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Her2 alterations in muscle-invasive bladder cancer: Patient selection beyond protein expression for targeted therapy
Bernhard Kiss1, Alexander W Wyatt2, James Douglas3
1Department of Urology, University of Bern, Bern, Switzerland.
Abstract:
Although the introduction of novel targeted agents has improved patient outcomes in several human cancers, no such advance has been achieved in muscle-invasive bladder cancer (MIBC). However, recent sequencing efforts have begun to dissect the complex genomic landscape of MIBC, revealing distinct molecular subtypes and offering hope for implementation of targeted therapies. Her2 (ERBB2) is one of the most established therapeutic targets in breast and gastric cancer but agents targeting Her2 have not yet demonstrated anti-tumor activity in MIBC. Through an integrated analysis of 127 patients from three centers, we identified alterations of Her2 at the DNA, RNA and protein level, and demonstrate that Her2 relevance as a tumor driver likely may vary even within ERBB2 amplified cases. Importantly, tumors with a luminal molecular subtype have a significantly higher rate of Her2 alterations than those of the basal subtype, suggesting that Her2 activity is also associated with subtype status. Although some of our findings present rare events in bladder cancer, our study suggests that comprehensively assessing Her2 status in the context of tumor molecular subtype may help select MIBC patients most likely to respond to Her2 targeted therapy.
Insights
Targeted therapies for muscle-invasive bladder cancer (MIBC) are lacking. This study reveals Her2 alterations in MIBC, suggesting Her2 status and molecular subtype are key to selecting patients for Her2-targeted treatments.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Muscle-invasive bladder cancer (MIBC) lacks targeted therapies despite advances in other cancers.
- Her2 (ERBB2) is a validated target in breast and gastric cancers, but its role in MIBC is unclear.
- Genomic sequencing is beginning to reveal molecular subtypes within MIBC.
Purpose of the Study:
- To investigate the role of Her2 (ERBB2) alterations in muscle-invasive bladder cancer (MIBC).
- To determine if Her2 alterations correlate with specific molecular subtypes of MIBC.
- To explore the potential of Her2-targeted therapies in MIBC based on molecular profiling.
Main Methods:
- Integrated analysis of DNA, RNA, and protein level Her2 (ERBB2) alterations in 127 MIBC patients from three centers.
- Correlation analysis between Her2 alteration status and MIBC molecular subtypes (luminal vs. basal).
- Assessment of Her2 protein expression and potential as a driver mutation.
Main Results:
- Identified various Her2 (ERBB2) alterations across DNA, RNA, and protein levels in MIBC.
- Demonstrated that the relevance of Her2 as a tumor driver can vary, even in cases with ERBB2 amplification.
- Found a significantly higher rate of Her2 alterations in luminal molecular subtype MIBC compared to basal subtype.
- Observed that Her2 activity is associated with MIBC molecular subtype.
Conclusions:
- Comprehensive assessment of Her2 (ERBB2) status in MIBC is crucial.
- Her2 status should be evaluated in the context of tumor molecular subtype (luminal vs. basal).
- This approach may help identify MIBC patients most likely to benefit from Her2-targeted therapies.
