Neeraj Agarwal1, Sumanta K Pal2, Andrew W Hahn1, Roberto H Nussenzveig1, Gregory R Pond3, Sumati V Gupta1, Jue Wang4, Mehmet A Bilen5, Gurudatta Naik6, Pooja Ghatalia7, Christopher J Hoimes8, Dharmesh Gopalakrishnan9, Pedro C Barata10, Alexandra Drakaki11, Bishoy M Faltas12, Lesli A Kiedrowski13, Richard B Lanman13, Rebecca J Nagy13, Nicholas J Vogelzang14, Kenneth M Boucher15, Ulka N Vaishampayan16, Guru Sonpavde17, Petros Grivas10. 1. Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah. 2. Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California. 3. Department of Oncology, McMaster University, Hamilton, Ontario, Canada. 4. Genitourinary Oncology Section, University of Arizona Cancer Center at Dignity Health, St. Joseph's Hospital and Medical Center, Phoenix, Arizona. 5. Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia. 6. Department of Oncology, University of Alabama at Birmingham, Birmingham, Alabama. 7. Department of Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania. 8. Division of Hematology/Oncology, Case Western Reserve University, Seidman Cancer Center, Cleveland, Ohio. 9. Department of Hospital Medicine, Cleveland Clinic, Cleveland, Ohio. 10. Division of Oncology, Department of Medicine, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, Washington. 11. Department of Hematology/Oncology, University of California at Los Angeles Medical Center, Los Angeles, California. 12. Department of Medical Oncology, Weill-Cornell Medical College, New York City, New York. 13. Guardant Health Inc, Redwood, California. 14. Department of Oncology, Comprehensive Cancer Centers of Nevada, Las Vegas, Nevada. 15. Division of Biostatistics, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah. 16. Department of Oncology, Karmanos Cancer Institute, Detroit, Michigan. 17. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Abstract
BACKGROUND: Biomarker-guided clinical trials are increasingly common in metastatic urothelial carcinoma (mUC), yet patients for whom contemporary tumor tissue is not available are not eligible. Technological advancements in sequencing have made cell-free circulating DNA (cfDNA) next-generation sequencing (NGS) readily available in the clinic. The objective of the current study was to determine whether the genomic profile of mUC detected by NGS of cfDNA is similar to historical tumor tissue NGS studies. A secondary objective was to determine whether the frequency of genomic alterations (GAs) differed between lower tract mUC (mLTUC) and upper tract mUC (mUTUC). METHODS: Patients from 13 academic medical centers in the United States who had a diagnosis of mUC between 2014 and 2017 and for whom cfDNA NGS results were available were included. cfDNA profiling was performed using a commercially available platform (Guardant360) targeting 73 genes. RESULTS: Of 369 patients with mUC, 294 were diagnosed with mLTUC and 75 with mUTUC. A total of 2130 GAs were identified in the overall mUC cohort: 1610 and 520, respectively, in the mLTUC and mUTUC cohorts. In the mLTUC cohort, frequently observed GAs were similar between cfDNA NGS and historical tumor tissue studies, including tumor protein p53 (TP53) (P = 1.000 and .115, respectively), AT-rich interaction domain 1A (ARID1A) (P = .058 and .058, respectively), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (P = .058 and .067, respectively), erb-b2 receptor tyrosine kinase 2 (ERBB2) (P = .565 and .074, respectively), and fibroblast growth factor receptor 3 (FGFR3) (P = .164 and .014, respectively). No significant difference was observed with regard to the frequency of GAs between patients with mLTUC and mUTUC. CONCLUSIONS: Among patients with mUC for whom no tumor tissue was available, cfDNA NGS was able to identify a similar profile of GAs for biomarker-driven clinical trials compared with tumor tissue. Despite the more aggressive clinical course, cases of mUTUC demonstrated a circulating tumor DNA genomic landscape that was similar to that of mLTUC. Cancer 2018;124:2115-24.
BACKGROUND: Biomarker-guided clinical trials are increasingly common in metastatic urothelial carcinoma (mUC), yet patients for whom contemporary tumor tissue is not available are not eligible. Technological advancements in sequencing have made cell-free circulating DNA (cfDNA) next-generation sequencing (NGS) readily available in the clinic. The objective of the current study was to determine whether the genomic profile of mUC detected by NGS of cfDNA is similar to historical tumor tissue NGS studies. A secondary objective was to determine whether the frequency of genomic alterations (GAs) differed between lower tract mUC (mLTUC) and upper tract mUC (mUTUC). METHODS:Patients from 13 academic medical centers in the United States who had a diagnosis of mUC between 2014 and 2017 and for whom cfDNA NGS results were available were included. cfDNA profiling was performed using a commercially available platform (Guardant360) targeting 73 genes. RESULTS: Of 369 patients with mUC, 294 were diagnosed with mLTUC and 75 with mUTUC. A total of 2130 GAs were identified in the overall mUC cohort: 1610 and 520, respectively, in the mLTUC and mUTUC cohorts. In the mLTUC cohort, frequently observed GAs were similar between cfDNA NGS and historical tumor tissue studies, including tumor protein p53 (TP53) (P = 1.000 and .115, respectively), AT-rich interaction domain 1A (ARID1A) (P = .058 and .058, respectively), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (P = .058 and .067, respectively), erb-b2 receptor tyrosine kinase 2 (ERBB2) (P = .565 and .074, respectively), and fibroblast growth factor receptor 3 (FGFR3) (P = .164 and .014, respectively). No significant difference was observed with regard to the frequency of GAs between patients with mLTUC and mUTUC. CONCLUSIONS: Among patients with mUC for whom no tumor tissue was available, cfDNA NGS was able to identify a similar profile of GAs for biomarker-driven clinical trials compared with tumor tissue. Despite the more aggressive clinical course, cases of mUTUC demonstrated a circulating tumor DNA genomic landscape that was similar to that of mLTUC. Cancer 2018;124:2115-24.
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