Current and Emerging Strategies to Treat Urothelial Carcinoma
Abstract
:Simple Summary
Abstract
1. Introduction
1.1. Overview
1.2. Environmental and Hereditary Risk Factors for Urothelial Cancers
1.3. Novel Approaches for Urothelial Cancers
2. Divergent Mechanisms Underlying Urothelial Tumorigenesis and Treatment Resistance
2.1. Invasive and Non-Invasive UCC
2.2. Cell Cycle Alterations
2.3. Influence of Angiogenesis on Invasion and Metastasis
2.4. Effect of Hypoxia on UCC Invasion and Metastasis
2.5. Immune Dysregulation in UCC
3. Screening, Diagnostic Approach and Staging of Urothelial Carcinoma
4. Current Treatment of UCC
4.1. Initial Treatment
4.2. Bladder Preservation in UCC
4.3. Surgical
4.4. Single Agent and Combination Chemotherapy
5. Emerging Strategies to Treat UCC
5.1. Targeting FGFR
5.2. Immune Checkpoint Inhibitors
5.3. Antibody-Drug Conjugates
5.4. Cellular Vaccines and Oncolytic Viruses
5.5. CAR-T Therapy
5.6. Antiangiogenics
5.7. Herbal Medicines
6. Molecular Classification as a Prognostic to Guide Treatment Decisions
Chemotherapy | No. of Patients | Patient Positivity, % | Stage of Disease | Comments |
---|---|---|---|---|
DNA Damage Repair Pathways Nucleotide Excision Repair ERCC1 Expression, ERCC2 Mutations | 100 Patients | 47 | Locally advanced and mUCC | mRNA obtained from patient tumor biopsies and analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) was used to measure mRNA levels of several DNA repair genes. Deleterious mutations in an NER pathway helicase, ERRC2, are predictive of cisplatin sensitivity in bladder cancer patients. DNA repair deficiency phenotype predicts benefit from platinum-based chemotherapy. |
Microsatellite Instability (MSI) | 44 patients | 40.6 | NMIBC and MIBC | DNA from patient tumor biopsies was used to assess microsatellite sequence length using Polymerase chain reaction (PCR). MSI-H status in UC predicts deep and durable responses to CPI and is associated with inferior chemotherapy responses. CPI should be considered for first-line treatment in this subset of patients [169] |
APOBEC mutational signature | 307 patients | Up to 70 | mUCC | Using patient tumor biopsies, genomic DNA was isolated and assayed using whole-exome sequencing (WES) and targeted next-generation sequencing (NGS) techniques to assess for APOBEC mutational signature. APOBEC-high are more likely to have mutations in DNA damage response genes (TP53, ATR, BRCA2) and chromatin regulatory genes (ARID1A, MLL, MLL3), potentially leading to a hypermutation phenotype and subsequent enhanced immune response against the tumor. IMvigor-130 trial- mUC patients with APOBEC mutational signature had significantly higher TMB and improved OS with atezolizumab containing regimens in the first-line cisplatin-ineligible scenario [170] |
Immunotherapy Markers | ||||
PD-L1—IHC | 40 patients | 20–72 | Locally advanced and mUCC | Patient tumor biopsies were assayed for PDL1 expression using immunohistochemistry (IHC) and expressed as a combined positive score (CPS, positive tumor cells and immune cells divided by the total number of cells). PD-L1 expression and high (TMB) may predict better responses to ICIs, but patients without these biomarkers may still respond to immunotherapy. Additional caveats include a lack of standardization, tumor heterogeneity and other factors influencing the TME. |
PD-L1 IHC PD-L1 (CD274)—Amplification TMB MSI | Genitourinary tumors (0.4%, 10/2420) | Protein expression- using a CPS 1 cutoff for UC, the positive prevalence was 83.6% (989/1183) Prevalence of 0.7% from 1183 patients TMB- Urothelial carcinoma (36.0%, 426/1183). MSI-H Prevalence 1.2% of 1183 patients | Locally advanced and mUCC | Retrospective pan-cancer analysis of PD-L1 immunohistochemistry and gene amplification, tumor mutation burden and microsatellite instability in 48,782 cases. analysis of all cases in which both PD-L1 IHC (using the DAKO 22C3 IHC assay with either tumor proportion score (TPS) or combined positive score (CPS); or the VENTANA SP142 assay with infiltrating immune cell score (IC)) and comprehensive genomic profiling (CGP) were tested at Foundation Medicine between January 2016 and November 2019. PD-L1 positivity was defined per the CDx indication and tumor proportion score (TPS ≥ 1) for indications without a CDx claim; and TMB positivity is defined as ≥10 mutations/Mb. A total of 48,782 cases were tested for PD-L1 IHC and CGP. Patient tumor biopsies were assayed for PD-L1 amplification using PD-L1 RNA in situ hybridization (RNAish). PD-L1 amplification was detected in only 0.7% of solid tumors. Amplification had a low correlation with PD-L1 IHC and did not correlate with TMB. |
Tumor Mutational Burden (TMB) | 401 patients | 30.4 | Locally advanced and mUCC | Genomic DNA was isolated from patient tumor biopsies and characterized for mutational burden using NGS. TMB ≥ 10 mutations per megabase was detected in 122 of 401 (30.4%) patients. Total of 191 linked to response to ICI. High TMB correlated with response in certain solid tumor types: melanoma and NSCLC. May correlate mUCC. TMB assessment is multi-factorial. |
Inflammatory Gene Signatures | Checkmate-275 trial indicated a better response to Nivolumab therapy. | |||
ARID1A mutation + CXCL13 expression levels | 275 patients + 348 patients | 50.5% 62% | Locally advanced and mUCC | DNA and RNA were isolated from patient tumor biopsies and characterized using NGS. Interrogated CXCL13 expression and ARID1A mutation as a combination biomarker in predicting response to ICT in CheckMate275 and IMvigor210. The combination of the two biomarkers in baseline tumor tissues suggested improved OS compared to either single biomarker. Cumulatively, this study revealed that the combination of CXCL13 plus ARID1A may improve prediction capability for patients receiving ICT. |
TRAF2 loss | 116 patients | 73% | Patient tumor biopsies were analyzed using whole-exome sequencing, RNA-seq, proteomic, and phosphoproteomic analysis to describe TRAF2 status. Proteomic analysis identified three groups reflecting distinct clinical prognoses and molecular signatures. Immune subtypes of UC tumors revealed a complex immune landscape and suggested that TRAF2 amplification is related to the increased expression of PD-L1. Increased GARS was validated to promote the pentose phosphate pathway by inhibiting activities of PGK1 and PKM2. | |
CCND1 amplification | 152 patients | Primary homogeneous 15% Primary- heterogeneous 6% Metastasis- homogeneous 22% Metastasis- heterogeneous 2% | Lymph node (LN)-positive UCC pts | CCND1 and expression of CyclinD1 were evaluated by fluorescence in situ hybridization and immunohistochemistry on patient tumor biopsies obtained from node-positive urothelial bladder cancers. |
Targeted Therapies | ||||
FGFR alterations | 87 patients | 10–30% | Locally advanced and mUCC | DNA was isolated from patient tumor biopsies and characterized using NGS for FGFR single nucleotide variants, gene fusions or copy number abnormalities. Aberrantly activated through single-nucleotide variants, gene fusions and CNA in 5–10% of all human cancers, frequency increases to 10–30% in UC. Numerous FGFR inhibitors are currently being assessed in preclinical, Phase 1, Phase 2 and Phase 3 clinical trials. Erdafitinib and pemigatinib are currently the only approved inhibitors for use in the treatment of patients with FGFR-altered UC and Cholangiocarcinoma. UC patients with an increased frequency of FGFR3 point mutations tend to respond better to TKI therapy FGFR fusions- Clinical-grade NGS diagnostics to detect FGFR fusions and SNVs using tissue and ctDNA. Rapid identification of patients for targeted therapies and the real-time detection of acquired mutations that signal impending treatment resistance and cancer progression. |
NECTIN4 | 169 patients | 59.7% | All NMIBC and MIBC were included | Patient tumor biopsies were analyzed using IHC for Nectin-4 expression. High expression of Nectin-4 in squamous cell carcinoma and adenocarcinoma may guide treatment with novel Nectin-4-directed ADCs and provide a high-risk patient collective with a new promising therapeutic option. Nectin-4-directed therapy enfortumab vedotin, an ADC comprised of a fully human monoclonal antibody specific for nectin-4 conjugated through a cleavable linker to the microtubule inhibitor MMAE. Nectin-4 was not prognostic in histological subtypes of BC [171] |
TROP2 | >1400 patients | Up to 82% | Refractory mUCC | Patient tumor biopsies were analyzed using IHC for TROP2 expression. Sacituzumab Govitecan (SG) is an ADC targeting TROP2, approved for treatment-refractory mUC. Using gene expression data from four clinical cohorts with >1400 patient samples of muscle-invasive BC and a BC tissue microarray, we found that TROP2 mRNA and protein are highly expressed across basal, luminal, and stroma-rich subtypes, but depleted in the neuroendocrine subtype. High levels of TROP2 in most subtypes were detected except in the neuroendocrine subtype. TROP2 expression is higher than NECTIN4 expression, and cells resistant to enfortumab vedotin, remain sensitive to SG. |
Erb2 (Her2, EGFR) | 128 patients | 10.5% | LN-positive disease and mUCC | Patient tumor biopsies were analyzed using IHC for ERBB2 expression. ERBB2 overexpression and amplification were linked with high-grade and high-stage upper-tract urothelial CA (UTUCs) tumors and with tumor progression. Results suggest that ERBB2 is a biomarker for progression in UTUCs. |
PI3K/AKT/mTOR/MAPK | 45 patients | ~42% in PI3K/AKT/mTOR 17% activating point mutations in PIK3CA 10% overexpression of AKT3 9% with mutations or deletions of TSC1/2 | Refractory UC | DNA was isolated from patient tumor biopsies and mutations in mTOR genes were assayed by NGS. Limited clinical benefit with targeting this pathway in advanced UC. Phase II, single-arm, non-randomized study with everolimus in refractory UC showed minimal response with median PFS 2.6 months, median OS 8.3 months, and 2 responses seen in 45 patients. |
DNA Damage Repair (DDR) Gene Abnormalities | 19 patients | Alterations in DDR in up to 25% | mUCC | DNA was isolated from patient tumor biopsies and alterations in DNA damage repair genes were assayed by NGS. Single-agent olaparib showed limited antitumor activity in patients with mUC and DDR alterations. May relate to poorly characterized functional implications of particular DDR alterations and/or cross-resistance with platinum-based chemotherapy [159] |
VEGF | 40 patients | 82% | LN-positive disease and mUCC | Patient tumor biopsies were analyzed using IHC for VEGF expression. The proportion of VEGF+ cells were defined to calculate a proportion score. The relative intensity was quantitated into an intensity score. Finally, a total immunostaining score was determined as the product of a proportion score and intensity score. Elevated VEGF correlates with worse outcome. VEGF pathway inhibition attenuates tumor proliferation and invasion. Ramucirumab, a fully humanized monoclonal antibody that binds VEGF receptor 2, has shown benefit both in randomized phase II and III trials. Results with sunitinib, pazopanib, vandetinib, or cabozantinib were not convincing. |
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Gene | Chromosomal Location | Genetic Alteration | Frequency Observed in MIBC Tumors |
---|---|---|---|
Chromosome | |||
9p | Deletion | 21–30% | |
9q | Deletion | 17% | |
Oncogenes | |||
HRAS | 11p15 | Activating mutation | 10–15% |
FGFR3 | 4p16 | Activating mutation | ~50% Overexpression |
15% Mutation | |||
PIK3CA | 3q26 | Activating mutation | 25% |
MDM2 | 12q13 | Overexpression | 4% Overexpression |
Tumor suppressor genes | |||
TP53 | 17p13 | Deletion or mutation | 70% |
RB1 | 13q14 | Deletion or mutation | 37% |
PTEN | 10q23 | Homozygous deletion or mutation | LOH 30–35% |
Mutation 17% | |||
CDKN2A | 9p21 | Homozygous deletion or methylation or mutation | HD 20–30% |
LOH ~60% | |||
PTCH | 9q22 | Deletion or mutation | LOH ~60% |
Mutation rare | |||
DBC1 | 9q32–33 | Deletion or methylation | LOH ~60% |
TSC1 | 9q34 | Deletion or mutation | LOH ~60% |
Mutation ~15% |
Trial | Patient Characteristics | Regimen | Primary & Secondary End Points | Common AEs | Results |
---|---|---|---|---|---|
BLC2001 Phase 2 study in mUCC patients | 99 patients with FGFR alteration, who have progressed on chemotherapy or immunotherapy | Erdafitinib 8 mg in either an intermittent or continuous regimen | Primary end point was ORR and secondary end points were PFS, OS and duration of response. | Hyperphosphatemia, Stomatitis and diarrhea. | ORR was 40%. |
KEYNOTE-045 Phase 3 trial in mUCC | 542 patients who recurred or progressed after platinum-based chemotherapy | Pembrolizumab at a dose of 200 mg every 3 weeks or the investigator’s choice of chemotherapy with paclitaxel, docetaxel, or vinflunine | Co-primary endpoints were OS and PFS, among all patients and among patients who had PD-L1 CPS of 10% or more. | Pruritus, fatigue, and nausea | OS was 8 vs. 5.2 mos. PFS did not demonstrate a significant difference. |
JAVELIN Bladder-100—Phase 3 trial in unresectable locally advanced & mUCC | 700 patients who completed 1st line chemotherapy without progression. | Maintenance avelumab 10 mg/kg IV q2 weekly vs. best supportive care | Primary end point was OS and secondary end points included PFS and safety. | Fatigue, pruritus and urinary tract infections. | OS at 1 year was 71.3 compared to 58.4%. Median PFS was 3.7 vs. 2.0 mos. |
CheckMate-274 Phase 3 trial with MIBC. | 709 patients with MIBC who had undergone radical cystectomy. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. | Adjuvant Nivolumab 240 mg IV or placebo q2 weeks for up to 1 year vs. Placebo. | Primary end point was DFS. Secondary end point was survival free from recurrence outside the urothelial tract. | Pruritus, fatigue, and diarrhea | DFS was 20.8 mos with nivolumab and 10.8 mos with placebo. Patients who were free from recurrence outside the urothelial tract at 6 mos was 77 vs. 63%. |
EV-301 Phase 3 trial in locally advanced or mUCC | 608 patients who had previously received platinum-containing CHT and had disease progression during or after treatment with a PD-1 or PD-L1 inhibitor | Enfortumab vedotin 1.25 mg/kg on days 1, 8, 15 of a 28-day cycle or investigator-chosen CHT on day 1 of a 21-day cycle. | The primary end point was overall survival. | Alopecia, Peripheral sensory neuropathy, Pruritus. | Median OS was 12.8 vs. 8.9 mos. |
TROPHY-U- Phase II in mUCC | 113 patients who previously received platinum-containing CHT and had disease progression during or after treatment with a PD-1 or PD-L1 inhibitor | Sacituzumab govitecan 10 mg/kg on days 1 and 8 of 21-day cycles | objective response rate (ORR) secondary end points were PFS, OS, duration of response, and safety | neutropenia (3%) leukopenia (18%), anemia | ORR of 27% |
DANUBE- Phase 3 trial | 1032 patients that had received Durvalumab (346), Durvalumab+ Tremelimumab(342), or chemotherapy(344) in patients with untreated, unresectable or locally advance mUCC | Durvalumab (1500 mg) IV q4 weeks; Durvalumab (1500 mg)+ Tremelimumab (75 mg) IV q4 weeks for up to 4 doses, followed by durvalumab maintenance (1500 mg) q4 weeks; or SOC chemotherapy (gemcitabine + cisplatin/carboplatin) IV for up to 6 cycles. | Co-primary endpoints were OS compared b/w durvalumab and CT in pts whose tumor cells and/or tumor-infiltrating immune cells express high levels of PD-L1 (≥25%) and between durvalumab + tremelimumab and CT regardless of PD-L1 expression | Increased lipase in the Durvalumab Group and neutropenia in the chemotherapy group. | Did not meet either of the co-primary endpoints. |
Checkmate 901 | 608 patients were randomized to either Nivolumab + Ipilumimab with chemotherapy or chemotherapy alone. | Nivolumab 360 mg combined with CHT every 3 weeks or CHT alone. | Dual endpoints were PFS and OS | Pruritis, fatigue, diarrhea, pneumonitis | Met its dual primary end points |
KEYNOTE-361 Phase 3 trial | 1010 patients were randomly assigned to receive Pembrolizumab with CHT or Pembrolizumab alone or CHT alone | Pembrolizumab 200 mg q3 weeks for a maximum of 35 cycles + IV CHT on D 1 and 8 vs. CHT on day 1 of every 3-week cycle for a maximum of 6 cycles | Dual primary endpoints of OS and PFS. Secondary endpoints included duration of response, disease control rate, overall response rate and safety | Fatigue, musculoskeletal pain, decreased appetite, constipation, rash, and diarrhea | Did not meet either of the endpoints. |
DISCUS (ONGOING) | 224 eligible and evaluable patients (112 in each arm) to receive 3 vs. 6 cycles of platinum-based CHT + Avelumab in 1st line of mUCC | Gemcitabine on D1 and D8 with Carboplatin/Cisplatin on D1 and Avelumab every 2weekly. | QoL as measured by the change from baseline in EORTC QLQ-C30 questionnaire GHS/QoL scale scores from baseline to the completion of 6 cycles of treatment | ||
Main-CAV Alliance A032001 (ONGOING) | Maintenance Cabozantinib+Avelumab vs. Avelumab in 1st line mUCC with clinical benefit after platinum-based CHT | Avelumab 800 mg IV q2 wk or combination of Avelumab and CABO 40 mg orally daily for up to 2 yrs | OS |
Type of Treatment | Examples | Mechanism of Action | Indications | Adverse Events |
---|---|---|---|---|
Chemotherapy | Gemcitabine, Cisplatin, Methotrexate | Kills rapidly dividing cancer cells | Advanced/metastatic stages. Contraindications include ECOG, hearing disorder, heart failure, peripheral neuropathy and Creatinine Cl <60. | Nausea and vomiting. Loss of appetite, Hair loss, Mouth sores, Diarrhea, Constipation |
Immunotherapy (PD-1/PD-L1 inhibitors) | Pembrolizumab, Atezolizumab | Blocks PD-1/PD-L1 interaction, boosting immune response | Advanced/metastatic stages. Unresponsive to other treatments. Indicated as frontline for platinum-ineligible patients. | Fatigue, Nausea, Loss of appetite, Fever, Urinary tract infections (UTIs) |
FGFR3 Inhibitors | Erdafitinib | Inhibits FGFR3, a gene mutation common in UCC | Advanced/metastatic with FGFR3 mutation. Progressed on prior treatment | Hyperphosphatemia, Stomatitis and diarrhea. |
Antibody-Drug Conjugates | Enfortumab vedotin | Targeted delivery of toxic agents to tumor cells that express Nectin-4 | Advanced/metastatic stages. Progressed on prior cisplatin-based therapy or immunotherapy. | Alopecia, Peripheral sensory neuropathy, pruritus. |
CAR-T Cell Therapy | Currently not approved for mUCC | Autologous patient T-cells engineered to express a chimeric antigen receptor (CAR) directed against a cancer cell target. Potential targets include EGFR, MUC1, PD-1, HER2 and PSMA. | Under clinical investigation | Immune effector cell-associated neurotoxicity syndrome (ICANS), Cytokine Release Syndrome (CRS) |
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Rani, B.; Ignatz-Hoover, J.J.; Rana, P.S.; Driscoll, J.J. Current and Emerging Strategies to Treat Urothelial Carcinoma. Cancers 2023, 15, 4886. https://doi.org/10.3390/cancers15194886
Rani B, Ignatz-Hoover JJ, Rana PS, Driscoll JJ. Current and Emerging Strategies to Treat Urothelial Carcinoma. Cancers. 2023; 15(19):4886. https://doi.org/10.3390/cancers15194886
Chicago/Turabian StyleRani, Berkha, James J. Ignatz-Hoover, Priyanka S. Rana, and James J. Driscoll. 2023. "Current and Emerging Strategies to Treat Urothelial Carcinoma" Cancers 15, no. 19: 4886. https://doi.org/10.3390/cancers15194886
APA StyleRani, B., Ignatz-Hoover, J. J., Rana, P. S., & Driscoll, J. J. (2023). Current and Emerging Strategies to Treat Urothelial Carcinoma. Cancers, 15(19), 4886. https://doi.org/10.3390/cancers15194886