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PTEN expression and mutations in TSC1 , TSC2 and MTOR are associated with response to rapalogs in patients with renal cell carcinoma
Author(s) -
RoldanRomero Juan M.,
Beuselinck Benoit,
Santos María,
RodriguezMoreno Juan F.,
Lanillos Javier,
Calsina Bruna,
Gutierrez Ana,
Tang Karin,
Lainez Nuria,
Puente Javier,
Castellano Daniel,
Esteban Emilio,
Climent Miguel A.,
Arranz Jose A.,
Albersen Maarten,
Oudard Stephane,
Couchy Gabrielle,
Caleiras Eduardo,
MonteroConde Cristina,
Cascón Alberto,
Robledo Mercedes,
RodríguezAntona Cristina,
GarcíaDonas Jesús
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32579
Subject(s) - pten , tsc1 , pi3k/akt/mtor pathway , immunohistochemistry , cancer research , medicine , renal cell carcinoma , univariate analysis , odds ratio , oncology , tsc2 , biology , multivariate analysis , signal transduction , genetics
The mammalian target of rapamycin (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 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 and 2 in TSC2 ). When comparing the molecular data to the response of the patients, we found that partial response was more frequent in cases with mTOR pathway mutations than in those without mutations (odds ratio [OR] = 0.08, 95% confidence interval [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.