HER2 Expression in Bladder Cancer: A Focused View on Its Diagnostic, Prognostic, and Predictive Role

Sanguedolce, Francesca; Zanelli, Magda; Palicelli, Andrea; Bisagni, Alessandra; Zizzo, Maurizio; Ascani, Stefano; Pedicillo, Maria Carmela; Cormio, Angelo; Falagario, Ugo Giovanni; Carrieri, Giuseppe; Cormio, Luigi

doi:10.3390/ijms24043720

Cited by 25 publications

(7 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Immunoexpression of HER-2 is observed in a subset of sarcomatoid and rhabdoid BUC, although most cases did not harbor HER-2 gene amplification. This data is comparable to what was observed in conventional BUC cases 10 . However, a HER-2 low-content may have impact on the use of new generation drugs which does have effect using the protein bridges of the membranes of neoplastic cells.…”

Section: Discussionsupporting

confidence: 90%

TROP-2, NECTIN-4 and predictive biomarkers in sarcomatoid and rhabdoid bladder urothelial carcinoma

Brunelli,

Gobbo,

Malpeli

et al. 2024

Pathologica

Self Cite

View full text Add to dashboard Cite

Summary Introduction The surface protein TROP-2/ TACSTD2 and the cell adhesion protein NECTIN-4/ NECTIN4 are responsible for the efficacy of anticancer therapies based on antibody-drug conjugates (ADC) targeting intracellular microtubules. In contrast with common histologic subtypes of bladder urothelial carcinoma (BUC), little is known of TROP-2 and NECTIN-4 expression in sarcomatoid and rhabdoid BUC. Aims In this study, we aimed to analyze TROP-2 and NECTIN-4 expression and additional predictive biomarkers by immunohistochemistry and fluorescence in situ hybridization (FISH) on 35 undifferentiated BUC (28 sarcomatoid and 7 rhabdoid). Wide genomic investigation was also performed on 411 BUC cases of the PanCancer Atlas, focusing on genes related to the microtubule pathways. Results Seven of 35 (20%) undifferentiated BUC showed expression of TROP-2. NECTIN-4 was expressed in 10 cases (29%). Seven cases (20%) co-expressed TROP-2 and NECTIN-4. HER-2 FISH was amplified in 5 cases (14%) while HER-2 immunoexpression was observed in 14 cases (40%). PD-L1 scored positive for combined proportion score (CPS) in 66% of cases and for tumor proportion score (TPS) in 51% of cases. Pan-NTRK1-2/3 was elevated in 9 cases (26%) and FGFR-2/3 was broken in 7 of 35 cases (20%). Of 28 sarcomatoid BUC, 9 (32%) were negative for all (TROP-2, NECTIN-4, PD-L1, HER-2 , FGFR and pan-NTRK) biomarkers and 3 (11%) expressed all five biomarkers. Among cases with rhabdoid dedifferentiation, 1 of 7 (14%) showed activation of all biomarkers, whereas 2 of 7 (28%) showed none. The mRNA analysis identified microtubule-related genes and pathways suitable for combined ADC treatments in BUC. Conclusion Sarcomatoid and rhabdoid BUC do harbor positive expression of the ADC targets TROP-2 or NECTIN-4 in a relatively modest subset of cases, whereas the majority do not. Different combinations of other positive biomarkers may help the choice of medical therapies. Overall, these findings have important clinical implications for targeted therapy for BUC.

show abstract

Section: Discussionsupporting

confidence: 90%

TROP-2, NECTIN-4 and predictive biomarkers in sarcomatoid and rhabdoid bladder urothelial carcinoma

Brunelli,

Gobbo,

Malpeli

et al. 2024

Pathologica

Self Cite

View full text Add to dashboard Cite

show abstract

“…HER2 levels are well established to have prognostic value in breast and some gastrointestinal cancers. 83 In bladder cancer, HER2 overexpression strongly correlates with tumor progression and a poor prognosis. 84 The success achieved with HER2-targeted ADCs in other cancers 85 has generated interest to study its potential efficacy in UC, with multiple completed and ongoing trials ( Tables 4 and 5 ).…”

Section: Her2 Targeting Therapiesmentioning

confidence: 99%

“…Some studies have shown that HER2 overexpression is associated with shorter PFS, whereas other studies have shown a more positive prognosis. 83 The Destiny-Pantumor-02 trial suggested that patients with higher levels of HER2 positivity may be associated with a better response to treatment with T-DXd, although patients with low expression may respond as well. 90 While some level of HER2 expression is a prerequisite for treatment with a HER2 ADC, the absolute level of expression may not substantially affect treatment decisions.…”

Section: Biomarkersmentioning

confidence: 99%

Systematic review of recent advancements in antibody-drug and bicycle toxin conjugates for the treatment of urothelial cancer

Domb,

Garcia,

Barata

et al. 2024

Therapeutic Advances in Urology

View full text Add to dashboard Cite

Antibody-drug conjugates and bicycle toxin conjugates represent a tremendous advance in drug delivery technology and have shown great promise in the treatment of urothelial cancer. Previously approved systemic therapies, including chemotherapy and immunotherapy, are often impractical due to comorbidities, and outcomes for patients with advanced disease remain poor, even when receiving systemic therapy. In this setting, antibody-drug and bicycle toxin conjugates have emerged as novel treatments, dramatically altering the therapeutic landscape. These drugs harness unique designs consisting of antibody or bicycle peptide, linker, and cytotoxic payload with more targeted delivery than conventional chemotherapy, thus eliminating malignant cells while reducing systemic toxicities. Potential targets investigated in urothelial cancer include Nectin-4, TROP2, HER2, and EphA2. Initial clinical trials demonstrated efficacy in treatment of refractory advanced urothelial cancer, as well as improvement in quality of life. These initial studies led to FDA approval of two antibody-drug conjugates, enfortumab vedotin and sacituzumab govitecan. Moreover, antibody-drug and bicycle toxin conjugates are being studied in ongoing clinical trials in frontline treatment of advanced disease as well as for localized cancer. These studies highlight the potential for additional future therapies with novel targets, novel antibodies, cytotoxic and immunomodulatory payloads, and unique structural designs enhancing efficacy and safety. There is increasing evidence that combinations with other cancer therapies, especially immunotherapy, improve treatment outcomes. The combination of enfortumab vedotin and pembrolizumab was recently approved for first-line treatment of advanced urothelial carcinoma. Despite the great promise of these novel drugs, robust predictive biomarkers are needed to determine the patients who would maximally benefit. This review surveys the rationale and current state of the evidence for these new drugs and describes future directions actively being explored.

show abstract

“…Globally, bladder cancer is the 7th most common cancer and the 13th most common cause of cancer-related death [1]. Urothelial carcinoma (UC) is the most common histologic type, constituting about 90% of all bladder cancers [2].…”

Section: Introductionmentioning

confidence: 99%

N-myc downstream–regulated gene 1 can promote vasculogenic mimicry and angiogenesis in urothelial carcinoma

Louis,

Abdelkawi,

Refaiy

et al. 2024

Virchows Arch

View full text Add to dashboard Cite

Urothelial carcinoma (UC) of the bladder is a common cause of cancer-related death worldwide. Vasculogenic mimicry (VM) is a process by which the malignant cells can generate vascular-like structures formed of periodic acid–Schiff (PAS) positive/CD31 negative extracellular matrix independent of angiogenesis and thus promotes tumor progression. N-myc downstream–regulated gene 1 (NDRG1) is a protein that can modulate tumor angiogenesis; however, its role in regulating tumor angiogenesis and VM formation has not been previously investigated in UC. This study aims to evaluate the role of intra-tumor microvessel density (MVD) (as a surrogate measure of angiogenesis), VM, and NDRG1 in UC and their correlation with different clinicopathologic features, then assess the correlation between them in UC. Sixty specimens of UC of the bladder were included. PAS-CD31 immunohistochemical double staining method was used to evaluate the intra-tumor MVD and VM. Immunohistochemical expression of NDRG1 was also examined. VM and NDRG1 expression were detected in 41.7% and 83.3% of UC specimens respectively. The mean of intra-tumor MVD, VM area, and NDRG1 was significantly higher in tumors with higher grade, lymphovascular invasion, and higher T stage. NDRG1 expression was positively correlated with MVD and VM. We can suggest that MVD, VM, and NDRG1 may serve as poor prognostic markers for UC. The positive correlation between NDRG1 and both MVD and VM may provide the first evidence that NDRG1 can induce tumor angiogenesis and VM in UC which may offer a novel pathway for further therapeutic strategies.

show abstract

HER2 Expression in Bladder Cancer: A Focused View on Its Diagnostic, Prognostic, and Predictive Role

Cited by 25 publications

References 96 publications

TROP-2, NECTIN-4 and predictive biomarkers in sarcomatoid and rhabdoid bladder urothelial carcinoma

TROP-2, NECTIN-4 and predictive biomarkers in sarcomatoid and rhabdoid bladder urothelial carcinoma

Systematic review of recent advancements in antibody-drug and bicycle toxin conjugates for the treatment of urothelial cancer

N-myc downstream–regulated gene 1 can promote vasculogenic mimicry and angiogenesis in urothelial carcinoma

Contact Info

Product

Resources

About