14 results on '"Kevin Lundgren"'
Search Results
2. Data from Mutational Analysis of 472 Urothelial Carcinoma Across Grades and Anatomic Sites
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David J. Kwiatkowski, Guru Sonpavde, Toni K. Choueiri, Kent W. Mouw, Joaquim Bellmunt, Fei Dong, Mark Preston, Eliezer M. Van Allen, Lauren Harshman, Kevin Lundgren, Jaegil Kim, Renato Umeton, and Amin H. Nassar
- Abstract
Purpose:The purpose of this study is to characterize the mutational landscape across the spectrum of urothelial carcinoma (UC) to identify mutational features and potential therapeutic targets.Experimental Design:Using targeted exome sequencing (n = 237 genes), we analyzed the mutation spectra of 82 low-grade nonmuscle-invasive bladder cancers (LG-NMIBC), 126 high-grade (HG) NMIBC, 199 muscle-invasive bladder cancers (MIBC), 10 LG-upper tract urothelial cancers (LG-UTUC), and 55 HG-UTUC.Results:FGFR3 and KDM6A mutations were significantly more common in LG-NMIBC (72% and 44%, respectively) versus other bladder subtypes. FGFR3 alterations were also enriched in LG-UTUC versus HG-UTUC tumors (80% vs. 16%). In contrast, TP53 and RB1 mutations were significantly more frequent in all 3 HG urothelial carcinoma subtypes than in LG-NIMBC (45%–58% vs. 4%; 9%–22% vs. 0; respectively). Among LG-NMIBC tumors, KDM6A mutations were more common in women than in men (71% vs. 38%). HG-NMIBC and MIBC had higher tumor mutational burden (TMB) than LG-NMIBC (P = 0.001 and P < 0.01, respectively). DNA-damage repair (DDR) alterations were associated with a higher TMB in HG-NMIBC and MIBC tumors, and these two tumor types were also enriched for an APOBEC mutational signature compared with LG-NMIBC and HG-UTUC. Alterations in FGFR3, PIK3CA, and EP300 correlated with worse overall survival in HG-UTUC and occurred concurrently.Conclusions:Our analysis suggests that a fraction of MIBCs likely arise from precursor lesions other than LG-NMIBC. KDM6A mutations are twice as common in women with LG-NIMBC than those in men. DDR gene mutations and APOBEC mutagenesis drive mutations in HG-NMIBC and MIBC. UTUC has a distinct mutation profile from bladder cancer.
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- 2023
3. Mutational Analysis of 472 Urothelial Carcinoma Across Grades and Anatomic Sites
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Joaquim Bellmunt, David J. Kwiatkowski, Kevin Lundgren, Amin Nassar, Mark A. Preston, Guru Sonpavde, Toni K. Choueiri, Kent W. Mouw, Jaegil Kim, Renato Umeton, Lauren C. Harshman, Eliezer M. Van Allen, and Fei Dong
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Adult ,Male ,0301 basic medicine ,APOBEC ,Urologic Neoplasms ,Cancer Research ,DNA Copy Number Variations ,DNA Mutational Analysis ,Gene mutation ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Exome Sequencing ,Biomarkers, Tumor ,medicine ,Humans ,Neoplasm Invasiveness ,Exome sequencing ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Mutation ,Mutation Spectra ,Bladder cancer ,business.industry ,Gene Expression Profiling ,Genomics ,Middle Aged ,Prognosis ,medicine.disease ,Gene expression profiling ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Disease Progression ,Cancer research ,Female ,Neoplasm Grading ,business - Abstract
Purpose: The purpose of this study is to characterize the mutational landscape across the spectrum of urothelial carcinoma (UC) to identify mutational features and potential therapeutic targets. Experimental Design: Using targeted exome sequencing (n = 237 genes), we analyzed the mutation spectra of 82 low-grade nonmuscle-invasive bladder cancers (LG-NMIBC), 126 high-grade (HG) NMIBC, 199 muscle-invasive bladder cancers (MIBC), 10 LG-upper tract urothelial cancers (LG-UTUC), and 55 HG-UTUC. Results: FGFR3 and KDM6A mutations were significantly more common in LG-NMIBC (72% and 44%, respectively) versus other bladder subtypes. FGFR3 alterations were also enriched in LG-UTUC versus HG-UTUC tumors (80% vs. 16%). In contrast, TP53 and RB1 mutations were significantly more frequent in all 3 HG urothelial carcinoma subtypes than in LG-NIMBC (45%–58% vs. 4%; 9%–22% vs. 0; respectively). Among LG-NMIBC tumors, KDM6A mutations were more common in women than in men (71% vs. 38%). HG-NMIBC and MIBC had higher tumor mutational burden (TMB) than LG-NMIBC (P = 0.001 and P < 0.01, respectively). DNA-damage repair (DDR) alterations were associated with a higher TMB in HG-NMIBC and MIBC tumors, and these two tumor types were also enriched for an APOBEC mutational signature compared with LG-NMIBC and HG-UTUC. Alterations in FGFR3, PIK3CA, and EP300 correlated with worse overall survival in HG-UTUC and occurred concurrently. Conclusions: Our analysis suggests that a fraction of MIBCs likely arise from precursor lesions other than LG-NMIBC. KDM6A mutations are twice as common in women with LG-NIMBC than those in men. DDR gene mutations and APOBEC mutagenesis drive mutations in HG-NMIBC and MIBC. UTUC has a distinct mutation profile from bladder cancer.
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- 2019
4. Enrichment of FGFR3-TACC3 Fusions in Patients With Bladder Cancer Who Are Young, Asian, or Have Never Smoked
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Guru Sonpavde, Amin Nassar, Joaquim Bellmunt, Xiao X. Wei, Eliezer M. Van Allen, Bradley Alexander McGregor, Kevin Lundgren, David J. Kwiatkowski, Mark Pomerantz, Graeme S. Steele, Kent W. Mouw, Mark A. Preston, Lauren C. Harshman, Atish D. Choudhury, and Toni K. Choueiri
- Subjects
musculoskeletal diseases ,Oncology ,Cancer Research ,medicine.medical_specialty ,Bladder cancer ,Somatic cell ,business.industry ,medicine.disease ,stomatognathic diseases ,Fibroblast growth factor receptor ,Internal medicine ,Cancer genome ,Cohort ,medicine ,Original Report ,Cancer gene ,In patient ,business ,Tyrosine kinase - Abstract
Purpose FGFR3-TACC3 (fibroblast growth factor receptor 3–transforming acidic coiled coil-containing protein 3) fusions have recently been identified as driver mutations that lead to the activation of FGFR3 in bladder cancer and other tumor types and are associated with sensitivity to tyrosine kinase inhibitors. We examined the clinical and molecular characteristics of patients with FGFR3-TACC3 fusions and hypothesized that they are enriched in a subset of patients with bladder cancer. Materials and Methods We correlated somatic FGFR3-TACC3 fusions with clinical and molecular features in two cohorts of patients with bladder cancer. The first cohort consisted of the muscle-invasive bladder cancer (MIBC) data set (n = 412) from The Cancer Genome Atlas. The second cohort consisted of patients with MIBC or high-grade non-MIBC at the Dana-Farber Cancer Institute that had targeted capture sequencing of a selected panel of cancer genes (n = 356). All statistical tests were two sided. The clinical response of one patient with FGFR3-TACC3 bladder cancer to an FGFR3 inhibitor was investigated. Results Overall, 751 patients with high-grade bladder cancer without FGFR3-TACC3 fusions and 17 with FGFR3-TACC3 fusions were identified in the pooled analysis of the data sets from The Cancer Genome Atlas and the Dana-Farber Cancer Institute. FGFR3-TACC3 fusions were enriched in patients age ≤ 50 years versus age 51 to 65 years versus those older than 65 years (pooled, P = .002), and were observed in four (12%) of 33 patients age ≤ 50 years in the pooled analysis. Similarly, FGFR3-TACC3 fusions were significantly more common in Asians (13%) compared with African Americans (4%) and whites (2%; pooled, P < .001), as well as in never smokers (5.6%) compared with ever smokers (1.1%; pooled, P < .001). One patient with the fusion who was treated with an FGFR3 inhibitor achieved complete remission for 10 months. Conclusion Clinical testing to identify FGFR3 fusions should be prioritized for patients with bladder cancer who are younger, never smokers, and/or Asian.
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- 2018
5. Everolimus and pazopanib (E/P) benefit genomically selected patients with metastatic urothelial carcinoma
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Stephanie A. Wankowicz, Eliezer M. Van Allen, Dominick Bossé, Joaquim Bellmunt, Laura Polacek, Nikhil Wagle, Toni K. Choueiri, Sussana Jacobus, Lauren C. Harshman, Irene Moreno, Aly-Khan A. Lalani, Jonathan E. Rosenberg, Kevin Lundgren, and David Y. Takeda
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Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Indazoles ,Metastatic Urothelial Carcinoma ,DNA Copy Number Variations ,Combination therapy ,Disease ,Article ,Tuberous Sclerosis Complex 1 Protein ,Pazopanib ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Tuberous Sclerosis Complex 2 Protein ,medicine ,Clinical endpoint ,Humans ,Receptor, Fibroblast Growth Factor, Type 3 ,Everolimus ,PI3K/AKT/mTOR pathway ,Carcinoma, Transitional Cell ,Sulfonamides ,business.industry ,High-Throughput Nucleotide Sequencing ,Sequence Analysis, DNA ,Metastatic urothelial carcinoma ,Survival Analysis ,Kidney Neoplasms ,Pyrimidines ,Treatment Outcome ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,Cohort ,Female ,business ,Microtubule-Associated Proteins ,medicine.drug - Abstract
BACKGROUND: Metastatic urothelial carcinoma (mUC) is a genomically diverse disease with known alterations in the mTOR pathway and tyrosine kinases including FGFR. We investigated the efficacy and safety of combination treatment with everolimus and pazopanib (E/P) in genomically profiled patients with mUC. METHODS: mUC patients enrolled on a Phase I dose escalation study and an expansion cohort treated with E/P were included. The primary end point was objective response rate (ORR); secondary end points were safety, duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Patients were assessed for mutations and copy number alterations in 300 relevant cancer-associated genes using next-generation sequencing and findings were correlated with outcomes. Time-to-event data were estimated with Kaplan-Meier methods. RESULTS: Of the 23 patients enrolled overall, 19 had mUC. ORR was 21% (one complete response (CR), three partial responses (PR), eight with stable disease (SD). DOR, PFS and OS were 6.5, 3.6, and 9.1 months, respectively. Four patients with clinical benefit (one CR, two PR, one SD) had mutations in TSC1/TSC2 or mTOR and a 5th patient with PR had a FGFR3-TACC3 fusion. CONCLUSIONS: Combination therapy with E/P is safe in mUC and select patients with alterations in mTOR or FGFR pathways derive significant clinical benefit.
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- 2018
6. Pembrolizumab in the treatment of advanced urothelial cancer
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Kevin Lundgren, Matthew S. Farina, and Joaquim Bellmunt
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Oncology ,Urologic Neoplasms ,Cancer Research ,medicine.medical_specialty ,Metastatic Urothelial Carcinoma ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,Immunomodulation ,03 medical and health sciences ,chemistry.chemical_compound ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,medicine ,Humans ,Molecular Targeted Therapy ,030212 general & internal medicine ,Neoplasm Metastasis ,Neoplasm Staging ,Cisplatin ,Clinical Trials as Topic ,Chemotherapy ,Vinflunine ,business.industry ,General Medicine ,Prognosis ,Interim analysis ,Treatment Outcome ,chemistry ,Paclitaxel ,Docetaxel ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
Pembrolizumab is a humanized monoclonal antibody that targets PD-1. In the Phase III trial KEYNOTE-045, pembrolizumab was associated with a significant overall survival benefit when compared with docetaxel, paclitaxel and vinflunine in second line metastatic urothelial carcinoma (UC). Additionally, in the first line, early results from an interim analysis of the Phase II trial Keynote-052 study indicated that pembrolizumab is efficacious for cisplatin-ineligible patients. Based on data from these trials, pembrolizumab was the most recent among the five checkpoint inhibitors tested in UC to be approved by the US FDA in May 2017. It was granted regular approval for patients with advanced-stage UC who progress after receiving platinum-based chemotherapy and accelerated approval in the first line for patients who are ineligible to receive cisplatin.
- Published
- 2017
7. Upper Tract Urothelial Carcinomas: Prognostic Factors and Outcomes in Patients With Non–Lymph Node Distant Metastasis
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Matthew S. Farina, Kevin Lundgren, Elena Sevillano, Guillermo Velasco, Dominick Bossé, Aly-Khan A. Lalani, Joaquim Bellmunt, Lillian Werner, Stephanie A. Wankowicz, Aranzazu Gonzalez del Alba, and Toni K. Choueiri
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Male ,Oncology ,Urologic Neoplasms ,medicine.medical_specialty ,Anemia ,Urology ,030232 urology & nephrology ,Antineoplastic Agents ,Nephroureterectomy ,Hemoglobins ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Internal medicine ,medicine ,Humans ,Neoplasm Metastasis ,Lymph node ,Survival analysis ,Aged ,Carcinoma, Transitional Cell ,Framingham Risk Score ,Performance status ,Proportional hazards model ,business.industry ,Cancer ,Middle Aged ,Prognosis ,medicine.disease ,Survival Analysis ,Clinical trial ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Cisplatin ,business - Abstract
Background Upper tract urothelial carcinomas (UTUCs) are increasingly recognized as separate malignancies. Additional insight into clinical outcomes and key prognostic factors are needed. Objectives To detail outcomes of patients with UTUCs recurring after radical nephroureterectomy (RNU) and to determine a risk score that predicts outcomes of patients with non–lymph node distant metastasis. Design, Setting, and Participants Chart review of all patients who had an extraurothelial recurrence after RNU for UTUC at Dana-Farber Cancer Institute between 2009 and 2014. Outcome Measurements and Statistical Analysis Median overall survival defined as time from chemotherapy for distant relapse to death. Prognostic relevance of performance status, hemoglobin, and receipt of cisplatin were assessed by Cox regression model. Results and Limitations A total of 102 patients were identified, 57 of whom had non–lymph node distant metastases at relapse; 45 received chemotherapy. Median follow-up was 29.8 months; median overall survival was 14.7 months. Objective response rate to any chemotherapy in the first-line setting was only 22%. Hemoglobin > 11 g/dL and receipt of cisplatin was associated with numerically longer median survival but did not reach statistical significance in univariate and multivariate analysis. Prognostic risk score scale including hemoglobin Conclusions Advanced UTUC portends a poor prognosis, and most patients cannot receive cisplatin-based chemotherapy. A risk score that includes anemia and receipt of cisplatin helps stratify patients with distant metastasis for inclusion into eventual clinical trials. More studies are needed to validate these findings. Patient Summary Metastatic UTUC is an aggressive disease, where anemia and ineligibility to receive cisplatin are adverse features associated with shorter survival.
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- 2017
8. Sequential Response to FGFR3 Inhibition With Subsequent Exceptional Response to Atezolizumab in a Patient With FGFR3-TACC3 Fusion–Positive Metastatic Urothelial Carcinoma
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Toni K. Choueiri, Joaquim Bellmunt, David J. Kwiatkowski, Jaegil Kim, Amin Nassar, Guru Sonpavde, and Kevin Lundgren
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Cancer Research ,Tumor microenvironment ,Bladder cancer ,Metastatic Urothelial Carcinoma ,biology ,business.industry ,Cancer ,Case Report ,medicine.disease ,Immune system ,Oncology ,Fibroblast growth factor receptor ,Atezolizumab ,medicine ,Cancer research ,biology.protein ,Antibody ,business - Abstract
Recent work has pointed to alterations in fibroblast growth factor receptors (FGFRs) as potential drivers of colder metastatic urothelial carcinoma (mUC) microenvironments.1,2 FGFRs mediate cell proliferation, migration, differentiation, and survival.3 Activating genomic alterations in FGFR3 are frequent in bladder cancer.4-6 In the muscle-invasive bladder cancer data set of The Cancer Genome Atlas, FGFR3 alterations were found to be enriched in the luminal papillary subtype.7 Clinical benefit from immune checkpoint inhibitors (ICIs) has been a major advance for many cancer types in recent years, including mUC, leading to US Food and Drug Administration approval.5 Although durable clinical benefit is seen in multiple cancer types, objective response rates in mUC are only 15% to 24%.8 Mechanisms contributing to ICI resistance and low response rates are poorly understood. A phase II trial comparing the association between The Cancer Genome Atlas mRNA subtypes and response to atezolizumab, an anti–programmed cell death ligand 1 (PD-L1) monoclonal immunoglobulin G1 antibody, showed that the luminal cluster (enriched for FGFR genomic alteration) was associated with lower expression levels of CD8+ genes and lower response rates (10%).1 Another study has shown that higher FGFR3 expression and FGFR3 pathway mutations are strongly associated with immune exclusion in bladder cancer.9 This association was also found in patients with bladder tumors harboring FGFR3-TACC3 fusions.2 These observations suggest that patients harboring FGFR3 alterations are relatively poor candidates for ICI therapy. Herein, we report a patient with metastatic bladder cancer harboring an FGFR3-TACC3 fusion and exhibiting an exceptional response to sequential FGFR3 inhibition and anti–PD-L1 blockade. We speculate that treatment of this patient with an FGFR3 inhibitor may have led to tumor microenvironment changes that enhanced the ICI response.
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- 2018
9. Immunotherapy in Urothelial Cancer: Recent Results and Future Perspectives
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Kevin Lundgren, Matthew S. Farina, and Joaquim Bellmunt
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Metastatic Urothelial Carcinoma ,Durvalumab ,Programmed Cell Death 1 Receptor ,Ipilimumab ,Antineoplastic Agents ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,B7-H1 Antigen ,Avelumab ,03 medical and health sciences ,0302 clinical medicine ,Atezolizumab ,Internal medicine ,Medicine ,Animals ,Humans ,Pharmacology (medical) ,CTLA-4 Antigen ,Drug Approval ,Bladder cancer ,business.industry ,United States Food and Drug Administration ,Antibodies, Monoclonal ,medicine.disease ,United States ,030104 developmental biology ,Nivolumab ,Urinary Bladder Neoplasms ,030220 oncology & carcinogenesis ,Immunology ,Immunotherapy ,Urothelium ,business ,medicine.drug - Abstract
Cytotoxic chemotherapy has been the only systemic treatment of locally advanced and metastatic urothelial carcinoma for decades. Long-term survival remains stagnant around 12–14 months for patients with advanced disease who have progressed on or recurred after receiving first-line platinum-based chemotherapy. Improving clinical outcomes for patients with urothelial carcinoma in all disease settings requires the development of novel treatments, especially for patients who failed on first-line chemotherapy. Since the discovery of intravesical Bacillus-Calmette Guerin (BCG) in the 1970s for non-muscle invasive disease, there have not been any major breakthrough drugs that exploit the immune-sensitivity of bladder cancer until recently. Immune-checkpoint inhibitors targeting the programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways have shown significant anti-tumor activity, tolerable safety profiles and durable, long-term responses in clinical trials. Atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab are promising PD-1/PD-L1 blockade drugs under investigation that will redefine the standard of care for bladder cancer. CTLA-4 inhibitors are also under investigation in this setting. Atezolizumab, approved in May 2016, and nivolumab, approved in February 2017, are the first Food and Drug Administration (FDA)-approved immune-checkpoint inhibitors in bladder cancer for platinum-pretreated patients based on phase II data. On March 16, 2017, results from the phase III trial KEYNOTE-045 demonstrated that survival was significantly longer in patients treated with pembrolizumab when compared with the standard second-line chemotherapy. Research into biomarkers such as PD-L1 expression, messenger RNA subtype, mutational and neoantigen load and gene signature expression will be crucial to determining why some patients respond to immunotherapy and others do not. This review article describes the advances in immunotherapy since the development of BCG, presents results from clinical trials investigating immune-checkpoint inhibitors and discusses biomarkers and prognostic factors associated with response to these new drugs.
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- 2017
10. First-line PD-1/PD-L1 inhibitor followed by carboplatin (carbo)-based chemotherapy (chemo) or the reverse sequence in cisplatin-ineligible metastatic urothelial cancer (mUC) patients (pts)
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Thomas Powles, Lucia Carril, Parissa Alerasool, Pedro Isaacsson Velho, Guru Sonpavde, Min Yuen Teo, Rana R. McKay, Xiao X. Wei, Kevin Lundgren, Noah M. Hahn, Daniele Raggi, Vadim S. Koshkin, Ravi Kanesvaran, Daniel Castellano, Andrea Necchi, Joaquim Bellmunt, Laura Morrison, Jacob Gaines, Petros Grivas, and Jonathan E. Rosenberg
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,First line ,medicine.medical_treatment ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Urothelial cancer ,Cisplatin ,Chemotherapy ,business.industry ,Perioperative ,Carboplatin ,Reverse order ,stomatognathic diseases ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,PD-L1 inhibitor ,business ,medicine.drug - Abstract
e16517Background: PD-1/PD-L1 inhibitors or carbo-based chemo are both reasonable therapeutic options in the first-line setting for cisplatin-ineligible mUC pts. However, optimal first-line therapy and sequencing of these regimens is unclear. Methods: We conducted a multicenter retrospective analysis of cisplatin-ineligible mUC pts treated with first-line PD-1/PD-L1 monotherapy followed by carbo-based chemo (P- > C) or the reverse order (C- > P). Perioperative cisplatin-based chemo was allowed if the interval between its completion and starting first-line mUC therapy was > 1 year. A multivariate analysis (MVA) examined the association of sequence of therapy with overall survival (OS) adjusted for baseline Hb ( C n = 33, C- > P n = 82) with median age 71, 74% men, and 85% ECOG PS 0-1 were included. Most pts (94.8%) had not received prior perioperative cisplatin-based chemo,...
- Published
- 2018
11. Model combining genomic and clinical factors to predict clinical benefit from PD1/PD-L1 inhibitors for advanced UC
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Bradley Alexander McGregor, Joaquim Bellmunt, Amin Nassar, Eliezer M. Van Allen, David J. Kwiatkowski, Mark Pomerantz, Chia Jen Liu, Lauren C. Harshman, Kevin Lundgren, Xiao X. Wei, Toni K. Choueiri, Mark A. Preston, Atish D. Choudhury, Guru Sonpavde, and Kent W. Mouw
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,business.industry ,Internal medicine ,PD-L1 ,medicine ,biology.protein ,business - Abstract
4539Background: Tumor mutational burden is associated with response to PD1/PD-L1 inhibitors in advanced UC. We explored the ability of copy-number variants (CNVs) and specific genomic alterations t...
- Published
- 2018
12. Comprehensive genomic characterization of urothelial carcinomas
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Kevin Lundgren, Renato Umeton, Lauren C. Harshman, Kent W. Mouw, Graeme S. Steele, Toni K. Choueiri, Eliezer M. Van Allen, Guru Sonpavde, Amin Nassar, Joaquim Bellmunt, and David J. Kwiatkowski
- Subjects
Cancer Research ,Bladder cancer ,Oncology ,business.industry ,Medicine ,Computational biology ,business ,medicine.disease ,Genetic analysis - Abstract
4527Background: While the genetic characteristics of muscle-invasive bladder cancer have been studied in detail, there are few reports using the same genetic analysis platform to investigate differ...
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- 2018
13. FGFR3-TACC3 fusion in bladder cancer: Enrichment in the young, never-smokers, and Asians
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Xiao X. Wei, Lauren C. Harshman, Joaquim Bellmunt, Amin Nassar, Mark A. Preston, Kevin Lundgren, Guru Sonpavde, David J. Kwiatkowski, Bradley Alexander McGregor, Mark Pomerantz, Toni K. Choueiri, Kent W. Mouw, Eliezer M. Van Allen, and Atish D. Choudhury
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Massive parallel sequencing ,Bladder cancer ,Wilcoxon signed-rank test ,business.industry ,Somatic cell ,medicine.disease ,Never smokers ,Internal medicine ,Cohort ,medicine ,business ,Gene ,Exome sequencing - Abstract
465 Background: Bladder cancer patients (pts) are typically elderly with median age ~70 years. We hypothesized that younger pts (≤age 50) with muscle-invasive bladder cancer (MIBC) have distinct molecular features, including potential driver mutations that could serve as therapeutic targets. Methods: We used the MIBC TCGA cohort (n = 412, Cell 2017) analyzed by whole exome sequencing as a discovery cohort, and then confirmed observations using 356 pts with MIBC and high grade (HG) non-MIBC analyzed at Dana Farber Cancer Institute (DFCI) by the Oncopanel assay. Oncopanel assesses 447 somatic cancer genes and 191 regions across 60 genes for rearrangement detection by massively parallel sequencing. We examined associations between age (≤50, 51-65, and > 65) and molecular features, using the χ2 test for discrete data, and the Wilcoxon Rank Sum Test for quantitative data. Nominal p values were obtained, and the FDR correction was employed to obtain q values. Results: The following DNA alterations were significantly enriched in the TCGA in ≤50 vs 51-65 vs > 65 age groups respectively: focal deletion in CREBBP (3/25 [12%] vs 2/137 [1.5%] vs 1/250 [0.4%], p < 0.0001, q = 0.0126); microRNA Cluster III (13/25 [52%] vs 53/137 [38.7%] vs 55/250 [22%], p = 0.0005, q = 0.0252); fusion in FGFR3-TACC3 (3/25 [12%] vs 2/137 [1.5%] vs 5/250 [2%], p = 0.0055, q = 0.1386). Given that FGFR3-TACC3 fusions are potential therapeutic targets, we examined the association between FGFR3-TACC3 fusions and clinical features in a pooled analysis combining the TCGA and DFCI cohorts totaling 768 pts. FGFR3-TACC3 fusions were enriched in: ≤50 age group vs 51-65 vs > 65 (4/33 [12.1%] vs 7/232 [3%] vs 6/503 [1.2%] respectively, p = 0.0001). Fusions were also significantly more common in Asians vs. Blacks vs. Whites (6/47 [12.8%] vs 1/28 [3.6%] vs 10/666 [1.5%] respectively, p < 0.0001) and in never-smokers vs. ever smokers (12/194 [6.2%] vs 5/545 [0.9%] respectively, p < 0.0001). Conclusions: FGFR3-TACC3 fusion, a known potentially actionable genomic alteration in MIBC, is significantly enriched in young pts, never-smokers and those of Asian ethnicity. Clinical testing to detect FGFR3-TACC3 fusion should be prioritized for MIBC and HG-non-MIBC pts meeting these criteria.
- Published
- 2018
14. Cell-free tumor DNA and TERT promoter mutations in bladder cancer
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Viktor A. Adalsteinsson, Sabina Signoretti, Levi A. Garraway, Sarah C. Reed, William C. Hahn, Irene Moreno, Joaquim Bellmunt, Franklin W. Huang, Toni K. Choueiri, Kevin Lundgren, Stephanie A. Mullane, Jesse Novak, Greg Gydush, and Mikael L. Rinne
- Subjects
0301 basic medicine ,Whole genome sequencing ,Cancer Research ,Chemotherapy ,Bladder cancer ,business.industry ,Somatic cell ,medicine.medical_treatment ,Cancer ,medicine.disease ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Oncology ,chemistry ,Cancer research ,Biomarker (medicine) ,Medicine ,Telomerase reverse transcriptase ,business ,DNA - Abstract
353 Background: Currently, there are no FDA-approved blood biomarkers for the prognosis or prediction of outcomes in urothelial carcinoma (UC). The telomerase reverse transcriptase ( TERT) promoter is recurrently mutated at high frequency in UC (50%). These mutations have been correlated with tumor recurrence and survival. Tumor cell-free DNA (cfDNA) with somatic genomic alterations can be found in the plasma of cancer patients and has the potential for use as a non-invasive cancer biomarker. Detection of TERT promoter mutations in cfDNA might be used as a prognostic tool to monitor disease outcome in UC patients. We set out to detect tumor cfDNA and TERT promoter mutations in cfDNA from patients with UC at different stages. Methods: UC patients receiving chemotherapy in the neoadjuvant, first or second-line metastatic setting had blood collected either before or during therapy. cfDNA was isolated from ~1ml plasma samples using the QIAmp (Qiagen) kit. Samples underwent ultra-low pass whole genome sequencing (ULP-WGS) to determine whether tumor cfDNA could be detected in these samples. TERT promoter mutations were detected using a sensitive qPCR assay. Results: 40 plasma samples from a total of 32 patients with urothelial carcinoma were analyzed. Sufficient amounts of plasma cfDNA were obtained for library construction and ULP-WGS in 11 patients. 6 of these 11 patients were determined to be positive for detectable tumor cfDNA and of these, all were metastatic and 50% (3/6) were positive for a TERT promoter mutation. In total, 8 out of 40 samples (20%) were positive for a TERT promoter mutation, including samples from two patients where total cfDNA yield was insufficient for library construction. A total of ~20% of patients with metastatic disease were positive for TERT promoter mutations in cfDNA. The low percentage of samples having sufficient cfDNA most likely reflects the low volume of plasma used. Conclusions: TERT promoter mutations were identified in cfDNA of UC patients. ULP-WGS showed tumor cfDNA in patients with a high tumor burden and metastatic disease. TERTpromoter mutations in cfDNA could potentially be used as a non-invasive method for detection of disease. These results have implications for the use of cfDNA in the evaluation of advanced UC.
- Published
- 2017
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