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Current Oncology
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Current Advances in Clinical Genomics and Treatment of Urothelial Carcinoma
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Current Advances in Clinical Genomics and Treatment of Urothelial Carcinoma

A special issue of Current Oncology (ISSN 1718-7729). This special issue belongs to the section "Genitourinary Oncology".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 22054

Special Issue Editor

Dr. Panagiotis Vlachostergios

E-Mail Website
Guest Editor
Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA
Interests: identification of biomarkers for prostate; kidney and bladder cancer; neuroendocrine prostate cancer; PSMA theranostics; upper tract urothelial carcinoma; treatment-resistant urothelial carcinoma; genomics and immunogenomics for urological cancers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Immense progress in large-scale genomics projects is transforming the therapeutic landscape of various cancers. Urothelial carcinoma is a common, potentially lethal malignancy, particularly in the advanced stage. Immune checkpoint inhibitors, antibody drug conjugates, and novel targeted agents have become part of the treatment armamentarium for urothelial carcinoma. An important challenge for clinicians is how to best utilize genomic approaches to predict treatment responses and identify patients who can derive a preferential benefit from these therapeutic options. This Special Issue aims at providing an update on recent advances in the molecular landscape of UC and how genomic alterations in key signaling pathways might serve in biomarker development, drug development, and prediction of patient outcomes. 

Dr. Panagiotis J. Vlachostergios
Guest Editor

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Keywords

  • urothelial carcinoma
  • genomics
  • genetics
  • molecular alterations
  • biomarker
  • sensitivity
  • resistance
  • therapeutics
  • immunotherapy
  • antibody–drug conjugates

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Published Papers (7 papers)

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Research

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18 pages, 2497 KiB  
Article
Urothelial Bladder Carcinomas with High Tumor Mutation Burden Have a Better Prognosis and Targetable Molecular Defects beyond Immunotherapies
by Ioannis A. Voutsadakis
Curr. Oncol. 2022, 29(3), 1390-1407; https://doi.org/10.3390/curroncol29030117 - 24 Feb 2022
Cited by 21 | Viewed by 3888
Abstract
Background: Urothelial bladder carcinomas had traditionally been difficult to treat cancers, with high morbidity and mortality rates when invasive and metastatic. In recent years, immunotherapy with immune checkpoint inhibitors has improved outcomes in several cancers, including bladder carcinomas. Despite positive overall results, many [...] Read more.
Background: Urothelial bladder carcinomas had traditionally been difficult to treat cancers, with high morbidity and mortality rates when invasive and metastatic. In recent years, immunotherapy with immune checkpoint inhibitors has improved outcomes in several cancers, including bladder carcinomas. Despite positive overall results, many bladder cancer patients do not respond to immunotherapies. Validated predictive biomarkers of response would advance the selection of patients for these treatments. Tumor mutation burden (TMB) has been suggested as an immunotherapy biomarker and thus delineation of attributes of tumors with a high TMB is clinically relevant. Methods: Publicly available genomic and clinical data from the urothelial bladder carcinoma cohort of The Cancer Genome Atlas (TCGA) project are used to analyze characteristics and molecular alterations of the subset of cancers with an increased tumor mutation number compared with those with lower number of mutations. The cut-off for the high mutation burden in the analysis was set at 10 mutations per Megabase (MB). Results: In addition to their sensitivity to immune checkpoint inhibitors, urothelial carcinomas with high TMB possess several molecular defects that could be exploited for combinatorial treatments. Compared with bladder carcinomas with low TMB, carcinomas with high TMB display higher prevalence of mutations in tumor suppressor TP53, PIK3CA, in FAT4 cadherin and in genes encoding for several epigenetic modifier enzymes. The frequency of mutations in mismatch repair and DNA damage response genes is higher in cancers with high TMB. The group of urothelial carcinomas with high TMB has a better prognosis than the group with low TMB. This improved Overall Survival (OS) stems from improved survival of stage III cancers with high TMB compared with stage III cancers with low TMB, while stage II and stage IV cancers have similar OS, independently of their TMB. Conclusion: Differences of the landscape of high and low TMB urothelial cancers provides leads for further pathogenesis investigations and may prove useful for development of combination therapies including immunotherapies with targeted inhibitors. Full article
(This article belongs to the Special Issue Current Advances in Clinical Genomics and Treatment of Urothelial Carcinoma)
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7 pages, 244 KiB  
Article
Renin-Angiotensin System Single Nucleotide Polymorphisms Are Associated with Bladder Cancer Risk
by Maria Samara, Maria Papathanassiou, Ioanna Farmakioti, Maria Anagnostou, Maria Satra, Lampros Mitrakas, Dimitrios Anastasiou, Georgios Chasiotis, Agamemnon Christopoulos, Athanasios Anagnostou, Anastasios Christodoulou, Alexandros Daponte, Maria Ioannou, George Koukoulis, Vassilios Tzortzis and Panagiotis J. Vlachostergios
Curr. Oncol. 2021, 28(6), 4702-4708; https://doi.org/10.3390/curroncol28060396 - 15 Nov 2021
Cited by 4 | Viewed by 2756
Abstract
The renin-angiotensin system (RAS), besides being a major regulator of blood pressure, is also involved in tumor angiogenesis. Emerging evidence suggests a correlation between the use of pharmacologic RAS inhibitors and a delay in urothelial bladder cancer (BC) progression. However, it is unknown [...] Read more.
The renin-angiotensin system (RAS), besides being a major regulator of blood pressure, is also involved in tumor angiogenesis. Emerging evidence suggests a correlation between the use of pharmacologic RAS inhibitors and a delay in urothelial bladder cancer (BC) progression. However, it is unknown whether RAS gene variants may predispose to the development of BC. This study examined the association of RAS single nucleotide polymorphisms (SNPs) including AT1R rs5186, AT2R rs11091046, REN rs12750834, ANG rs4762, and ANG rs699 with the risk of developing non-invasive BC. Peripheral blood samples from 73 patients with T1 urothelial BC (66 men, seven women) and an equal number of healthy subjects (control group) were collected. The TT genotype of the REN rs12750834 SNP (OR: 2.8 [1.3–6.05], p = 0.008) and to a lesser extent the presence of the T allele (OR: 2.3 [1.2–4.48], p = 0.01) conferred a higher risk of BC. The highest risk for BC within SNP carriers of the RAS system was associated with the presence of the CC genotype (OR: 17.6 [7.5–41.35], p < 0.001) and C allele (OR: 17.7 [8.8–35.9], p < 0.001) of the ANG rs699 SNP. The presence of the AT2R rs11091046 SNP, particularly the AA genotype, was associated with a protective effect against developing BC (OR: 0.268 [0.126–057], p < 0.001). In conclusion, these results support the clinical utility of RAS gene SNPs AT2R rs11091046, REN rs12750834, and ANG rs699 in the genetic cancer risk assessment of patients and families with BC. Full article
(This article belongs to the Special Issue Current Advances in Clinical Genomics and Treatment of Urothelial Carcinoma)
11 pages, 1175 KiB  
Article
ERCC1 19007 Polymorphism in Greek Patients with Advanced Urothelial Cancer Treated with Platinum-Based Chemotherapy: Effect of the Changing Treatment Paradigm: A Cohort Study by the Hellenic GU Cancer Group
by Aristotelis Bamias, Konstantinos Koutsoukos, Nikos Gavalas, Roubini Zakopoulou, Kimon Tzannis, Nikos Dedes, Anna Boulouta, Charalampos Fragkoulis, Eythymios Kostouros, Athanasios Dellis, Iraklis Mitsogiannis, Ioannis Adamakis, Ioannis Anastasiou, Andreas Skolarikos, Athanasios Papatsoris, Konstantinos Stravodimos, Nikolaos Ferakis, Stamatina Pagoni, Konstantinos Ntoumas, Dionysios Mitropoulos, Charalambos Deliveliotis, Constantinos A. Constantinides and Meletios A. Dimopoulosadd Show full author list remove Hide full author list
Curr. Oncol. 2021, 28(6), 4474-4484; https://doi.org/10.3390/curroncol28060380 - 5 Nov 2021
Cited by 1 | Viewed by 1933
Abstract
We previously showed that ERCC1 19007 C>T polymorphism was associated with cancer-specific survival (CSS) after platinum-based chemotherapy in patients with advanced urothelial cancer (aUC). We aimed to confirm this association in a different cohort of patients. Genotyping of the 19007C>T polymorphism was carried [...] Read more.
We previously showed that ERCC1 19007 C>T polymorphism was associated with cancer-specific survival (CSS) after platinum-based chemotherapy in patients with advanced urothelial cancer (aUC). We aimed to confirm this association in a different cohort of patients. Genotyping of the 19007C>T polymorphism was carried out by polymerase chain reaction (PCR) amplification and restriction fragment length polymorphism (RFLP) in 98 aUC patients, treated with platinum-based chemotherapy. Median age of the patients was 68.8, 13.3% of them were female, 90.8% had ECOG PS of 0 or 1, and 48% received cisplatin-based chemotherapy. In addition to chemotherapy, 32.7% of the patients received immunotherapy, and 19.4% vinflunine. Eighty-one patients (82.7%) were carriers of the 19007T polymorphic allele: 46 (46.9%) were heterozygotes, and 35 (35.7%) were homozygotes. The ERCC1 polymorphism was not associated with CSS, progression-free (PFS), or overall (OS) survival in the total population. Nevertheless, there was a significant interaction between the prognostic significance of ERCC1 polymorphism and the use of modern immunotherapy: the T allele was associated with worse outcome in patients who received chemotherapy only, while this association was lost in patients who received both chemotherapy and immune checkpoint inhibitors. Our study suggests that novel therapies may influence the significance of ERCC1 polymorphism in patients with aUC. Its determination may be useful in the changing treatment landscape of the disease. Full article
(This article belongs to the Special Issue Current Advances in Clinical Genomics and Treatment of Urothelial Carcinoma)
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7 pages, 225 KiB  
Article
DNA Repair Gene Polymorphisms and Susceptibility to Urothelial Carcinoma in a Southeastern European Population
by Maria Samara, Maria Papathanassiou, Lampros Mitrakas, George Koukoulis, Panagiotis J. Vlachostergios and Vassilios Tzortzis
Curr. Oncol. 2021, 28(3), 1879-1885; https://doi.org/10.3390/curroncol28030174 - 14 May 2021
Cited by 2 | Viewed by 2008
Abstract
Single nucleotide polymorphisms (SNPs) in DNA repair genes may predispose to urothelial carcinoma of the bladder (UCB). This study focused on three specific SNPs in a population with high exposure to environmental carcinogens including tobacco and alcohol. A case-control study design was used [...] Read more.
Single nucleotide polymorphisms (SNPs) in DNA repair genes may predispose to urothelial carcinoma of the bladder (UCB). This study focused on three specific SNPs in a population with high exposure to environmental carcinogens including tobacco and alcohol. A case-control study design was used to assess for presence of XPC PAT +/−, XRCC3 Thr241Met, and ERCC2 Lys751Gln DNA repair gene SNPs in peripheral blood from patients with UCB and healthy individuals. One hundred patients and equal number of healthy subjects were enrolled. The XPC PAT +/+ genotype was associated with a 2-fold increased risk of UCB (OR = 2.16; 95%CI: 1.14–4; p = 0.01). The −/+ and +/+ XPC PAT genotypes were more frequently present in patients with multiple versus single tumors (p = 0.01). No association was detected between ERCC2 Lys751Gln genotypes/alleles, and risk for developing UCB. Presence of the XRCC3 TT genotype (OR = 0.14; 95%CI:0.07–0.25; p < 0.01) and of the T allele overall (OR = 0.26; 95%CI:0.16–0.41; p < 0.01) conferred a protective effect against developing UCB. The XPC PAT −/+ and XRCC3 Thr241Met SNPs are associated with predisposition to UCB. The XPC PAT −/+ SNP is also an indicator of bladder tumor multiplicity, which might require a more individualized surveillance and treatment. Full article
(This article belongs to the Special Issue Current Advances in Clinical Genomics and Treatment of Urothelial Carcinoma)

Review

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14 pages, 270 KiB  
Review
Do Cancer Genetics Impact Treatment Decision Making? Immunotherapy and Beyond in the Management of Advanced and Metastatic Urothelial Carcinoma
by Gavin Hui, Dimitrios Stefanoudakis, Yuliya Zektser, Dayna Jill Isaacs, Christopher Hannigan, Allan J. Pantuck and Alexandra Drakaki
Curr. Oncol. 2023, 30(8), 7398-7411; https://doi.org/10.3390/curroncol30080536 - 4 Aug 2023
Cited by 2 | Viewed by 2590
Abstract
Bladder cancer is one of the most commonly diagnosed genitourinary malignancies. For many years, the primary treatment for metastatic urothelial cancer (mUC) was predicated on the use of platinum-based chemotherapy. More recently, immune checkpoint inhibitors (ICIs) were approved by regulatory agencies such as [...] Read more.
Bladder cancer is one of the most commonly diagnosed genitourinary malignancies. For many years, the primary treatment for metastatic urothelial cancer (mUC) was predicated on the use of platinum-based chemotherapy. More recently, immune checkpoint inhibitors (ICIs) were approved by regulatory agencies such as the US FDA for use in both the first- and second-line settings. This review outlines the approved ICIs for mUC in the second-line setting and as an alternative to chemotherapy in the first-line setting, as well as the novel agents that have also been incorporated into the treatment of this malignancy. Single-agent ICIs are often used in second-line settings in mUC, and there are three drugs currently approved for those who progress after receiving platinum-based chemotherapy. In the first-line setting, the preferred treatment regimen remains cisplatin-based chemotherapy. However, single-agent ICI can be an alternative first-line treatment for those who are not candidates for cisplatin-based therapy. There are also clinical trials adding ICIs to chemotherapy as combination regimens. However, treatment for mUC has now expanded even beyond immunotherapy. Newer targeted agents such as erdafitinib, a fibroblast growth factor receptor inhibitor, and two antibody–drug conjugates, enfortumab vedotin and sacituzumab govitecan, have been recently approved. As new drug agents are discovered, it will be important to assess both the treatment outcomes as well as the effects on patients’ quality of life. Furthermore, integrating genetic and molecular information can help guide treatment decisions as next-generation sequencing is more commonly acquired during the evaluation of newly diagnosed patients with advanced and metastatic cancer. Full article
(This article belongs to the Special Issue Current Advances in Clinical Genomics and Treatment of Urothelial Carcinoma)
20 pages, 933 KiB  
Review
Genomics and Immunomics in the Treatment of Urothelial Carcinoma
by Veronica Mollica, Francesco Massari, Alessandro Rizzo, Roberto Ferrara, Arjun K. Menta and Jacob J. Adashek
Curr. Oncol. 2022, 29(5), 3499-3518; https://doi.org/10.3390/curroncol29050283 - 12 May 2022
Cited by 8 | Viewed by 3646
Abstract
Urothelial carcinoma is a complex cancer with genomic immunomic drivers that have prognostic and predictive treatment implications. Identifying potential targetable alterations via next-generation sequencing and RNA sequencing may allow for elucidation of such targets and exploitation with targeted therapeutics. The role of immunotherapy [...] Read more.
Urothelial carcinoma is a complex cancer with genomic immunomic drivers that have prognostic and predictive treatment implications. Identifying potential targetable alterations via next-generation sequencing and RNA sequencing may allow for elucidation of such targets and exploitation with targeted therapeutics. The role of immunotherapy in treating urothelial carcinoma has shown benefit, but it is unclear in which patients immunotherapeutics have the highest yield. Continuing efforts into better identifying which patients may benefit most from targeted therapies, immunotherapies, and combination therapies may ultimately lead to improved outcomes for patients with this disease. Full article
(This article belongs to the Special Issue Current Advances in Clinical Genomics and Treatment of Urothelial Carcinoma)
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11 pages, 562 KiB  
Review
Current Advances in Immune Checkpoint Inhibition and Clinical Genomics in Upper Tract Urothelial Carcinoma: State of the Art
by Gianluigi Califano, Idir Ouzaid, Paul Laine-Caroff, Arthur Peyrottes, Claudia Collà Ruvolo, Benjamin Pradère, Vincent Elalouf, Vincent Misrai, Jean-François Hermieu, Shahrokh F. Shariat and Evanguelos Xylinas
Curr. Oncol. 2022, 29(2), 687-697; https://doi.org/10.3390/curroncol29020060 - 29 Jan 2022
Cited by 17 | Viewed by 4081
Abstract
Upper tract urothelial carcinoma (UTUC) is a rare and challenging-to-treat malignancy. In most patients it is a sporadic tumor entity, less commonly it falls on the spectrum of Lynch syndrome, an autosomal dominant familial tumor syndrome. Localized UTUC with high-risk features as well [...] Read more.
Upper tract urothelial carcinoma (UTUC) is a rare and challenging-to-treat malignancy. In most patients it is a sporadic tumor entity, less commonly it falls on the spectrum of Lynch syndrome, an autosomal dominant familial tumor syndrome. Localized UTUC with high-risk features as well as the metastatic disease scenario might require systemic therapy. Platinum-based combination chemotherapy is currently the recommended management option. However, the introduction of immune checkpoint inhibitors into the therapeutic armamentarium has led to a paradigm shift in treatment standards. Immunotherapy has been shown to be safe and effective in treating at least metastatic UTUC, although UTUC-specific high-level evidence is still lacking. Recent technological advances and noteworthy research efforts have greatly improved the general understanding of the biological landscape of UTUC. According to the main findings, UTUC represent a particular subtype of urothelial carcinoma frequently associated with activated FGFR3 signaling, a luminal–papillary phenotype and a T-cell-depleted microenvironment. This improved knowledge promises precision oncology approaches that match treatment decision strategies and genomic profile to ultimately result in better clinical outcomes. The aim of this review was to summarize the main currently available evidence on immune checkpoint inhibition and clinical genomics in UTUC. Full article
(This article belongs to the Special Issue Current Advances in Clinical Genomics and Treatment of Urothelial Carcinoma)
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