Urachal and Nonurachal Adenocarcinomas of the Urinary Bladder: A Comprehensive Genomic Profiling Study.

PURPOSE: Although both urachal (U) and nonurachal (NU) bladder adenocarcinomas (adenoCas) share several histologic similarities, they differ in location and sometimes in therapeutic options. We analyzed the differences in genomic alterations (GAs) between these tumor entities, with the aim of identifying potential therapeutic targets for clinical trials. MATERIALS AND METHODS: Overall, 133 U and 328 NU adenoCas were analyzed. Hybrid capture-based comprehensive genomic profiling (CGP) was performed to evaluate all classes of GA. Germline status of GA was predicted using a validated somatic-germline computational method. CGP was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc). RESULTS: The most frequent GA in both U and NU cohorts included TP53 (86.5% v 81.1%) and KRAS (34.6% v 27.7%). GAs characteristic of colorectal adenoCa, such as SMAD4 (P = .069) and GNAS (P = .071), were more common in U versus NU. Conversely, TERT (P < .01) and RB1 (P = .071) were more prevalent in NU adenoCa. Notably, both U and NU adenoCas exhibited possibly targetable GA in PIK3CA (7.5% v 7.9%) and ERBB2 (6.8% v 7.6%). Biomarkers associated with potential benefit from anti-PD-1/L1 were infrequent. Median tumor mutational burden was 2.6 and 3.5 mutations per megabase for U and NU, respectively, and PD-L1 expression >1% was rare. Genomic ancestry and genomic signature distribution were similar in both tumor types. GAs were most commonly of somatic nature. Limitations include lack of clinical data, tumor heterogeneity, and retrospective nature. CONCLUSION: U and NU adenoCAs revealed differences in GA, with PIK3CA and ERBB2 being identified as putative therapeutic targets. Biomarkers of response to anti-PD-(L)1 were uncommon. Results highlight the potential of CGP to personalize treatment options of bladder adenoCa and inform clinical trial designs.

Frequency and Nature of Genomic Alterations in ERBB2-Altered Urothelial Bladder Cancer.

BACKGROUND: Human epidermal growth factor-2 (HER2) overexpression is an oncogenic driver in many solid tumors, including urothelial bladder cancer (UBC). In addition, activating mutations in the ERBB2 gene have been shown to play an oncogenic role similar to ERBB2 amplification. OBJECTIVE: To describe and compare the frequency and nature of genomic alterations (GA) of ERBB2-altered (mutations, amplification) and ERBB2 wild-type UBC. PATIENTS AND METHODS: Using a hybrid capture-based comprehensive profiling assay, 9518 UBC cases were grouped by ERBB2 alteration and evaluated for all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genome-wide loss of heterozygosity (gLOH), and genomic mutational signature. PD-L1 expression was measured by immunohistochemistry (Dako 22C3). Categorical statistical comparisons were performed using Fisher's exact tests. RESULTS: A total of 602 (6.3%) UBC cases featured ERBB2 extracellular domain short variant (SV) GA (ECDmut+), 253 (2.7%) cases featured ERBB2 kinase domain SV GA (KDmut+), 866 (9.1%) cases had ERBB2 amplification (amp+), and 7797 (81.9%) cases were ERBB2 wild-type (wt). European genetic ancestry of ECDmut+ was higher than ERBB2wt. Numerous significant associations were observed when comparing GA by group. Notably among these, CDKN2A/MTAP loss were more frequent in ERBB2wt versus ECDmut+ and amp+. ERBB3 GA were more frequent in ECDmut+ and KDmut+ than ERBB2wt. TERT GA were more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. TOP2A amplification was significantly more common in ECDmut+ and amp+ versus ERBB2wt, and TP53 SV GA were significantly higher in ERBB2 amp+ versus ERBB2wt. Mean TMB levels were significantly higher in ECDmut+, KDmut+, and amp+ than in ERBB2wt. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBEC) signature was more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. No significant differences were observed in PD-L1 status between groups, while gLOH-high status was more common in amp+ versus ERBB2wt. MSI-high status was more frequent in KDmut+ versus ERBB2wt, and in ERBB2wt than in amp+. CONCLUSIONS: We noted important differences in co-occurring GA in ERBB2-altered (ECDmut+, KDmut+, amp+) versus ERBB2wt UBC, as well as higher mean TMB and higher APOBEC mutational signature in the ERBB2-altered groups. Our results can help refine future clinical trial designs and elucidate possible response and resistance mechanisms for ERBB2-altered UBC.

Genomic Profiles and Clinical Outcomes of Penile Squamous Cell Carcinoma With Elevated Tumor Mutational Burden.

Importance: Tumor mutational burden (TMB) is a putative biomarker of efficacy for immune checkpoint inhibitor (ICI) therapies of solid tumors, but not specifically for penile squamous cell carcinoma (PSCC). Objective: To characterize biomarker features and ICI therapy outcomes associated with high TMB in PSCC in the routine clinical practice setting. Design, Setting, and Participants: In this cohort study, 397 PSCC cases were analyzed to identify genomic alterations in more than 300 cancer-associated genes and genomic signatures, including TMB, using a hybrid capture-based comprehensive genomic profiling assay. Tumor mutational burden was categorized as low (<10 mutations per megabase [mut/Mb]), high (10-19 mut/Mb), or very high (≥20 mut/Mb). Germline status of genetic alterations was predicted using a validated somatic-germline computational method. Clinical outcomes of patients with metastatic PSCC receiving first-line ICI were abstracted using the deidentified nationwide Clinico-Genomic Database (CGDB) from January 1, 2011, through December 31, 2022. Exposure: Comprehensive genomic profiling was performed using FoundationOne and FoundationOne CDx assays from Foundation Medicine Inc. Main outcomes and measures: The spectrum of genetic alterations by TMB level in PSCC, the percentage of germline genetic alterations, and the outcome (overall survival with routine clinical treatment) by TMB of chemotherapy-naive patients with PSCC who received ICI treatment up front were assessed in this descriptive study. Results: Among 397 patients (median [IQR] age, 65 [54-73] years; 266 [67.0%] of European, 83 [20.9%] of admixed American, and 34 [8.5%] of African or other genomic ancestry), the median (IQR) age (eg, 65 [53-73] years for low TMB vs 68 [61-78] years for TMB ≥10 mut/Mb) and genomic ancestry distribution (eg, European 228 of 339 [67.3%] for low TMB vs 38 of 58 [65.5%] for TMB ≥10 mut/Mb) were similar between TMB subgroups. There were 339 PSCC cases (85.4%) with low TMB, 40 cases (10.1%) with high TMB, and 18 cases (4.5%) with very high TMB. Comparisons of TMB of 10 mut/Mb or higher vs low TMB showed an enrichment of genetic alterations in PIK3CA (48.3% vs 18.3%; P < .001) and KMT2D (29.3% vs 7.7%; P < .001) and less frequent genetic alterations in CDKN2A (25.9% vs 45.7%; P = .05). Most genetic alterations did not co-occur. Human papillomavirus identification was more frequent as TMB increased: 28.3% for low TMB, 50.0% for high, and 72.2% for very high. In total, 95 of 1377 genetic alterations (6.9%) were germline. Of 10 patients identified from the CGDB receiving frontline ICIs, median (IQR) follow-up was 9.9 months. Four patients had overall survival with clinical treatment of more than 12 months, including 2 of 3 patients with TMB of 10 mut/Mb or higher. Conclusions and Relevance: In this cohort study of advanced metastatic PSCC based on TMB levels, significant differences were observed for biomarkers in nearly 15% of patients with a TMB of 10 mut/Mb or higher. Germline testing and ICI-based therapy should be integrated into the management of selected PSCC cases.