Next-Generation Sequencing and In Silico Analysis Facilitate Prolonged Response to Pazopanib in a Patient With Metastatic Urothelial Carcinoma of the Renal Pelvis.
With the advent of widespread tumor genetic profiling, an increased number of mutations with unknown significance are being identified. Often, a glut of uninterpretable findings may confuse the clinician and provide little or inappropriate guidance in therapeutic decision-making. This report describes a method of protein modeling by in silico analysis (ie, using computer simulation) that is easily accessible to the practicing clinician without need for further laboratory analysis, which can potentially serve as a guide in therapeutic decisions based on poorly characterized tumor mutations. An example of this model is given wherein poorly characterized KIT, PDGFRB, and ERBB2 mutations were discovered in a patient with treatment-refractory metastatic transitional cell carcinoma of the renal pelvis. The KIT and PDGFRB mutations were predicted to be pathogenic using in silico analysis, whereas the ERBB2 mutation was predicted to be benign. Based on these findings, the patient was treated with pazopanib and achieved a partial response that lasted for 7.5 months. We propose that in silico analysis be explored as a potential means to further characterize genetic abnormalities found by tumor profiling assays, such as next-generation sequencing.
From the Department of Internal Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee; Department of Internal Medicine, Washington University in St. Louis, St. Louis, Missouri; and Department of Hematology/Oncology, The West Cancer Center, Memphis, Tennessee.
Andrew W
AW
Hahn
From the Department of Internal Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee; Department of Internal Medicine, Washington University in St. Louis, St. Louis, Missouri; and Department of Hematology/Oncology, The West Cancer Center, Memphis, Tennessee.
Smith
S
Giri
From the Department of Internal Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee; Department of Internal Medicine, Washington University in St. Louis, St. Louis, Missouri; and Department of Hematology/Oncology, The West Cancer Center, Memphis, Tennessee.
Dilan
D
Patel
From the Department of Internal Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee; Department of Internal Medicine, Washington University in St. Louis, St. Louis, Missouri; and Department of Hematology/Oncology, The West Cancer Center, Memphis, Tennessee.
Heather
H
Sluder
From the Department of Internal Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee; Department of Internal Medicine, Washington University in St. Louis, St. Louis, Missouri; and Department of Hematology/Oncology, The West Cancer Center, Memphis, Tennessee. From the Department of Internal Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee; Department of Internal Medicine, Washington University in St. Louis, St. Louis, Missouri; and Department of Hematology/Oncology, The West Cancer Center, Memphis, Tennessee.
Ari
A
Vanderwalde
From the Department of Internal Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee; Department of Internal Medicine, Washington University in St. Louis, St. Louis, Missouri; and Department of Hematology/Oncology, The West Cancer Center, Memphis, Tennessee. From the Department of Internal Medicine, The University of Tennessee Health Science Center, Memphis, Tennessee; Department of Internal Medicine, Washington University in St. Louis, St. Louis, Missouri; and Department of Hematology/Oncology, The West Cancer Center, Memphis, Tennessee.
Mike G
MG
Martin
D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D003198:Computer Simulation; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007191:Indazoles; D007682:Kidney Pelvis / Q000187:drug effects / Q000473:pathology; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D009362:Neoplasm Metastasis; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000235:genetics*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000737:chemistry / Q000235:genetics*; D013449:Sulfonamides / Q000627:therapeutic use; D019459:Urothelium / Q000187:drug effects / Q000473:pathology
D007191:Indazoles; D019009:Proto-Oncogene Proteins c-kit; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D013449:Sulfonamides; C516667:pazopanib; C508053:ERBB2 protein, human; C000605860:PDGFRB protein, human