title: Whole-Exome Sequencing in Two Extreme Phenotypes of Response to VEGF-Targeted Therapies in Patients With Metastatic Clear Cell Renal Cell Carcinoma.
abstract: Advances in next-generation sequencing have provided a unique opportunity to understand the biology of disease and mechanisms of sensitivity or resistance to specific agents. Renal cell carcinoma (RCC) is a heterogeneous disease and highly variable clinical responses have been observed with vascular endothelial growth factor (VEGF)-targeted therapy (VEGF-TT). We hypothesized that whole-exome sequencing analysis might identify genotypes associated with extreme response or resistance to VEGF-TT in metastatic (mRCC). Patients with mRCC who had received first-line sunitinib or pazopanib and were in 2 extreme phenotypes of response were identified. Extreme responders (ERs) were defined as those with partial response or complete response for 3 or more years (n=13) and primary refractory patients (PRPs) were defined as those with progressive disease within the first 3 months of therapy (n=14). International Metastatic RCC Database Consortium prognostic scores were not significantly different between the groups (P=.67). Considering the genes known to be mutated in RCC at significant frequency, PBRM1 mutations were identified in 7 ERs (54%) versus 1 PRP (7%) (P=.01). In addition, mutations in TP53 (n=4) were found only in PRPs (P=.09). Our data suggest that mutations in some genes in RCC may impact response to VEGF-TT.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
authors.forename: Andre P
authors.initials: AP
authors.lastname: Fay
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
authors.forename: Guillermo
authors.initials: G
authors.lastname: de Velasco
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
authors.forename: Thai H
authors.initials: TH
authors.lastname: Ho
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts|Broad Institute of MIT and Harvard, Cambridge, Boston, Massachusetts
authors.forename: Eliezer M
authors.initials: EM
authors.lastname: Van Allen
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Boston, Massachusetts
authors.forename: Bradley
authors.initials: B
authors.lastname: Murray
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
authors.forename: Laurence
authors.initials: L
authors.lastname: Albiges
authors.affiliation: Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
authors.forename: A Ari
authors.initials: AA
authors.lastname: Hakimi
authors.affiliation: Department of Laboratory Medicine/Pathology, Mayo Clinic, Scottsdale, Arizona
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Stanton
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bellmunt
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts|Department of Medical Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts|Broad Institute of MIT and Harvard, Cambridge, Boston, Massachusetts
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
mesh_terms: D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D042461:Vascular Endothelial Growth Factor A