Urothelial carcinoma of the renal pelvis (UCRP) and the ureter is a rare disease, representing 5% of all urothelial malignancies. The incidence of UCRP in the general US population is estimated to be 1.15 per 100,000 person-years.1 Although radical nephroureterectomy is the therapy of choice for nonmetastatic UCRP, the rate of tumor recurrence is still high. For metastatic UCRP (mUCRP), cisplatin-based chemotherapies are often used as first-line agents with limited response, largely based on experience from urothelial tumors of the bladder.2 However, second-line chemotherapies for urothelial malignancies have significantly lower response rates and no significant survival benefit over supportive care.2
Whole-genome studies of metastatic urothelial cancer have shown profound genomic heterogeneity at the nucleotide and chromosomal levels.3,4 Furthermore, the mutation profiles of histologically similar tumors may vary widely, explaining the variable response to chemotherapy observed in small clinical trials.5 The availability of next-generation sequencing (NGS) has made it feasible for clinicians to analyze genetic profiles of an individual's cancer. When these results are coupled with the continual development of targeted therapies, personalized medicine is possible. However, interpretation of the numerous genetic variants that NGS provides and selection of an appropriate targeted therapy presents a novel challenge to clinicians. This report documents the successful use of NGS coupled with in silico analysis to select a targeted therapy, pazopanib, from numerous potential mutations in a patient with heavily pretreated mUCRP.
The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.
Author Contributions: MGM treated the patient and performed in silico analysis; MGM, AWH, and SG wrote the initial manuscript; MGM, AWH, DP, AV, HS, and SG completed all revisions.
RamanJDMesserJSielatyckiJAHollenbeakCS. Incidence and survival of patients with carcinoma of the ureter and renal pelvis in the USA, 1973-2005. BJU Int2011;107:1059–1064.
GallagherDJMilowskyMIBajorinDF. Advanced bladder cancer: status of first-line chemotherapy and the search for active agents in the second-line setting. Cancer2008;113:1284–1293.
MorrisonCDLiuPWoloszynska-ReadA. Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer. Proc Natl Acad Sci U S A2014;111:E672–681.
RossJSWangKAl-RohilRN. Advanced urothelial carcinoma: next-generation sequencing reveals diverse genomic alterations and targets of therapy. Mod Pathol2014;27:271–280.
WallaceMDPfefferleADShenL. Comparative oncogenomics implicates the neurofibromin 1 gene (NF1) as a breast cancer driver. Genetics2012;192:385–396.
GanjooKNVillalobosVMKamayaA. A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib. Ann Oncol2014;25:236–240.
KwakCLeeSEJeongIGKuJH. Adjuvant systemic chemotherapy in the treatment of patients with invasive transitional cell carcinoma of the upper urinary tract. Urology2006;68:53–57.
DasanuCAOng-BacayACodreanuI. Newer developments in the therapeutics of the transitional cell carcinoma of renal pelvis. J Oncol Pharm Pract2012;18:97–103.
SternbergCNYagodaAScherHI. Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse. Cancer1989;64:2448–2458.
RossJSWangKGayL. Comprehensive genomic profiling of carcinoma of unknown primary site: new routes to targeted therapies. JAMA Oncol2015;1:40–49.
BaoRHuangLAndradeJ. Review of current methods, applications, and data management for the bioinformatics analysis of whole exome sequencing. Cancer Inform2014;13(Suppl 2):67–82.
YadavSSLiJLaveryHJ. Next-generation sequencing technology in prostate cancer diagnosis, prognosis, and personalized treatment. Urol Oncol2015;33:267.e1–13.
Precipio DiagnosticsSmartGen. Available at: http://www.precipiodx.com/Smartgen.html#sthash.u6OFvI6n.dpbs. Accessed September 9 2015.
TavtigianSVGreenblattMSLesueurFByrnesGB. In silico analysis of missense substitutions using sequence-alignment based methods. Hum Mutat2008;29:1327–1336.
ChanPADuraisamySMillerPJ. Interpreting missense variants: comparing computational methods in human disease genes CDKN2A, MLH1, MSH2, MECP2, and tyrosinase (TYR). Human Mutat2007;28:683–693.
ChaoECVelasquezJLWitherspoonMS. Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). Human Mutat2008;29:852–860.
SternbergCNDavisIDMardiakJ. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol2010;28:1061–1068.
PiliRQinRFlynnPJ. A phase II safety and efficacy study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor pazopanib in patients with metastatic urothelial cancer. Clin Genitourin Cancer2013;11:477–483.
NecchiAMarianiLZaffaroniN. Pazopanib in advanced and platinum-resistant urothelial cancer: an open-label, single group, phase 2 trial. Lancet Oncol2012;13:810–816.
GerullisHEimerCEckeTH. Combined treatment with pazopanib and vinflunine in patients with advanced urothelial carcinoma refractory after first-line therapy. Anticancer Drugs2013;24:422–425.
GallagherDJMilowskyMIGerstSR. Phase II study of sunitinib in patients with metastatic urothelial cancer. J Clin Oncol2010;28:1373–1379.
PowlesTEderJPFineGD. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature2014;515:558–562.