies. However, they are only present in a limited frequency across most common tumor types. At this regard, we performed a genomic screening aimed to identifying rare variants associated to advanced prostate cancer development. METHODS: Tumoral tissue genomic screening of 41 patients developing advanced prostate cancer was performed at our center as part of the GETHI XX study. The project, sponsored by the Spanish Collaborative Group in Rare Cancers (GETHI), aims to analyze the molecular background of rare tumors and to discover unfrequent molecular variants in common tumors. RESULTS: Here we present the clinical outcome and an in-deep molecular analysis performed in a case harboring a SND1-BRAF fusion gene. The identification of such rearrangement in a patient refractory to standard therapies led to the administration of trametinib (MEK inhibitor). Despite unsensitive to standard therapies, the patient achieved a dramatic response to trametinib. A comprehensive study of the tumor demonstrated this event to be a trunk alteration with higher expression of MEK in areas of tumor invasion. CONCLUSIONS: Our study describes the patient-driven discovery of the first BRAF fusion-driven prostate cancer effectively treated with trametinib. Consequently, MAPK pathway activation could define a new subtype of prostate cancer susceptible to a tailored management.
PURPOSE: The identification of subpopulations harboring druggable targets has become a major step forward in the subclassification of solid tumors into small groups suitable for specific therapies. BRAF fusions represent a paradigm of uncommon and targetable oncogenic events and have been widely correlated to the development of specific malignancies. However, they are only present in a limited frequency across most common tumor types. At this regard, we performed a genomic screening aimed to identifying rare variants associated to advanced prostate cancer development. METHODS: Tumoral tissue genomic screening of 41 patients developing advanced prostate cancer was performed at our center as part of the GETHI XX study. The project, sponsored by the Spanish Collaborative Group in Rare Cancers (GETHI), aims to analyze the molecular background of rare tumors and to discover unfrequent molecular variants in common tumors. RESULTS: Here we present the clinical outcome and an in-deep molecular analysis performed in a case harboring a SND1-BRAF fusion gene. The identification of such rearrangement in a patient refractory to standard therapies led to the administration of trametinib (MEK inhibitor). Despite unsensitive to standard therapies, the patient achieved a dramatic response to trametinib. A comprehensive study of the tumor demonstrated this event to be a trunk alteration with higher expression of MEK in areas of tumor invasion. CONCLUSIONS: Our study describes the patient-driven discovery of the first BRAF fusion-driven prostate cancer effectively treated with trametinib. Consequently, MAPK pathway activation could define a new subtype of prostate cancer susceptible to a tailored management.
Authors: Justin M Drake; Nicholas A Graham; Tanya Stoyanova; Amir Sedghi; Andrew S Goldstein; Houjian Cai; Daniel A Smith; Hong Zhang; Evangelia Komisopoulou; Jiaoti Huang; Thomas G Graeber; Owen N Witte Journal: Proc Natl Acad Sci U S A Date: 2012-01-17 Impact factor: 11.205
Authors: Nallasivam Palanisamy; Bushra Ateeq; Shanker Kalyana-Sundaram; Dorothee Pflueger; Kalpana Ramnarayanan; Sunita Shankar; Bo Han; Qi Cao; Xuhong Cao; Khalid Suleman; Chandan Kumar-Sinha; Saravana M Dhanasekaran; Ying-bei Chen; Raquel Esgueva; Samprit Banerjee; Christopher J LaFargue; Javed Siddiqui; Francesca Demichelis; Peter Moeller; Tarek A Bismar; Rainer Kuefer; Douglas R Fullen; Timothy M Johnson; Joel K Greenson; Thomas J Giordano; Patrick Tan; Scott A Tomlins; Sooryanarayana Varambally; Mark A Rubin; Christopher A Maher; Arul M Chinnaiyan Journal: Nat Med Date: 2010-06-06 Impact factor: 53.440
Authors: Justin M Drake; Evan O Paull; Nicholas A Graham; John K Lee; Bryan A Smith; Bjoern Titz; Tanya Stoyanova; Claire M Faltermeier; Vladislav Uzunangelov; Daniel E Carlin; Daniel Teo Fleming; Christopher K Wong; Yulia Newton; Sud Sudha; Ajay A Vashisht; Jiaoti Huang; James A Wohlschlegel; Thomas G Graeber; Owen N Witte; Joshua M Stuart Journal: Cell Date: 2016-08-04 Impact factor: 41.582
Authors: Claire M Faltermeier; Justin M Drake; Peter M Clark; Bryan A Smith; Yang Zong; Carmen Volpe; Colleen Mathis; Colm Morrissey; Brandon Castor; Jiaoti Huang; Owen N Witte Journal: Proc Natl Acad Sci U S A Date: 2015-11-30 Impact factor: 11.205
Authors: Nathan V Lee; Maruja E Lira; Adam Pavlicek; Jingjing Ye; Dana Buckman; Shubha Bagrodia; Sreesha P Srinivasa; Yongjun Zhao; Samuel Aparicio; Paul A Rejto; James G Christensen; Keith A Ching Journal: PLoS One Date: 2012-06-22 Impact factor: 3.240
Authors: Nicholas G Nickols; Ramin Nazarian; Shuang G Zhao; Victor Tan; Vladislav Uzunangelov; Zheng Xia; Robert Baertsch; Elad Neeman; Allen C Gao; George V Thomas; Lauren Howard; Amanda M De Hoedt; Josh Stuart; Theodore Goldstein; Kim Chi; Martin E Gleave; Julie N Graff; Tomasz M Beer; Justin M Drake; Christopher P Evans; Rahul Aggarwal; Adam Foye; Felix Y Feng; Eric J Small; William J Aronson; Stephen J Freedland; Owen N Witte; Jiaoti Huang; Joshi J Alumkal; Robert E Reiter; Matthew B Rettig Journal: Prostate Cancer Prostatic Dis Date: 2019-02-25 Impact factor: 5.554