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International Journal of Molecular... Jun 2023The treatment of cancer patients has dramatically changed over the past decades with the advent of monoclonal antibodies, immune-checkpoint inhibitors, bispecific... (Review)
Review
The treatment of cancer patients has dramatically changed over the past decades with the advent of monoclonal antibodies, immune-checkpoint inhibitors, bispecific antibodies, and innovative T-cell therapy. Antibody-drug conjugates (ADCs) have also revolutionized the treatment of cancer. Several ADCs have already been approved in hematology and clinical oncology, such as trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and sacituzumab govitecan (SG) for the treatment of metastatic breast cancer, and enfortumab vedotin (EV) for the treatment of urothelial carcinoma. The efficacy of ADCs is limited by the emergence of resistance due to different mechanisms, such as antigen-related resistance, failure of internalization, impaired lysosomal function, and other mechanisms. In this review, we summarize the clinical data that contributed to the approval of T-DM1, T-DXd, SG, and EV. We also discuss the different mechanisms of resistance to ADCs, as well as the ways to overcome this resistance, such as bispecific ADCs and the combination of ADCs with immune-checkpoint inhibitors or tyrosine-kinase inhibitors.
Topics: Humans; Immune Checkpoint Inhibitors; Carcinoma, Transitional Cell; Urinary Bladder Neoplasms; Immunoconjugates; Ado-Trastuzumab Emtansine
PubMed: 37298631
DOI: 10.3390/ijms24119674 -
Journal of Clinical Oncology : Official... Jul 2023JCO Initial results from the phase III JAVELIN Bladder 100 trial (ClinicalTrials.gov identifier: NCT02603432) showed that avelumab first-line (1L) maintenance plus best... (Randomized Controlled Trial)
Randomized Controlled Trial
JCO Initial results from the phase III JAVELIN Bladder 100 trial (ClinicalTrials.gov identifier: NCT02603432) showed that avelumab first-line (1L) maintenance plus best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) who were progression-free after 1L platinum-containing chemotherapy. Avelumab 1L maintenance treatment is now a standard of care for aUC. Here, we report updated data with ≥ 2 years of follow-up in all patients, including OS (primary end point), PFS, safety, and additional novel analyses. Patients were randomly assigned 1:1 to receive avelumab plus BSC (n = 350) or BSC alone (n = 350). At data cutoff (June 4, 2021), median follow-up was 38.0 months and 39.6 months, respectively; 67 patients (19.5%) had received ≥2 years of avelumab treatment. OS remained longer with avelumab plus BSC versus BSC alone in all patients (hazard ratio, 0.76 [95% CI, 0.63 to 0.91]; 2-sided = .0036). Investigator-assessed PFS analyses also favored avelumab. Longer-term safety was consistent with previous analyses; no new safety signals were identified with longer treatment duration. In conclusion, longer-term follow-up continues to show clinically meaningful efficacy benefits with avelumab 1L maintenance plus BSC versus BSC alone in patients with aUC. An interactive visualization of data reported in this article is available.
Topics: Humans; Carcinoma, Transitional Cell; Follow-Up Studies; Urinary Bladder; Urinary Bladder Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37071838
DOI: 10.1200/JCO.22.01792 -
International Journal of Molecular... Aug 2023Urothelial carcinoma (UC), the sixth most common cancer in Western countries, includes upper tract urothelial carcinoma (UTUC) and bladder carcinoma (BC) as the most... (Review)
Review
Urothelial carcinoma (UC), the sixth most common cancer in Western countries, includes upper tract urothelial carcinoma (UTUC) and bladder carcinoma (BC) as the most common cancers among UCs (90-95%). BC is the most common cancer and can be a highly heterogeneous disease, including both non-muscle-invasive (NMIBC) and muscle-invasive (MIBC) forms with different oncologic outcomes. Approximately 80% of new BC diagnoses are classified as NMIBC after the initial transurethral resection of the bladder tumor (TURBt). In this setting, intravesical instillation of Bacillus Calmette-Guerin (BCG) is the current standard treatment for intermediate- and high-risk patients. Unfortunately, recurrence occurs in 30% to 40% of patients despite adequate BCG treatment. Radical cystectomy (RC) is currently considered the standard treatment for NMIBC that does not respond to BCG. However, RC is a complex surgical procedure with a recognized high perioperative morbidity that is dependent on the patient, disease behaviors, and surgical factors and is associated with a significant impact on quality of life. Therefore, there is an unmet clinical need for alternative bladder-preserving treatments for patients who desire a bladder-sparing approach or are too frail for major surgery. In this review, we aim to present the strategies in BCG-unresponsive NMIBC, focusing on novel molecular therapeutic targets.
Topics: Humans; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; BCG Vaccine; Non-Muscle Invasive Bladder Neoplasms; Quality of Life; Mycobacterium bovis
PubMed: 37628785
DOI: 10.3390/ijms241612596 -
European Urology Jul 2023In the phase 3 JAVELIN Bladder 100 trial, avelumab first-line (1L) maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In the phase 3 JAVELIN Bladder 100 trial, avelumab first-line (1L) maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (aUC) who were progression-free following 1L platinum-based chemotherapy, leading to regulatory approval in various countries.
OBJECTIVE
To analyze clinically relevant subgroups from JAVELIN Bladder 100.
DESIGN, SETTING, AND PARTICIPANTS
Patients with unresectable locally advanced or metastatic UC without progression on 1L gemcitabine + cisplatin or carboplatin were randomized to receive avelumab + BSC (n = 350) or BSC alone (n = 350). Median follow-up was >19 mo in both arms (data cutoff October 21, 2019). This trial is registered on ClinicalTrials.gov as NCT02603432.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
OS (primary endpoint) and PFS were analyzed in protocol-specified and post hoc subgroups using the Kaplan-Meier method and Cox proportional hazards models.
RESULTS AND LIMITATIONS
Hazard ratios (HRs) for OS with avelumab + BSC versus BSC alone were <1.0 across all subgroups examined, including patients treated with 1L cisplatin + gemcitabine (HR 0.69, 95% confidence interval [CI] 0.50-0.93) or carboplatin + gemcitabine (HR 0.64, 95% CI 0.46-0.90), patients with PD-L1 tumors treated with carboplatin + gemcitabine (HR 0.67, 95% CI 0.39-1.14), and patients whose best response to chemotherapy was a complete response (HR 0.80, 95% CI 0.46-1.37), partial response (HR 0.62, 95% CI 0.46-0.84), or stable disease (HR 0.70, 95% CI 0.46-1.06). Observations were similar for PFS. Limitations include the smaller size and post hoc evaluation without multiplicity adjustment for some subgroups.
CONCLUSIONS
Analyses of OS and PFS in clinically relevant subgroups were consistent with results for the overall population, further supporting avelumab 1L maintenance as standard-of-care treatment for patients with aUC who are progression-free following 1L platinum-based chemotherapy.
PATIENT SUMMARY
In the JAVELIN Bladder 100 study, maintenance treatment with avelumab helped many different groups of people with advanced cancer of the urinary tract to live longer.
Topics: Humans; Cisplatin; Carboplatin; Carcinoma, Transitional Cell; Urinary Bladder; Urinary Bladder Neoplasms; Deoxycytidine; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37121850
DOI: 10.1016/j.eururo.2023.03.030 -
Cell Reports. Medicine Sep 2023Upper tract urothelial carcinoma (UTUC) is often diagnosed late and exhibits poor prognosis. Limited data are available on potential non-invasive biomarkers for disease...
Upper tract urothelial carcinoma (UTUC) is often diagnosed late and exhibits poor prognosis. Limited data are available on potential non-invasive biomarkers for disease monitoring. Here, we investigate the proteomic profile of plasma in 362 UTUC patients and 239 healthy controls. We present an integrated tissue-plasma proteomic approach to infer the signature proteins for identifying patients with muscle-invasive UTUC. We discover a protein panel that reflects lymph node metastasis, which is of interest in identifying UTUC patients with high risk and poor prognosis. We also identify a ten-protein classifier and establish a progression clock predicting progression-free survival of UTUC patients. Finally, we further validate the signature proteins by parallel reaction monitoring assay in an independent cohort. Collectively, this study portrays the plasma proteomic landscape of a UTUC cohort and provides a valuable resource for further biological and diagnostic research in UTUC.
Topics: Humans; Carcinoma, Transitional Cell; Urinary Bladder Neoplasms; Proteomics; Lymphatic Metastasis; Muscles
PubMed: 37633276
DOI: 10.1016/j.xcrm.2023.101166 -
Science Translational Medicine May 2023The recommended treatment for patients with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) is tumor resection followed by adjuvant Bacillus Calmette-Guérin...
The recommended treatment for patients with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) is tumor resection followed by adjuvant Bacillus Calmette-Guérin (BCG) bladder instillations. However, only 50% of patients benefit from this therapy. If progression to advanced disease occurs, then patients must undergo a radical cystectomy with risks of substantial morbidity and poor clinical outcome. Identifying tumors unlikely to respond to BCG can translate into alternative treatments, such as early radical cystectomy, targeted therapies, or immunotherapies. Here, we conducted molecular profiling of 132 patients with BCG-naive HR-NMIBC and 44 patients with recurrences after BCG (34 matched), which uncovered three distinct BCG response subtypes (BRS1, 2 and BRS3). Patients with BRS3 tumors had a reduced recurrence-free and progression-free survival compared with BRS1/2. BRS3 tumors expressed high epithelial-to-mesenchymal transition and basal markers and had an immunosuppressive profile, which was confirmed with spatial proteomics. Tumors that recurred after BCG were enriched for BRS3. BRS stratification was validated in a second cohort of 151 BCG-naive patients with HR-NMIBC, and the molecular subtypes outperformed guideline-recommended risk stratification based on clinicopathological variables. For clinical application, we confirmed that a commercially approved assay was able to predict BRS3 tumors with an area under the curve of 0.87. These BCG response subtypes will allow for improved identification of patients with HR-NMIBC at the highest risk of progression and have the potential to be used to select more appropriate treatments for patients unlikely to respond to BCG.
Topics: Humans; BCG Vaccine; Non-Muscle Invasive Bladder Neoplasms; Urinary Bladder Neoplasms; Adjuvants, Immunologic; Biological Assay
PubMed: 37224225
DOI: 10.1126/scitranslmed.abn4118 -
Cancer Research Jun 2023N6-Methyladenosine (m6A) is the most prevalent internal modification of mammalian mRNAs. Recent studies have shown that m6A methyltransferases METTL3 and METTL14 play...
UNLABELLED
N6-Methyladenosine (m6A) is the most prevalent internal modification of mammalian mRNAs. Recent studies have shown that m6A methyltransferases METTL3 and METTL14 play important roles in urothelial bladder carcinoma (BLCA). To provide a more comprehensive understanding of the m6A regulatory landscape in bladder cancer, we investigated the role of YTHDF2, a crucial m6A reader, in BLCA. YTHDF2 was frequently upregulated at both the RNA and protein level in BLCA. Functionally, YTHDF2 promoted the proliferation and tumor growth of BLCA cells in vitro and in vivo, respectively. Integrative RNA sequencing and m6A sequencing analyses identified RIG-I as a downstream target of YTHDF2. Mechanistically, YTHDF2 bound to the coding sequence of DDX58 mRNA, which encodes RIG-I, and mediated its degradation in an m6A-dependent manner. Knockdown of RIG-I inhibited apoptosis and promoted the proliferation of BLCA cells. Depleting RIG-I was also able to reverse the effects of YTHDF2 deficiency. YTHDF2-deficient BLCA cells implanted orthotopically in recipient mice activated an innate immune response and promoted recruitment of CD8+ T lymphocytes into the tumor bed and the urothelium. Moreover, YTHDF2 deficiency enhanced the efficacy of Bacillus Calmette-Guérin immunotherapy treatment. This study reveals that YTHDF2 acts as an oncogene in BLCA. YTHDF2 inhibits RIG-I to facilitate immune evasion, supporting testing YTHDF2 inhibition in combination with immunotherapy.
SIGNIFICANCE
YTHDF2 regulates RIG-I-mediated innate immune signaling to support bladder cancer progression, highlighting the functional importance of m6A modifications in bladder cancer and uncovering therapeutic opportunities to improve patient outcomes.
Topics: Animals; Mice; DEAD Box Protein 58; Immunity; Methyltransferases; Signal Transduction; Urinary Bladder; Urinary Bladder Neoplasms; Humans
PubMed: 36939388
DOI: 10.1158/0008-5472.CAN-22-2485 -
Molecular Biology Reports Sep 2023Urothelial bladder carcinoma (UC) ranks among the top ten most commonly diagnosed cancers worldwide on an annual basis. The standardized classification system for... (Review)
Review
Urothelial bladder carcinoma (UC) ranks among the top ten most commonly diagnosed cancers worldwide on an annual basis. The standardized classification system for urothelial bladder tumors is the Tumor, Node, Metastasis classification, which reflects differences between non-muscle-invasive bladder carcinoma (NMIBC) and muscle-invasive bladder carcinoma (MIBC) and it depends on the extent to which tumor has infiltrated the bladder wall and other tissues and organs. NMIBC and MIBC exhibit great intrinsic heterogeneity regarding different prognoses, survival, progression, and treatment outcomes. In recent years, studies based on mRNA expression profiling revealed the existence of biologically relevant molecular subtypes of UC, which show variant molecular features that can provide more precise stratification of UC patients. Here, we present a complex classification of UC based on mRNA expression studies and molecular subtypes of NMIBC and MIBC in detail with regard to different mRNA expression profiles, mutational signatures, and infiltration by non-tumor cells. The possible impact of molecular subtyping on treatment decisions and patients' outcomes is outlined, too.
Topics: Humans; Urinary Bladder; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Mutation; Neoplasm Invasiveness
PubMed: 37525073
DOI: 10.1007/s11033-023-08689-7 -
Advanced Science (Weinheim,... Sep 2023Although immune checkpoint blockade (ICB) therapies have been approved for bladder cancer (BLCA), only a minority of patients respond to these therapies, and there is an...
Although immune checkpoint blockade (ICB) therapies have been approved for bladder cancer (BLCA), only a minority of patients respond to these therapies, and there is an urgent need to explore combined therapies. Systematic multi-omics analysis identified S100A5 as a novel immunosuppressive target for BLCA. The expression of S100A5 in malignant cells inhibited CD8 T cell recruitment by decreasing pro-inflammatory chemokine secretion. Furthermore, S100A5 attenuated effector T cell killing of cancer cells by inhibiting CD8 T cell proliferation and cytotoxicity. In addition, S100A5 acted as an oncogene, thereby promoting tumor proliferation and invasion. Targeting S100A5 synergized with the efficacy of anti-PD-1 treatment by enhancing infiltration and cytotoxicity of CD8 T cells in vivo. Clinically, there was a spatially exclusive relationship between S100A5 tumor cells and CD8 T cells in tissue microarrays. Moreover, S100A5 negatively correlated with immunotherapy efficacy in our real-world and several public immunotherapy cohorts. In summary, S100A5 shapes a non-inflamed tumor microenvironment in BLCA by inhibiting the secretion of pro-inflammatory chemokines and the recruitment and cytotoxicity of CD8 T cells. Targeting S100A5 converts cold tumors into hot tumors, thus enhancing the efficacy of ICB therapy in BLCA.
Topics: Humans; CD8-Positive T-Lymphocytes; Urinary Bladder; Immunotherapy; Urinary Bladder Neoplasms; Carcinoma; Tumor Microenvironment
PubMed: 37414584
DOI: 10.1002/advs.202300110 -
European Review For Medical and... Nov 2023Bladder urothelial carcinoma is a rare condition that primarily affects the elderly and is rare in people under 40 years of age. There is no definitive information about...
OBJECTIVE
Bladder urothelial carcinoma is a rare condition that primarily affects the elderly and is rare in people under 40 years of age. There is no definitive information about the prognosis and clinical behavior of bladder cancer in young individuals. In our study, we aimed to investigate the prognosis and clinicopathological features of bladder tumors in patients under 40.
PATIENTS AND METHODS
A retrospective analysis was performed on patients diagnosed with urothelial neoplasia who underwent bladder surgery between January 2008 and December 2020. The patient's medical records in our cancer database were collected. The study included stage, grade, multifocality, smoking habits, recurrence, and survival. The cases were divided into two groups: those under 40 (Group 1) and those over 40 (Group 2). The clinical and pathological features of young and old patients were compared.
RESULTS
17 patients (14 men and 3 women) under 40 were identified. The age ranged between 19 and 40, and the average was 30.6. One infiltrating urothelial carcinoma (pT1), twelve papillary urothelial carcinomas (pTa), two papillary urothelial neoplasias with low malignant potential, and two urothelial papillomas were all identified by pathology. Dysuria was the primary symptom that initially manifested. Recurrence occurred in two of 12 patients with low-grade papillary urothelial carcinoma in the young patient group. In a similar group of patients over 40, recurrence was detected in 7 out of 10 patients. Patients with urothelial carcinoma under the age of 40 have been noted to have single, small tumors, unlike older patients. No tumor progression was detected in young patients. All young patients are still alive and have not experienced any recurrences. In the group of older patients, tumor progression was observed in 11 patients (16.4%).
CONCLUSIONS
Patients under 40 typically have low-grade and low-stage bladder urothelial cancer. Because urothelial tumors in young people frequently have a good prognosis and seldom recur, transurethral excision is the preferred treatment method for bladder tumors.
Topics: Male; Humans; Female; Adolescent; Aged; Urinary Bladder Neoplasms; Carcinoma, Transitional Cell; Retrospective Studies; Prognosis; Neoplasm Recurrence, Local
PubMed: 37975369
DOI: 10.26355/eurrev_202311_34320