Comprehensive genomic profiling of urothelial carcinoma of the kidney and ureter: Comparison with urothelial carcinoma of the bladder and impact on potential for targeted therapy selection.

Abstract

371 Background: Urothelial carcinoma of the upper tract (UTUC) has distinct clinical and pathologic features from UC of the bladder (UCB). We compared the comprehensive genomic profile (CGP) of UTUC with UCB. Methods: DNA was extracted from 40 microns of FFPE sections from 195 consecutive cases of relapsed/metastatic UTUC and 295 cases of UCB. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 627X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Genomic alterations (GA) included base substitutions (SUB), insertions/deletions (INDELs), copy number alterations (CNA) and fusions/rearrangements. Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: The median age of the UTUC patients was 65.7 years (range, 35-86); 74 (38%) were female and 121 (62%) were male. There were 174 (89%) kidney and 21 (11%) ureteral UTUCs assessed. In total, 51 (26%) and 138 (71%) were stage III and IV, respectively, at the time of CGP. Samples for sequencing were obtained from primary tumor in 157 (81%) cases and from metastatic sites in 38 (19%) cases. There were 1,243 total GA (6.4 GA/sample) involving 203 individual genes and 384 CRGA (1.97 CRGA/sample) involving 51 genes. The most frequent GA were non-CRGA mutations in TP53 (46%), CDKN2A (43%) and CDKN2B (36%). The most frequent CRGA were in FGFR3 (28%), PIK3CA (15%) and CCND1 (12%). In comparison with UCB, statistically equivalent CRGA in FGFR3 (28% vs 21%), PIK3CA (15% vs 20%) and total ERBB2 (11% vs 16%) were identified. Of the 14 UTUC with ERBB2 non-amplification alterations, 6 (43%) featured a micropapillary growth pattern virtually identical to the frequency in UCB (40%). Conclusions: CGP of UTUC uncovers a wide variety of CRGA that can respond to targeted therapy including frequent CRGA in FGFR3, PIK3CA and ERBB2. CRGA in UTUC are generally similar to those found in UCB. Further study of targeted therapy for genomically characterized cases in a clinical trial setting for UTUC appears warranted.