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114 Clonal mTOR pathway activation as a predictive biomarker for mTOR inhibitor therapy in clear cell renal cell carcinoma
114
Clonal mTOR pathway activation as a predictive biomarker for mTOR inhibitor therapy in clear cell renal cell carcinoma Eur Urol Suppl 2016;15(3);e114
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Stares M. 1 , Nicol D.2 , O'Brien T.3 , Challacombe B. 3 , Rowan A. 1 , Horswell S. 4 , Salm M. 4 , Soultati A. 5 , Hazell S. 6 , Chandra A. 7 , López J. 8 , Fisher R.9 , Chowdhury S. 5 , Rudman S. 5 , Gore M. 9 , Matthews N.10 , Fotiadis N.11 , Larkin J. 9 , Turajlic S. 1 , Swanton C.1 1 The
Francis Crick Institute, Translational Cancer Therapeutics Laboratory, London, United Kingdom, 2 The Royal Marsden Hospital NHS
Foundation Trust, Dept. of Urology, London, United Kingdom, 3 Guy's and St Thomas' NHS Foundation Trust, Dept. of Urology, London, United Kingdom, 4 The Francis Crick Institute, Bioinformatics and Biostatistics, London, United Kingdom, 5 Guy's and St Thomas' NHS Foundation Trust, Dept. of Medicine, London, United Kingdom, 6 The Royal Marsden Hospital NHS Foundation Trust, Dept. of Pathology, London, United Kingdom, 7 Guy's and St Thomas' NHS Foundation Trust, Dept. of Pathology, London, United Kingdom, 8 Cruces University Hospital, Dept. of Pathology, Bilbao, Spain, 9 The Royal Marsden Hospital NHS Foundation Trust, Dept. of Medicine, London, United Kingdom, 10 The Francis Crick Institute, Advanced Sequencing Facility, London, United Kingdom, 11 The Royal Marsden Hospital NHS Foundation Trust, Dept. of Interventional Radiology, London, United Kingdom INTRODUCTION & OBJECTIVES: Despite the widespread use of targeted therapies, including the inhibitors of mammalian Target Of Rapamycin (mTOR), in the management of metastatic clear cell Renal Cell Carcinoma (ccRCC) there are currently no validated predictive biomarkers to direct their use. Activation of the mTOR pathway has been associated with response to mTOR inhibitor therapy in several tumour types. To investigate potential markers of response to mTOR inhibitors we examined the genomic landscape of a patient with a profound clinical response to the mTOR inhibitor everolimus. MATERIAL & METHODS: We performed Whole Exome Sequencing (WES) on seven spatially separate primary tumour samples collected at nephrectomy from a patient (RK39) with metastatic ccRCC. RESULTS: Case RK39 presented with a primary ccRCC with lung and ipsilateral adrenal gland metastases. The patient underwent nephrectomy during first-line medical treatment with axitinib, at which point tumour samples were collected. After 2 years of treatment with axitinib Computed Tomography (CT) assessment demonstrated significant disease progression within the renal bed, and everolimus was commenced. CT assessment after 6 months demonstrated a 40% reduction in size of the renal bed lesion and complete resolution of a target lung lesion present since diagnosis. The patient continues on everolimus at 1 year with ongoing disease control. A total of 113 nonsynonymous somatic mutations were identified across 7 tumour regions and used to construct a phylogenetic tree (Fig. 1). ccRCC driver gene mutations and somatic copy number alterations (SCNAs) were mapped to the tree. In addition to the well-characterised events of VHL inactivation and chromosome 3p loss, mutations in the ccRCC driver genes MTOR and PBRM1 (polybromo-1) mapped to the trunk of the phylogenetic tree. Immunohistochemical staining of the mTOR substrates S6K and 4E-BP1 was consistent with activation of the mTOR pathway.
CONCLUSIONS: In this patient activation of the mTOR pathway by an MTOR mutation offers a possible explanation for a profound clinical response to everolimus. Although only the primary tumour was sampled, we suggest that as a clonal event it is likely to be found within the metastatic regions assessed. Approximately 6% of ccRCC harbour inactivating mutations in the MTOR gene, with deregulation of the wider mTOR pathway seen in 20%. However, unlike in the case under study these events are frequently subclonal, which may explain why
significantly fewer patients achieve excellent clinical responses to mTOR inhibition.
Clonal mTOR pathway activation as a predictive biomarker for mTOR inhibitor therapy in clear cell renal cell carcinoma Eur Urol Suppl 2016;15(3);e114
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Stares M. 1 , Nicol D.2 , O'Brien T.3 , Challacombe B. 3 , Rowan A. 1 , Horswell S. 4 , Salm M. 4 , Soultati A. 5 , Hazell S. 6 , Chandra A. 7 , López J. 8 , Fisher R.9 , Chowdhury S. 5 , Rudman S. 5 , Gore M. 9 , Matthews N.10 , Fotiadis N.11 , Larkin J. 9 , Turajlic S. 1 , Swanton C.1 1 The
Francis Crick Institute, Translational Cancer Therapeutics Laboratory, London, United Kingdom, 2 The Royal Marsden Hospital NHS
Foundation Trust, Dept. of Urology, London, United Kingdom, 3 Guy's and St Thomas' NHS Foundation Trust, Dept. of Urology, London, United Kingdom, 4 The Francis Crick Institute, Bioinformatics and Biostatistics, London, United Kingdom, 5 Guy's and St Thomas' NHS Foundation Trust, Dept. of Medicine, London, United Kingdom, 6 The Royal Marsden Hospital NHS Foundation Trust, Dept. of Pathology, London, United Kingdom, 7 Guy's and St Thomas' NHS Foundation Trust, Dept. of Pathology, London, United Kingdom, 8 Cruces University Hospital, Dept. of Pathology, Bilbao, Spain, 9 The Royal Marsden Hospital NHS Foundation Trust, Dept. of Medicine, London, United Kingdom, 10 The Francis Crick Institute, Advanced Sequencing Facility, London, United Kingdom, 11 The Royal Marsden Hospital NHS Foundation Trust, Dept. of Interventional Radiology, London, United Kingdom INTRODUCTION & OBJECTIVES: Despite the widespread use of targeted therapies, including the inhibitors of mammalian Target Of Rapamycin (mTOR), in the management of metastatic clear cell Renal Cell Carcinoma (ccRCC) there are currently no validated predictive biomarkers to direct their use. Activation of the mTOR pathway has been associated with response to mTOR inhibitor therapy in several tumour types. To investigate potential markers of response to mTOR inhibitors we examined the genomic landscape of a patient with a profound clinical response to the mTOR inhibitor everolimus. MATERIAL & METHODS: We performed Whole Exome Sequencing (WES) on seven spatially separate primary tumour samples collected at nephrectomy from a patient (RK39) with metastatic ccRCC. RESULTS: Case RK39 presented with a primary ccRCC with lung and ipsilateral adrenal gland metastases. The patient underwent nephrectomy during first-line medical treatment with axitinib, at which point tumour samples were collected. After 2 years of treatment with axitinib Computed Tomography (CT) assessment demonstrated significant disease progression within the renal bed, and everolimus was commenced. CT assessment after 6 months demonstrated a 40% reduction in size of the renal bed lesion and complete resolution of a target lung lesion present since diagnosis. The patient continues on everolimus at 1 year with ongoing disease control. A total of 113 nonsynonymous somatic mutations were identified across 7 tumour regions and used to construct a phylogenetic tree (Fig. 1). ccRCC driver gene mutations and somatic copy number alterations (SCNAs) were mapped to the tree. In addition to the well-characterised events of VHL inactivation and chromosome 3p loss, mutations in the ccRCC driver genes MTOR and PBRM1 (polybromo-1) mapped to the trunk of the phylogenetic tree. Immunohistochemical staining of the mTOR substrates S6K and 4E-BP1 was consistent with activation of the mTOR pathway.
CONCLUSIONS: In this patient activation of the mTOR pathway by an MTOR mutation offers a possible explanation for a profound clinical response to everolimus. Although only the primary tumour was sampled, we suggest that as a clonal event it is likely to be found within the metastatic regions assessed. Approximately 6% of ccRCC harbour inactivating mutations in the MTOR gene, with deregulation of the wider mTOR pathway seen in 20%. However, unlike in the case under study these events are frequently subclonal, which may explain why
significantly fewer patients achieve excellent clinical responses to mTOR inhibition.