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Comprehensive Genomic Profiling of Metastatic Tumors in a Phase 2 Biomarker Study of Everolimus in Advanced Renal Cell Carcinoma.
- Source :
-
Clinical genitourinary cancer [Clin Genitourin Cancer] 2018 Oct; Vol. 16 (5), pp. 341-348. Date of Electronic Publication: 2018 Apr 25. - Publication Year :
- 2018
-
Abstract
- Introduction: Genomic events leading to activation of mechanistic target of rapamycin (mTOR) are common in renal cell carcinoma (RCC). Everolimus is an allosteric mTOR inhibitor with efficacy in metastatic RCC. We characterized the genomic profile of RCC tumors from metastatic sites and assessed whether particular alterations correlate with clinical response to everolimus.<br />Patients and Methods: An open-label, single-arm phase 2 biomarker study of everolimus 10 mg daily was conducted in metastatic RCC patients. Needle biopsy or metastasectomy was performed on metastatic tumors before everolimus initiation. Next-generation sequencing was performed using a targeted hybrid capture panel detecting alterations within exons and key introns of ≥ 300 cancer-associated genes. Disease assessments were obtained every 8 weeks using standard radiographic modalities and evaluated by Response Evaluation Criteria in Solid Tumors criteria.<br />Results: Objective response was seen in 1 (4.2%) of 24 patients. Two patients (8.3%) had stable disease lasting > 6 months. Median (90% confidence interval) overall and progression-free survival were 20.1 (8.6, NA) and 3.8 (2.4, 5.4) months, respectively. Next-generation sequencing was successful on 18 pretreatment specimens and 3 on-treatment specimens. Alterations in the phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway were identified in 8 (44%) of 18 pretreatment samples. An mTOR E2419D mutation was identified in the patient who experienced partial response. Alterations in VHL, PBRM1, SETD2, KDM5C, and ATM were common in the RCC metastases before initiation of everolimus.<br />Conclusion: Nearly half of heavily pretreated RCC metastases may harbor mutations in components of the PI3K-AKT-mTOR pathway. Commonly mutated genes in primary RCC were also altered at a high frequency in RCC metastases.<br /> (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Subjects :
- Aged
Aged, 80 and over
Biopsy, Needle
Carcinoma, Renal Cell genetics
Everolimus therapeutic use
Female
High-Throughput Nucleotide Sequencing methods
Humans
Kidney Neoplasms genetics
Male
Middle Aged
Mutation
Neoplasm Metastasis genetics
Signal Transduction
Carcinoma, Renal Cell drug therapy
Everolimus administration & dosage
Kidney Neoplasms drug therapy
Neoplasm Metastasis pathology
Sequence Analysis, DNA methods
Subjects
Details
- Language :
- English
- ISSN :
- 1938-0682
- Volume :
- 16
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Clinical genitourinary cancer
- Publication Type :
- Academic Journal
- Accession number :
- 29754934
- Full Text :
- https://doi.org/10.1016/j.clgc.2018.04.001