PMID- 31335987
OWN - NLM
STAT- MEDLINE
DCOM- 20200214
LR  - 20211204
IS  - 1097-0215 (Electronic)
IS  - 0020-7136 (Linking)
VI  - 146
IP  - 5
DP  - 2020 Mar 1
TI  - PTEN expression and mutations in TSC1, TSC2 and MTOR are associated with response 
      to rapalogs in patients with renal cell carcinoma.
PG  - 1435-1444
LID - 10.1002/ijc.32579 [doi]
AB  - 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.
CI  - (c) 2019 UICC.
FAU - Roldan-Romero, Juan M
AU  - Roldan-Romero JM
AUID- ORCID: 0000-0002-5651-4313
AD  - Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish 
      National Cancer Research Centre (CNIO), Madrid, Spain.
FAU - Beuselinck, Benoit
AU  - Beuselinck B
AD  - Laboratory of Experimental Oncology, Department of Oncology, University of 
      Leuven, Leuven, Belgium.
FAU - Santos, Maria
AU  - Santos M
AD  - Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish 
      National Cancer Research Centre (CNIO), Madrid, Spain.
FAU - Rodriguez-Moreno, Juan F
AU  - Rodriguez-Moreno JF
AD  - Genitourinary and Gynecological Cancer Unit, HM Hospitales - Centro Integral 
      Oncologico HM Clara Campal, Madrid, Spain.
FAU - Lanillos, Javier
AU  - Lanillos J
AD  - Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish 
      National Cancer Research Centre (CNIO), Madrid, Spain.
FAU - Calsina, Bruna
AU  - Calsina B
AD  - Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish 
      National Cancer Research Centre (CNIO), Madrid, Spain.
FAU - Gutierrez, Ana
AU  - Gutierrez A
AD  - Hospital HM Puerta del Sur, Mostoles, Spain.
FAU - Tang, Karin
AU  - Tang K
AD  - Hospital Universitario de Mostoles, Mostoles, Spain.
FAU - Lainez, Nuria
AU  - Lainez N
AD  - Complejo Hospitalario de Navarra, Pamplona, Spain.
FAU - Puente, Javier
AU  - Puente J
AD  - Medical Oncology Department, Hospital Clinico San Carlos, Instituto de 
      Investigacion Sanitaria del Hospital Clinico San Carlos (IdISSC), CIBERONC, 
      Madrid, Spain.
FAU - Castellano, Daniel
AU  - Castellano D
AD  - Hospital Universitario Doce de Octubre, Madrid, Spain.
FAU - Esteban, Emilio
AU  - Esteban E
AD  - Hospital Central de Asturias, Oviedo, Spain.
FAU - Climent, Miguel A
AU  - Climent MA
AD  - Fundacion Instituto Valenciano de Oncologia, Valencia, Spain.
FAU - Arranz, Jose A
AU  - Arranz JA
AD  - Hospital General Universitario Gregorio Maranon, Madrid, Spain.
FAU - Albersen, Maarten
AU  - Albersen M
AD  - Department of Urology, University Hospitals Leuven, Leuven, Belgium.
FAU - Oudard, Stephane
AU  - Oudard S
AD  - Department of Medical Oncology, Hopital Europeen Georges-Pompidou, Paris, France.
FAU - Couchy, Gabrielle
AU  - Couchy G
AD  - Inserm UMR 1162, Universite Paris-Descartes, Paris, France.
FAU - Caleiras, Eduardo
AU  - Caleiras E
AD  - Histopathology Core Unit, Spanish National Cancer Research Centre (CNIO), Madrid, 
      Spain.
FAU - Montero-Conde, Cristina
AU  - Montero-Conde C
AD  - Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish 
      National Cancer Research Centre (CNIO), Madrid, Spain.
FAU - Cascon, Alberto
AU  - Cascon A
AD  - Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish 
      National Cancer Research Centre (CNIO), Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Madrid, 
      Spain.
FAU - Robledo, Mercedes
AU  - Robledo M
AD  - Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish 
      National Cancer Research Centre (CNIO), Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Madrid, 
      Spain.
FAU - Rodriguez-Antona, Cristina
AU  - Rodriguez-Antona C
AUID- ORCID: 0000-0001-8750-7338
AD  - Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish 
      National Cancer Research Centre (CNIO), Madrid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Madrid, 
      Spain.
FAU - Garcia-Donas, Jesus
AU  - Garcia-Donas J
AD  - Genitourinary and Gynecological Cancer Unit, HM Hospitales - Centro Integral 
      Oncologico HM Clara Campal, Madrid, Spain.
CN  - Spanish Oncology Genitourinary Group (SOGUG)
LA  - eng
PT  - Journal Article
PT  - Observational Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20190809
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (TSC1 protein, human)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Tuberous Sclerosis Complex 1 Protein)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 624KN6GM2T (temsirolimus)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents/*pharmacology/therapeutic use
MH  - Biomarkers, Tumor/antagonists & inhibitors/*genetics/metabolism
MH  - Carcinoma, Renal Cell/*drug therapy/genetics/mortality
MH  - DNA Mutational Analysis
MH  - Drug Resistance, Neoplasm/*genetics
MH  - Everolimus/pharmacology/therapeutic use
MH  - Female
MH  - Follow-Up Studies
MH  - Humans
MH  - Kidney/pathology
MH  - Kidney Neoplasms/*drug therapy/genetics/mortality
MH  - Male
MH  - Middle Aged
MH  - Mutation
MH  - PTEN Phosphohydrolase/metabolism
MH  - Prognosis
MH  - Progression-Free Survival
MH  - Prospective Studies
MH  - Signal Transduction/drug effects/genetics
MH  - Sirolimus/analogs & derivatives/pharmacology/therapeutic use
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/metabolism
MH  - Tuberous Sclerosis Complex 1 Protein/genetics
MH  - Tuberous Sclerosis Complex 2 Protein/genetics
EDAT- 2019/07/25 06:00
MHDA- 2020/02/15 06:00
CRDT- 2019/07/24 06:00
PHST- 2019/01/25 00:00 [received]
PHST- 2019/05/31 00:00 [revised]
PHST- 2019/06/14 00:00 [accepted]
PHST- 2019/07/25 06:00 [pubmed]
PHST- 2020/02/15 06:00 [medline]
PHST- 2019/07/24 06:00 [entrez]
AID - 10.1002/ijc.32579 [doi]
PST - ppublish
SO  - Int J Cancer. 2020 Mar 1;146(5):1435-1444. doi: 10.1002/ijc.32579. Epub 2019 Aug 
      9.