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Published on: January 22, 2013
Correlation Between Molecular Subclassifications of Clear Cell Renal Cell Carcinoma and Targeted Therapy Response
Thai H Ho1, Toni K Choueiri2, Kai Wang3
1Epigenomics Program, Center for Individualized Medicine, Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA.
Background:
Vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR)-directed therapies are the standard of care in metastatic clear cell renal cell carcinoma (mccRCC) but are not used based on molecular subclassifications of ccRCC.
Objective:
To determine if an association exists between genomic alterations (GAs) detected by comprehensive genomic profiling (CGP) in the course of clinical care and the response to anti-VEGF receptor (VEGFR) and anti-MTOR pathway targeted therapies in a cohort of patients with treated mccRCC.
Design, Setting, And Participants:
CGP, using a Clinical Laboratory Improvement Amendments-certified platform, was performed on 31 formalin-fixed, paraffin-embedded tissue specimens (84% from cytoreductive nephrectomies) obtained from patients with metastatic renal cell carcinoma who had received VEGFR and/or mTOR inhibitors. Duration of treatment (DOT) and extent and duration of clinical response were obtained from review of medical records.
Outcome Measurements And Statistical Analysis:
All classes of GAs-base substitutions, short insertions, deletions, gene fusions, rearrangements, and copy number-were assessed via hybrid capture-based CGP. Descriptive statistics were used to determine the frequency of GAs in groups segregated by the DOT with VEGF-directed agents.
Results And Limitations:
The most common GAs detected in this series were in VHL (70%), PBRM1 (48%), SETD2 (32%), TSC1 (29%), MLL (19%), TERT (16%), ARID1B (16%), and KDM5C (16%). Across 61 administrations of VEGF-directed therapy in 27 patients, exceptional responses (DOT >21 mo) were more frequent among patients with GAs in KDM5C, PBRM1, and VHL. Conversely, these patients also featured a lower frequency of GA associated with response to mTOR-directed therapy, such as TSC1.
Conclusions:
Molecular subclassifications may affect response to VEGF-directed therapy. The predictive and prognostic nature of these molecular subclassifications in the metastatic setting should be explored in an extended series.
Patient Summary:
Comprehensive genomic profiling in the course of clinical care in the community oncology setting can delineate subgroups of patients with advanced kidney cancer who stand to benefit more from specific molecular-targeted agents.
Insights
Genomic alterations in metastatic clear cell renal cell carcinoma (mccRCC) correlate with treatment response. Comprehensive genomic profiling (CGP) can identify subgroups benefiting from targeted therapies like anti-VEGF receptor (VEGFR) and anti-mTOR agents.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) therapies are standard for metastatic clear cell renal cell carcinoma (mccRCC).
- Current treatments are not guided by molecular subclassifications of ccRCC.
Purpose of the Study:
- To investigate the association between genomic alterations (GAs) and response to anti-VEGF receptor (VEGFR) and anti-mTOR therapies in mccRCC patients.
- To determine if comprehensive genomic profiling (CGP) can identify patient subgroups that benefit from targeted therapies.
Main Methods:
- CGP was performed on 31 mccRCC tissue specimens using a Clinical Laboratory Improvement Amendments-certified platform.
- Genomic alterations (base substitutions, insertions, deletions, fusions, rearrangements, copy number) were assessed.
- Duration of treatment (DOT) and clinical response were analyzed in relation to GAs.
Main Results:
- Common GAs include VHL (70%), PBRM1 (48%), SETD2 (32%), and TSC1 (29%).
- Exceptional responses to VEGFR-directed therapy were more frequent in patients with GAs in KDM5C, PBRM1, and VHL.
- Patients with GAs linked to VEGFR therapy response showed fewer GAs associated with mTOR therapy response (e.g., TSC1).
Conclusions:
- Molecular subclassifications may influence response to VEGF-directed therapy in mccRCC.
- CGP in community oncology settings can identify patient subgroups likely to benefit from specific molecular-targeted agents.
- Further studies with larger cohorts are needed to explore the predictive and prognostic value of these molecular subclassifications.
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