mTOR pathway inhibitors are key drugs for the treatment of many tumor types, however, there are no predictive biomarkers in clinical use. Here, we performed a molecular and immunohistochemical characterization of key mTOR pathway components in a series of 105 renal cell carcinoma (RCC) patients treated with rapalogs, aimed at identifying markers of treatment response. Mutational analysis in MTOR, TSC1 and TSC2 was performed through targeted next-generation sequencing (NGS), and immunohistochemistry (IHC) was performed for PTEN, pAKT, pS6K1, pS6 and p21. Among patients with NGS data, 11 of 87 (13%) had mTOR pathway mutations (8 in MTOR, 1 in TSC1, 2 in TSC2). When comparing the molecular data with the response of the patients, we found that partial response was more frequent in cases with mTOR pathway mutations than in those without mutations (OR=0.08, 95%CI=0.008-0.79, P=0.030 univariate; P=0.038 multivariable). Regarding IHC, negative PTEN staining was detected in 58% of the tumors, and it was more frequent in rapalog responder patients (OR=0.24, 95%CI=0.065-0.86, P=0.029 univariate; P=0.029 multivariable). Mutations and PTEN IHC were not mutually exclusive events and its combination improved response prediction (OR=0.16, 95%CI=0.04-0.62, P=0.008 univariate; P=0.013 multivariable). The staining of other proteins did not show and association with response and no association with PFS was observed in unselected patients. In conclusion, our findings suggest that mTOR pathway mutations, negative PTEN IHC, and their combination, are potential markers of rapalog response. This article is protected by copyright. All rights reserved.
International journal of cancer. 2019 Jul 23 [Epub ahead of print]
Juan M Roldan-Romero, Benoit Beuselinck, María Santos, Juan F Rodriguez-Moreno, Javier Lanillos, Bruna Calsina, Ana Gutierrez, Karin Tang, Nuria Lainez, Javier Puente, Daniel Castellano, Emilio Esteban, Miguel A Climent, Jose A Arranz, Marteen Albersen, Stephane Oudard, Gabrielle Couchy, Eduardo Caleiras, Cristina Montero-Conde, Alberto Cascón, Mercedes Robledo, Cristina Rodríguez-Antona, Jesús García-Donas, Spanish Oncology Genitourinary Group (SOGUG)
Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain., Laboratory of Experimental Oncology, Department of Oncology, University of Leuven, Leuven, Belgium., Genitourinary and Gynecological Cancer Unit, HM Hospitales – Centro Integral Oncológico HM Clara Campal., Hospital HM Puerta del Sur, Móstoles, Spain., Hospital Universitario de Móstoles, Móstoles, Spain., Complejo Hospitalario de Navarra, Pamplona, Spain., Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), CIBERONC, Madrid, Spain., Hospital Universitario Doce de Octubre, Madrid, Spain., Hospital Central de Asturias, Oviedo, Spain., Fundación Instituto Valenciano de Oncologia, Valencia, Spain., Hospital General Universitario Gregorio Marañón, Madrid, Spain., Department of Urology, University Hospitals Leuven, KULeuven, Belgium., Department of Medical Oncology, Hôpital Européen Georges-Pompidou, Paris, France., Inserm UMR 1162, Université Paris-Descartes, Paris, France., Histopathology Core Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.