PURPOSE
To compare oncologic outcomes and genomic alteration profiles in patients with bladder and urachal adenocarcinoma, urothelial carcinoma (UC) with glandular differentiation, and UC, not otherwise specified (NOS) undergoing surgical resection, with emphasis on response to systemic therapy.
METHODS
We identified patients with bladder cancer with glandular variants who underwent surgical resection at Memorial Sloan Kettering from 1995 to 2018 (surgical cohort) and/or patients who had tumor sequencing using a targeted next-generation sequencing platform (genomics cohort). Pathologic complete and partial response rates to neoadjuvant chemotherapy (NAC) and recurrence-free and cancer-specific survival were measured. Alteration frequencies between histologic subtypes were compared.
RESULTS
Thirty-seven patients with bladder adenocarcinoma, 46 with urachal adenocarcinoma, 84 with UC with glandular differentiation, and 1,049 with UC, NOS comprised the surgical cohort. Despite more advanced disease in patients with bladder and urachal adenocarcinoma, no significant differences in recurrence or cancer-specific survival by histology were observed after adjusting for stage. In patients with UC with glandular differentiation, NAC resulted in partial (≤ pT1N0) and complete (pT0N0) responses in 28% and 17%, respectively. Bladder and urachal adenocarcinoma genomic profiles resembled colorectal adenocarcinoma with frequent TP53, KRAS, and PIK3CA alterations while the genomic profile of UC with glandular differentiation more closely resembled UC, NOS. Limitations include retrospective nature of analysis and small numbers of nonurothelial histology specimens.
CONCLUSION
The genomic profile of bladder adenocarcinomas resembled colorectal adenocarcinomas, whereas UC with glandular differentiation more closely resembled UC, NOS. Differences in outcomes among patients with glandular bladder cancer variants undergoing surgical resection were largely driven by differences in stage. Cisplatin-based NAC demonstrated activity in UC with glandular differentiation, suggesting NAC should be considered for this histologic variant.
INTRODUCTION
Although most bladder cancers arise from the urothelium with pure or predominant urothelial histology, a subset exhibits a spectrum of glandular morphologic features.1,2 Such tumors include pure adenocarcinomas or mixed histology tumors with features of both urothelial carcinoma (UC) and adenocarcinoma present (UC with glandular differentiation). Urachal adenocarcinomas are a rare subtype of bladder adenocarcinoma arising from a urachal remnant and account for an estimated 0.2%-0.3% of bladder tumors.3,4
CONTEXT
Key Objective
Glandular variants of bladder cancer are common and comprise a spectrum of tumors from urothelial carcinoma (UC) with glandular differentiation to pure adenocarcinoma of the bladder or urachus. There is no consensus on the optimal treatment for these tumors. We sought to define the clinical outcomes and genomic profiles of bladder tumors with glandular features.
Knowledge Generated
We found no significant differences in recurrence or cancer-specific survival between glandular variants and pure UC, not otherwise specified (NOS) after adjusting for stage. Bladder and urachal adenocarcinoma frequently harbor MAPK pathway alterations such as in KRAS and other genes commonly altered in colorectal cancers and lack alterations characteristic of UC, NOS. UC with glandular differentiation was genomically similar to UC, NOS, including frequent DNA damage response gene alterations.
Relevance
UC with glandular differentiation more closely resembles UC, NOS and should be managed similarly. Genomic sequencing of bladder and urachal adenocarcinoma may identify actionable alterations to guide therapy.
Most therapeutic trials in bladder cancer exclude patients with pure histologic variants, including pure adenocarcinomas as they are presumed to have distinct biologic and clinical features and, therefore, variable sensitivity to systemic therapies.5 Conflicting observations exist as to whether outcomes of patients with these rare histology tumors after surgery differ from patients with UC, not otherwise specified (NOS).6,7 Furthermore, molecular characterization efforts, such as the urothelial Cancer Genome Atlas (TCGA) project, excluded nonurothelial histology tumors,8,9 and only small series have been reported on the genomic landscape of bladder and urachal adenocarcinomas and UC with glandular differentiation.10-14
The primary objective of this study was to compare oncologic outcomes among patients undergoing surgical resection for primary adenocarcinoma of the bladder, urachal adenocarcinoma, UC with glandular differentiation, and UC, NOS. Furthermore, we sought to characterize and compare the frequency of alterations in cancer-associated genes, assess the incidence of alterations in select biomarkers predictive of therapeutic response to systemic therapy, and examine response to immune checkpoint blockade in patients with urachal or primary adenocarcinoma of the bladder. Finally, we illustrate the potential clinical utility of genomic sequencing of these rare tumor types in a patient with advanced urachal adenocarcinoma with an outlier response to targeted therapy.15
METHODS
Surgical Cohort
Under an institutional review board–approved protocol (No. 12-245), the Memorial Sloan Kettering (MSK) Cancer Center bladder cancer database was queried to identify all patients with primary adenocarcinoma of the bladder or urachal adenocarcinoma managed with partial or radical cystectomy (RC) from 1995 to 2018. Patients were classified on the basis of histology of the primary tumor site at the time of surgery with exclusion of an alternative primary site of disease required for diagnosis of primary bladder adenocarcinoma. Patients with UC with glandular differentiation without evidence of other coexisting variant histology treated with RC were also identified and comprised the UC with glandular differentiation subtype. Patients with UC, NOS treated with RC from 2005 through 2015 were identified for the UC, NOS subtype. Patients with UC, NOS with variant histology on the TURBT or RC were excluded from this cohort. Pathology was reviewed at the time of surgery by a board-certified pathologist specializing in genitourinary pathology. Analysis was restricted to patients treated through 2015 to allow enough follow-up to define recurrence-free survival (RFS) in these subtypes with greater patient numbers.
Genomic Cohort
A cohort of patients with bladder adenocarcinoma, urachal adenocarcinoma, UC with glandular differentiation, and UC, NOS were identified from our institutional database of primary bladder tumors with next-generation sequencing (NGS) using a hybridization capture-based targeted exon sequencing platform of up to 468 cancer-associated genes (MSK Integrated Mutation Profiling of Actionable Cancer Targets)16 This cohort (termed the genomic cohort) is partially overlapping with the surgical cohort. Oncogenic or likely oncogenic somatic alterations were delineated using the OncoKB knowledgebase17 or alterations identified at least 10 times in the Catalogue of Somatic Mutations in Cancer18 or cBioPortal19 databases. Variants of unknown significance that did not meet these criteria were excluded from analysis. Deleterious DNA damage response (DDR) gene alterations were defined as any ERCC2 alteration and truncating alterations (nonsense, frameshift, and splice site) in a predefined panel of DDR genes altered in UC (Data Supplement). Histology was reviewed by two board-certified genitourinary pathologists (A.T. and H.A.-A.). No microdissection of samples was performed however the area of the slide corresponding to the greatest focus of tumor was selected for sequencing. A cohort of patients with colorectal adenocarcinoma whose primary tumors underwent sequencing with MSK Integrated Mutation Profiling of Actionable Cancer Targets were identified from our institutional sequencing database for comparison of genomic profiles.
Statistical Analysis
Summary statistics were used to describe the cohorts. In the clinical cohort, the primary end point of interest was RFS, defined as time from surgery to first recurrence, death, or last scan for those who remained alive without recurrence. Patients without postoperative staging scan were omitted from this analysis because of lack of follow-up. Cancer-specific mortality was also analyzed, defined as death due to bladder cancer. Death from unknown cause and death from other cause (including death from upper tract UC) were considered competing events, and cumulative incidences of each event were calculated using competing risk analysis, considering death from other cause and death from unknown cause as competing events for death from bladder cancer. Univariable and multivariable Fine-Gray regressions on cause-specific and competing mortalities were performed for the variables selected for the primary end point analysis.
In the genomics cohort, we summarized the frequencies of alterations in all sequenced genes across histology subtypes. Genes with at least 5% alteration frequency in any of the subtypes were included in further analysis. Alteration frequencies were compared between subtypes using Fisher's exact tests, and P values were adjusted using false discovery rate correction. A Euclidean distance matrix of mutation probabilities was calculated in which closer distances (lower values) reflect increased similarity between two sample subtypes. All analyses were performed using R version 3.2.1.
RESULTS
Surgical Cohort—Baseline Characteristics and Outcomes
Thirty-seven patients with primary bladder adenocarcinoma, 46 with urachal adenocarcinoma, 84 with UC with glandular differentiation, and 889 with UC, NOS with organ-confined disease who underwent curative-intent surgical resection were identified. Clinicodemographic characteristics are presented in Table 1. Patients with primary bladder adenocarcinoma and urachal adenocarcinoma were more likely to have locally advanced disease (pT3-4; 57% and 63%, respectively) compared with patients with UC with glandular differentiation or UC, NOS (pT3-4; 47% and 23%, respectively). Among 29 patients with UC with glandular differentiation who received neoadjuvant chemotherapy (NAC), five (17%) demonstrated a complete pathologic response (pT0N0) and 8 (28%) had pathologic downstaging (≤ pT1N0), compared with 48 of 189 patients (25%) with complete pathologic response and 114 patients (60%) with pathologic downstaging (≤ pT1N0) in the UC, NOS subtype. Neoadjuvant and adjuvant therapy details for bladder adenocarcinoma and urachal adenocarcinoma patients are presented in the Data Supplement. A total of five patients with bladder adenocarcinoma were treated with NAC, one of whom demonstrated a complete pathologic response to cisplatin and fluorouracil (FU). One patient with urachal adenocarcinoma was treated with six cycles of ifosfamide, docetaxel, and cisplatin but had residual pT3 disease at cystectomy. No patient with bladder adenocarcinoma was treated with adjuvant therapy, and a total of eight patients with urachal adenocarcinoma were treated with adjuvant therapy. The small number of patients with bladder and urachal adenocarcinoma who received neoadjuvant and/or adjuvant therapy precluded statistical analysis of efficacy.
TABLE 1.
Surgical Cohort, Clinicodemographic Characteristics of Patients With Localized Disease Managed With Partial or Radical Cystectomy
An analysis of the site of recurrence stratified by histologic cohort is shown in the Data Supplement. No significant differences in visceral, brain, lung, bone or non-pelvic lymph nodes were found between the histologic subtypes. Rates of pelvic lymph node recurrence appeared higher in the bladder adenocarcinoma (50%) and the UC with glandular differentiation (50%). Furthermore, urachal carcinoma was more likely recur in the abdominal or with peritoneal carcinoma.
For the RFS analysis, 24 patients were excluded because of lack of postcystectomy imaging. All excluded patients were UC, NOS except one primary bladder adenocarcinoma and two UC with glandular differentiation. The Kaplan-Meier estimates of RFS across all four subtypes are presented in Figure 1. RFS was significantly different across histologic groups (log-rank P < .0001), with an estimated 2-year probability of survival of 81% (95% CI, 78 to 83) for UC, NOS; 64% (95% CI, 54 to 76) for UC with glandular differentiation; 63% (95% CI, 48 to 81) for primary adenocarcinoma of the bladder; and 54% (95% CI, 41 to 72) for urachal adenocarcinoma. However, in a multivariable Cox model adjusting for variables of clinical importance and univariable significance, histology was no longer significantly associated with RFS (Table 2). Similar findings were observed for cancer-specific survival (Data Supplement).
FIG 1.
RFS analysis of surgical cohort. NOS, not otherwise specified; RFS, recurrence-free survival; UC, urothelial carcinoma.
TABLE 2.
Surgical Cohort: Predictors of Disease Recurrence on Univariable and Multivariable Cox Regression Analysis (n = 1,032)
Genomic Landscape
The genomic cohort of patients with sequenced primary or metastatic tumors, including a subset of patients from the surgical cohort, comprised 13 patients with primary bladder adenocarcinoma, 29 with urachal adenocarcinoma, and 34 with UC with glandular differentiation. Baseline demographic and treatment-related characteristics are summarized in the Data Supplement. For comparison of genomic alterations, 488 patients with UC, NOS and 1,034 patients with colorectal adenocarcinoma with sequenced primary tumors were identified from our institutional database.
We compared the frequency of mutations in all sequenced genes with at least 5% mutational prevalence in any of the subtypes (Data Supplement). We focused on the differences in 22 of the most frequently altered genes in the urothelial TCGA (indicated with * in the Data Supplement and highlighted in Figs 2 and 3). We found that primary adenocarcinoma of the bladder demonstrated a high incidence of oncogenic alterations in TP53, KRAS, and PIK3CA, similar to frequencies observed in colorectal adenocarcinoma. The urachal adenocarcinoma subtype uniquely demonstrated a high frequency of SMAD4 alterations (24%), which were not observed in any primary bladder adenocarcinomas but were detected in 12% of colorectal adenocarcinomas. TERT promoter alterations were less commonly observed in primary bladder adenocarcinomas (15%) or urachal adenocarcinomas (0%), consistent with prior reports.20 Chromatin modifying was frequently altered in UC, NOS and UC with glandular features yet were rarely observed in primary bladder adenocarcinomas and urachal adenocarcinomas.
FIG 2.
Representative histopathologic sections (all stained with hematoxylin and eosin) and oncoprint demonstrating the spectrum of genomic alterations in patients with (A) bladder adenocarcinoma, (B) urachal adenocarcinoma, (C) UC with glandular differentiation, and (D) UC, NOS. NOS, not otherwise specified; UC, urothelial carcinoma.
FIG 3.
Comparisons of genomic alterations in patients with bladder adenocarcinoma, urachal adenocarcinoma, UC with glandular differentiation, UC, NOS, and colorectal adenocarcinoma. NOS, not otherwise specified; UC, urothelial carcinoma.
Euclidean distance analysis of genomic profiles indicated that primary bladder adenocarcinoma and urachal adenocarcinoma were more similar to each other (d = 0.646) than they were to UC, NOS (d = 1.035 and d = 1.123, respectively) or UC with glandular differentiation (d = 0.992 and d = 1.094, respectively). Bladder adenocarcinoma and urachal adenocarcinoma more closely resembled colorectal adenocarcinoma (d = 0.786 and d = 0.872, respectively) than the UC, NOS or UC with glandular differentiation subtypes (Data Supplement).
Alterations in DDR genes have been shown to be associated with improved outcomes in patients with muscle-invasive and advanced UC treated with platinum-based chemotherapy.21-23 Given these clinical implications, we evaluated the frequency of truncating (deleterious) alterations or germline alterations in DDR genes (Data Supplement) within each subtype. Deleterious DDR gene alterations were observed in one patient (7%) with primary adenocarcinoma of the bladder, one patient (3%) with urachal adenocarcinoma, four patients (12%) with UC with glandular differentiation, and 58 patients (12%) with UC, NOS (Data Supplement).
Response to Immune Checkpoint Blockade in Patients With Urachal or Primary Adenocarcinoma
We identified four patients with either bladder or urachal adenocarcinoma who were treated with immune checkpoint blockade. Three of the four patients were treated with multiple lines of systemic therapy (Data Supplement). The median duration of immune checkpoint inhibitor therapy was 12 months (interquartile range 6-18) and included one patient who had an ongoing response when treatment was discontinued after 6 months because of autoimmune pneumonitis. One additional patient had durable disease control and remained on therapy at last follow-up 18 months after starting therapy.
Response to MAPK-Targeted Therapy in KRAS-Altered Bladder Cancer
A 61-year-old woman underwent partial cystectomy with en bloc resection of the urachus and umbilicus and bilateral pelvic lymphadenectomy for a 3-cm urachal adenocarcinoma with enteric features, Sheldon stage IIIA (Fig 4). The patient received five cycles of adjuvant FU-based therapy. Recurrence was detected 19 months later. Tumor sequencing revealed an alteration in KRAS (Q61L), suggesting sensitivity to MAPK pathway inhibition. The MEK inhibitor trametinib was initiated as off-label treatment. The patient demonstrated stable disease on trametinib with ongoing clinical benefit for 30 months, at which time disease progression led to a change in therapy. The patient received palliative radiotherapy to pelvic metastases and was then started on nivolumab, with therapy continuing for an additional 19 months until disease progression. She ultimately succumbed to disease approximately 10 months later after receipt of additional FU-based chemotherapy.
FIG 4.
Case report of metastatic urachal adenocarcinoma with an oncogenic KRAS alteration treated with MAPK-targeted therapy. Left inset: Representative hematoxylin and eosin staining of primary tumor. Middle inset: CT at the time of disease recurrence demonstrating disease within the bladder and pelvis (outlined in red). Right inset: CT 15 months after initiating trametinib, demonstrating stable disease in the bladder and pelvis. CT, computed tomography; FU, fluorouracil; NGS, next-generation sequencing.
DISCUSSION
The spectrum of malignant glandular neoplasms of the bladder includes pure adenocarcinomas and mixed histology UCs with glandular differentiation. In the current study, we sought to characterize oncologic outcomes after surgical resection and to define the genomic profile of bladder neoplasms with glandular morphology. Although patients with a primary bladder malignant glandular neoplasm demonstrated worse RFS after surgical resection when compared with patients with UC, NOS, these differences were largely driven by the more advanced primary tumor stage at presentation. Importantly, tumor histology demonstrated no independent association with RFS or cause-specific survival after adjusting for primary tumor stage on multivariable analyses. These observations highlight the need for the development of effective perioperative therapies for this subset of patients.
With emerging evidence demonstrating an association between specific genomic alterations and response to systemic therapy in the metastatic and neoadjuvant settings, we additionally sought to define the genomic profile of bladder cancer with glandular morphologies using a targeted exon capture NGS platform. UC, NOS and UC with glandular differentiation exhibited similar genomic alteration profiles including frequent mutations in TERT, TP53, chromatin remodeling genes, and DDR pathway genes. In contrast, Euclidean distance analysis revealed that primary adenocarcinoma and urachal adenocarcinomas more closely resembled colorectal adenocarcinoma with frequent alterations in APC, SMAD4, and KRAS and an absence of TERT promoter alterations.
DDR gene alterations that are associated with pathologic response to cisplatin-based chemotherapy were rarely seen in primary bladder or urachal adenocarcinoma. Conversely, DDR alterations were observed with similar frequency in UC with glandular differentiation and UC, NOS, highlighting the genomic similarities between tumor types. The 17% complete and 28% partial pathologic response rates observed among patients with UC with glandular differentiation compare favorably with pathologic response rates in the UC, NOS subtype and with our previously published institutional series of all patients receiving NAC.24 These findings inform an existing literature of conflicting evidence on NAC efficacy in bladder cancers with variant histology.25-27 Previous studies are difficult to interpret as several histologic variants were grouped together with UC with glandular differentiation when assessing pathologic outcomes25,26 or using data from cancer registries that lack centralized, expert pathologic review.27 Our data suggest that cisplatin-based NAC should be considered in patients with muscle-invasive UC with glandular differentiation before RC.
Although no consensus exists as to the optimal systemic treatment for primary bladder and urachal adenocarcinomas, FU-based regimens are often used on the basis of histologic similarity to colorectal adenocarcinoma.28 Here, we report clinical activity of immune checkpoint inhibitors in patients with advanced bladder or urachal adenocarcinoma, with two of four patients exhibiting stable disease at the last follow-up (18 months on treatment) or at the time of treatment discontinuation from autoimmune toxicity (6 months on treatment). Trials of checkpoint blockade are currently recruiting patients with metastatic, nonurothelial histology tumors that should help to clarify the role of immunotherapy in these histologic subtypes. Furthermore, we describe an outlier response to trametinib, a selective inhibitor of MEK, in a patient with urachal adenocarcinoma whose tumor harbored an oncogenic KRAS hotspot mutation, suggesting MAPK pathway inhibition as another therapeutic option. At the time of progression, the patient was treated with checkpoint blockade and again experienced a durable response. Although this is a single patient anecdote, it is consistent with other reported cases of response to immune checkpoint blockade13 or targeted therapy in patients with actionable alterations in EGFR and GNAS.11,29
Studies assessing genomic alterations in primary adenocarcinoma of the bladder and urachal adenocarcinoma have been limited to small series because of the rarity of these tumors. Roy and colleagues used a 51-gene targeted NGS platform to evaluate genomic alterations in 15 primary bladder adenocarcinoma tumors.10 The most commonly altered genes were TP53, KRAS, PIK3CA, and CTNNB1, with alterations in APC and SMAD4 less frequently observed when compared with colorectal adenocarcinoma. Using targeted NGS, two groups have described the genomic alterations observed in urachal adenocarcinoma cohorts of 10 and 13 patients, respectively.11,13 In both studies, KRAS alterations were also observed with a similar frequency to primary bladder adenocarcinoma; however, unlike primary adenocarcinoma of the bladder, urachal adenocarcinoma demonstrated a high incidence of SMAD4 alterations similar to that seen in colorectal adenocarcinoma, suggesting the presence of aberrant transforming growth factor β signaling in these tumors.10,13 A recent study by Maurer et al reported similar findings in their cohort of bladder and urachal adenocarcinomas.30 Investigators from the University of North Carolina additionally performed RNA sequencing of a cohort of bladder adenocarcinomas and observed gene expression similarities between urachal adenocarcinomas and colorectal adenocarcinomas profiled by TCGA,13 further highlighting the molecular similarities between these tumor types that we also observed in the current study using targeted NGS.
Our study has several limitations. The surgical cohort included patients treated over a 20-year experience with variability in approach and surgeon to identify enough patients with rare histology for statistical comparisons. Additionally, our genomic analysis was restricted to a predefined set of up to 468 genes. Broader sequencing approaches such as whole-exome or -genome analysis may have resulted in the discovery of additional recurrent genomic alterations and a more complete comparison to urothelial and colorectal TCGA cohorts. Additionally, lineage plasticity driven through epigenetic reprogramming, which could contribute to variant differentiation, could not be captured in the current effort and would require integrated analyses, such as macro-dissection of mixed histology tumors or single-cell sequencing. We also sequenced a single tumor site collected at a single time point during a patient's disease, limiting our ability to delineate tumor heterogeneity. Finally, as described in the methods, there was only partial overlap of our surgical and genomics cohort. Given the rarity of these tumors, larger, multi-institutional series will be needed to validate and confirm these findings.
In summary, our study demonstrates that bladder and urachal adenocarcinomas have a genomic profile that more closely resembles colorectal adenocarcinoma compared with UC with glandular differentiation and UC, NOS. Furthermore, we found similar rates of DDR gene alterations in patients with UC with glandular differentiation compared with UC, NOS, suggesting a biologic mechanism for the observed pathologic responses within this subtype. Although limited by small numbers, we anecdotally identified patients who responded to immunotherapy and one patient with a KRAS alteration with a durable response to MAPK-targeted therapy. Taken together, these data suggest that NAC should be further studied in patients with UC with glandular differentiation and genomic sequencing should be considered in patients with adenocarcinoma to guide treatment selection.
Helen Won
Employment: Loxo
Stock and Other Ownership Interests: Lilly
Sahussapont J. Sirintrapun
Consulting or Advisory Role: Alcimed
Eugene J. Pietzak
Honoraria: UpToDate
Consulting or Advisory Role: Merck, Chugai Pharma, QED Therapeutics, Janssen, Urogen pharma
Research Funding: Janssen
Alvin C. Goh
Consulting or Advisory Role: Medtronic
Travel, Accommodations, Expenses: Medtronic
Bernard H. Bochner
Consulting or Advisory Role: Olympus
Min Yuen Teo
Consulting or Advisory Role: Janssen Oncology
Research Funding: Bristol Myers Squibb (Inst), Clovis Oncology (Inst), Pharmacyclics (Inst)
Samuel A. Funt
Employment: ByHeart (I)
Stock and Other Ownership Interests: Kite, a Gilead Company, Urogen Pharma, Allogene Therapeutics, Neogene Therapeutics, Kronos Bio, Vida Ventures, IconOVir Bio, Doximity
Consulting or Advisory Role: Merck, Immunai
Research Funding: Genentech/Roche (Inst), AstraZeneca (Inst), Decibel Therapeutics (Inst)
Travel, Accommodations, Expenses: Bristol Myers Squibb, AstraZeneca/MedImmune
Jonathan E. Rosenberg
Honoraria: UpToDate, Medscape, Peerview, Research To Practice, Intellisphere, Clinical Care Options, Physicans' Education Resource, MJH Life Sciences, EMD Serono
Consulting or Advisory Role: Lilly, Merck, Roche/Genentech, AstraZeneca/MedImmune, Bristol Myers Squibb, Seattle Genetics, Bayer, BioClin Therapeutics, QED Therapeutics, Pharmacyclics, GlaxoSmithKline, Janssen Oncology, Astellas Pharma, Boehringer Ingelheim, Pfizer/EMD Serono, Mirati Therapeutics, Immunomedics, Tyra Biosciences, Infinity Pharmaceuticals, Gilead Sciences, Hengrui Pharmaceutical, Alligator Bioscience
Research Funding: Genentech/Roche (Inst), Seattle Genetics (Inst), Bayer (Inst), AstraZeneca (Inst), QED Therapeutics (Inst), Astellas Pharma (Inst)
Patents, Royalties, Other Intellectual Property: Predictor of platinum sensitivity (Inst)
Victor E. Reuter
Consulting or Advisory Role: Cepheid
Uncompensated Relationships: Paige.AI
Dean F. Bajorin
Consulting or Advisory Role: Merck, Dragonfly Therapeutics, Fidia Farmaceutici S. p. A, Bristol Myers Squibb Foundation
Research Funding: Novartis (Inst), Merck (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst), Astellas Pharma (Inst), Seattle Genetics/Astellas (Inst)
Travel, Accommodations, Expenses: Merck
David B. Solit
Stock and Other Ownership Interests: Scorpion Therapeutics, Vividion Therapeutics, Fore Biotherapeutics
Consulting or Advisory Role: Pfizer, Lilly, BridgeBio Pharma, Scorpion Therapeutics, Vividion Therapeutics, Syros Pharmaceuticals
Hikmat Al-Ahmadie
Consulting or Advisory Role: Bristol Myers Squibb, EMD Serono, AstraZeneca/MedImmune, Janssen Biotech, Paige.AI
Gopa Iyer
Consulting or Advisory Role: Bayer, Janssen, Mirati Therapeutics, Basilea, Flare Therapeutics, Loxo/Lilly
Speakers' Bureau: Gilead Sciences, Lynx Group
Research Funding: Mirati Therapeutics (Inst), Novartis (Inst), Debiopharm Group (Inst), Bayer (Inst), Janssen (Inst), Seattle Genetics (Inst)
No other potential conflicts of interest were reported.
SUPPORT
Supported by Cycle for Survival (H.A.-A., D.B.S.), an MSK Society grant (G.I.), the Albert Institute for Bladder Cancer Care and Research, an ASCO Young Investigator Award (E.J.J.), Parker Institute for Cancer Immunotherapy, R01 CA233899, P01CA221757, SPORE in Bladder Cancer P50CA221745, a Sloan Kettering Institute for Cancer Research Cancer Center Support Grant No. (P30CA008748), and the Marie-Josée and Henry R Kravis Center for Molecular Oncology.
N.A., K.W., A.T., and A.T.L. contributed equally to this work. H.A.A. and G.I. contributed equally as senior authors to this work.
AUTHOR CONTRIBUTIONS
Conception and design: Nima Almassi, Karissa Whiting, Timothy F. Donahue, Jonathan E. Rosenberg, David B. Solit, Hikmat Al-Ahmadie, Gopa Iyer
Financial support: David B. Solit, Gopa Iyer
Administrative support: Ashley M. Regazzi, Timothy F. Donahue, S. Machele Donat, David B. Solit, Gopa Iyer
Provision of study materials or patients: Ying-Bei Chen, Alvin C. Goh, Harry W. Herr, S. Machele Donat, Guido Dalbagni, Min Yuen Teo, Jonathan E. Rosenberg, Victor E. Reuter, David B. Solit, Gopa Iyer
Collection and assembly of data: Nima Almassi, Karissa Whiting, Antoun Toubaji, Andrew T. Lenis, Emmet J. Jordan, Ashley M. Regazzi, Ying-Bei Chen, Samson W. Fine, Satish K. Tickoo, Eugene J. Pietzak, Eugene K. Cha, Timothy F. Donahue, Harry W. Herr, Samuel A. Funt, Jonathan E. Rosenberg, Victor E. Reuter, David B. Solit, Gopa Iyer
Data analysis and interpretation: Nima Almassi, Karissa Whiting, Andrew T. Lenis, Helen Won, Anuradha Gopalan, Sahussapont J. Sirintrapun, Satish K. Tickoo, Irina Ostrovnaya, Eugene J. Pietzak, Alvin C. Goh, Timothy F. Donahue, S. Machele Donat, Guido Dalbagni, Bernard H. Bochner, Min Yuen Teo, Samuel A. Funt, Jonathan E. Rosenberg, Victor E. Reuter, Dean F. Bajorin, David B. Solit, Hikmat Al-Ahmadie, Gopa Iyer
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Helen Won
Employment: Loxo
Stock and Other Ownership Interests: Lilly
Sahussapont J. Sirintrapun
Consulting or Advisory Role: Alcimed
Eugene J. Pietzak
Honoraria: UpToDate
Consulting or Advisory Role: Merck, Chugai Pharma, QED Therapeutics, Janssen, Urogen pharma
Research Funding: Janssen
Alvin C. Goh
Consulting or Advisory Role: Medtronic
Travel, Accommodations, Expenses: Medtronic
Bernard H. Bochner
Consulting or Advisory Role: Olympus
Min Yuen Teo
Consulting or Advisory Role: Janssen Oncology
Research Funding: Bristol Myers Squibb (Inst), Clovis Oncology (Inst), Pharmacyclics (Inst)
Samuel A. Funt
Employment: ByHeart (I)
Stock and Other Ownership Interests: Kite, a Gilead Company, Urogen Pharma, Allogene Therapeutics, Neogene Therapeutics, Kronos Bio, Vida Ventures, IconOVir Bio, Doximity
Consulting or Advisory Role: Merck, Immunai
Research Funding: Genentech/Roche (Inst), AstraZeneca (Inst), Decibel Therapeutics (Inst)
Travel, Accommodations, Expenses: Bristol Myers Squibb, AstraZeneca/MedImmune
Jonathan E. Rosenberg
Honoraria: UpToDate, Medscape, Peerview, Research To Practice, Intellisphere, Clinical Care Options, Physicans' Education Resource, MJH Life Sciences, EMD Serono
Consulting or Advisory Role: Lilly, Merck, Roche/Genentech, AstraZeneca/MedImmune, Bristol Myers Squibb, Seattle Genetics, Bayer, BioClin Therapeutics, QED Therapeutics, Pharmacyclics, GlaxoSmithKline, Janssen Oncology, Astellas Pharma, Boehringer Ingelheim, Pfizer/EMD Serono, Mirati Therapeutics, Immunomedics, Tyra Biosciences, Infinity Pharmaceuticals, Gilead Sciences, Hengrui Pharmaceutical, Alligator Bioscience
Research Funding: Genentech/Roche (Inst), Seattle Genetics (Inst), Bayer (Inst), AstraZeneca (Inst), QED Therapeutics (Inst), Astellas Pharma (Inst)
Patents, Royalties, Other Intellectual Property: Predictor of platinum sensitivity (Inst)
Victor E. Reuter
Consulting or Advisory Role: Cepheid
Uncompensated Relationships: Paige.AI
Dean F. Bajorin
Consulting or Advisory Role: Merck, Dragonfly Therapeutics, Fidia Farmaceutici S. p. A, Bristol Myers Squibb Foundation
Research Funding: Novartis (Inst), Merck (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst), Astellas Pharma (Inst), Seattle Genetics/Astellas (Inst)
Travel, Accommodations, Expenses: Merck
David B. Solit
Stock and Other Ownership Interests: Scorpion Therapeutics, Vividion Therapeutics, Fore Biotherapeutics
Consulting or Advisory Role: Pfizer, Lilly, BridgeBio Pharma, Scorpion Therapeutics, Vividion Therapeutics, Syros Pharmaceuticals
Hikmat Al-Ahmadie
Consulting or Advisory Role: Bristol Myers Squibb, EMD Serono, AstraZeneca/MedImmune, Janssen Biotech, Paige.AI
Gopa Iyer
Consulting or Advisory Role: Bayer, Janssen, Mirati Therapeutics, Basilea, Flare Therapeutics, Loxo/Lilly
Speakers' Bureau: Gilead Sciences, Lynx Group
Research Funding: Mirati Therapeutics (Inst), Novartis (Inst), Debiopharm Group (Inst), Bayer (Inst), Janssen (Inst), Seattle Genetics (Inst)
No other potential conflicts of interest were reported.
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