Her-2 Targeted Therapy in Advanced Urothelial Cancer: From Monoclonal Antibodies to Antibody-Drug Conjugates

Abstract

Metastatic urothelial cancer, associated with a poor prognosis, is still major cause of cancer-related death, with scarce options of effective treatment after progression to platinum-based chemotherapy and immunotherapy. The human epithelial growth factor receptor 2 (Her-2) has been identified as a new therapeutic target in medical oncology. However, despite the encouraging results in breast and gastric cancers, clinical trials with anti-Her-2 monoclonal antibodies and tyrosine-kinase inhibitors have shown limited efficacy of this strategy in urothelial tumors. Notably, more favorable data have been recently shown that antibody-drug conjugates are currently emerging as a novel promising approach for Her-2 targeted therapy in advanced urothelial cancer.

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

“…Higher HER2 levels have well-known prognostic and predictive roles in breast and gastroesophageal cancers, where immunohistochemistry (IHC) is routinely used to assess HER2 status at the protein level [ 15 ]. In this setting, patients are stratified according to the presence/absence, intensity, and completeness of the membrane staining in the tumor cells, whereas in situ hybridization methods (namely, chromogenic in situ hybridization (CISH) and fluorescence in situ hybridization (FISH)), are regarded as second-level techniques to be performed in case of equivocal results [ 16 , 17 ]. HER2-positivity is currently defined as intense protein overexpression in >10% of the tumor cells by IHC, or HER2 gene amplification by FISH in breast and gastroesophageal cancer [ 18 ]; these classification systems have been applied by most but not all studies, resulting in poor validation.…”

“…However, a high concordance between HER2 protein overexpression and gene amplification in BC has been described in studies based on large data sets [ 18 , 21 , 22 ]. Conversely, other authors have failed to report an optimal correlation between HER2 gene amplification and protein overexpression, possibly due to epigenetic factors and technique-related factors [ 16 , 17 ]. Obviously, literature findings should be weighted in relation to the geographical, clinical, and pathological characteristics, as well as the number of study cohorts.…”

“…Over the years, HER2 expression has been evaluated in BC as well, among other potential biomarkers, with a view to implementing its use in clinical practice [ 23 , 24 ]. As a potential therapeutic target, HER2 has been assessed in clinical trials using anti-HER2 monoclonal antibodies and tyrosine-kinase inhibitors, either in monotherapy or combined with conventional chemotherapy, as second-line treatments in patients with advanced or metastatic BC; however, such phase II trials did not yield acceptable results, with low overall response rates [ 16 ]. More recently, ADCs targeting HER2 (among other molecules), such as trastuzumab emtansine, trastuzumab duocarmazine, and disitamab vedotin, showed promising results in multi-tumor basket clinical trials; a further such agent with an enhanced pharmacokinetic profile, namely trastuzumab deruxtecan, is currently under evaluation [ 16 ].…”

Molecular Targeting of the Human Epidermal Growth Factor Receptor-2 (HER2) Genes across Various Cancers

“…Urothelial cancer has the third highest rate of HER2 overexpression after breast and gastric cancers, with a wide range from 8.5% to 81% of cases and mutations in and amplifications of HER2 in approximately 6-17% of tumors [141,142]. HER2 overexpression could be correlated with lymph node positivity, a greater tumor stage, and lower OS, and, thus, overall a worse prognosis [142][143][144]. However, HER2 amplification could also be a bystander event in most muscle-invasive bladder cancers (MIBCs).…”

“…Anti-HER2 TKIs and antibody-drug conjugates are currently being investigated in different clinical trials [142]. Currently, anti-HER2 therapy is not yet approved or recommended in bladder cancer.…”