Abstract
Real world genomics in metastatic urothelial carcinoma (mUC).
Author
Sulin Wu
University Hospitals Seidman Cancer Center, Department of Internal Medicine, Department of Medical Genetics, Cleveland, OH
info_outline
Sulin Wu, Ravi Kumar Kyasaram, Chen-Han Wilfred Wu, Pingfu Fu, Seunghee P. Margevicius, Jorge A. Garcia, Pedro C. Barata, Prateek Mendiratta, Jason R Brown
Full text
Authors
Sulin Wu
University Hospitals Seidman Cancer Center, Department of Internal Medicine, Department of Medical Genetics, Cleveland, OH
info_outline
Sulin Wu, Ravi Kumar Kyasaram, Chen-Han Wilfred Wu, Pingfu Fu, Seunghee P. Margevicius, Jorge A. Garcia, Pedro C. Barata, Prateek Mendiratta, Jason R Brown
Organizations
University Hospitals Seidman Cancer Center, Department of Internal Medicine, Department of Medical Genetics, Cleveland, OH, University Hospitals Seidman Cancer Center, Cancer Informatics, Cleveland, OH, Department of Genetics and Genomic Sciences, Department of Urology, Case Western Reserve University, University Hospitals, and Case Comprehensive Cancer Center, Cleveland, OH, Case Western Reserve University School of Medicine, Cleveland, OH, University Hospitals Seidman Cancer Center, Cleveland, OH, Seidman Cancer Center, Cleveland, OH
Abstract Disclosures
Research Funding
No funding received
None.
Background:
Next generation sequencing (NGS) has therapeutic value in mUC. Beyond FGFR3 alteration and tumor mutational burden, genetic testing can identify novel predictive and prognostic biomarkers. In clinical practice, variability is introduced between assays due to genomic coverage, sequencing depth, timing, and tissue used.
Methods:
A single-institution retrospective database of patients (pts) diagnosed with mUC between 2013 and 2022 was generated. Clinicopathologic features and NGS results, including mutations, fusions, and copy number alterations, were abstracted from pt records. Progression free survival was calculated from start of first-line (1L) treatment (PFSFLT) and of 1L/maintenance/2L immunotherapy (PFSIO) to date of disease progression or death, censored at last follow up for pts alive without progression. Overall survival (OS) was calculated from diagnosis date of mUC to the date of death or censored at last follow up. Association between two categorical factors was estimated by chi-square test. Time-to-event data were analyzed by Kaplan-Meier method with log-rank test and Cox model.
Results:
251 records were reviewed, of which 79 unique mUC pts with somatic NGS testing were identified. Pts were predominantly male (70.9%), white (86.1%), past/present smokers (65.8%), with bladder primary site (78.5%) and urothelial histology (72.2%). NGS was performed on 37 (46.8%) primary and 42 (53.2%) metastatic specimens, including 57 solid tumor (72.2%), 12 liquid biopsy (15.2%), and 10 (12.7%) with both. NGS was performed prior to or during 1L treatment for 61 pts (77.2%) and later for 18 pts (22.8%). Median TMB, where measured (n = 43), was 9 mut/Mb (2-40). The most prevalent genes with pathogenic variants identified were
TP53
(37, 46.8%),
TERT
(32, 40.5%),
PIK3CA
(22, 27.8%),
FGFR3
(18, 22.8%),
ARID1A
(16, 20.3%),
CDKN2A/B
(13, 16.5%) and
ERBB2
(13, 16.5%). Several
TP53
(45) and
ARID1A
variants (19) were observed, and fewer
TERT
(3) and
FGFR3
(6) variants were seen. Among prevalent mutant genes,
TP53
and
TERT
were most commonly concordant (68.4%, p = 0.0068).
TERT
was significantly co-mutated with
ARID1A
(64.6% concordant, p = 0.00479) and exclusive with mutant
PIK3CA
(41.8% concordant, p = 0.012).
ERBB2
and
FGFR3
alterations were mutually exclusive.
ERBB2
alterations significantly correlated with lack of metastasis to lung, liver, or bone (p = 0.00355), though no genes predicted metastasis to those sites.
ERBB2
alterations also correlated with improved PFSIO (HR 0.3, 95% CI 0.09-0.99, p = 0.049), but not with PFSFLT.
FGFR3
mutation is associated with inferior OS (HR 1.88., 95% CI: 1.03 – 3.43, p = 0.04), especially for male pts (HR 2.85, 95% CI: 1.26-6.51, p = 0.013).
Conclusions:
A diverse array of NGS testing was performed on mUC pts, collected at varying timepoints. Despite inherent heterogeneity, these results yielded prognostic and predictive information for
ERBB2
and
FGFR3
alterations to be further studied in larger cohorts.
11 organizations
2 drugs
2 targets
Organization
University Hospitals Seidman Cancer CenterOrganization
Department of Medical GeneticsOrganization
Cleveland, OHOrganization
Cancer InformaticsOrganization
Department of Genetics and Genomic SciencesOrganization
University Hospitals Sussex NHS Foundation TrustOrganization
Case Comprehensive Cancer CenterOrganization
Seidman Cancer CenterDrug
ERBB2Drug
FGFR3Target
FGFR3Target
ERBB2