ERBB2 Copy Number Alterations and Protein Expression in Bladder Cancer Treated by Cystectomy

Area of Science:

• Oncology
• Genetics
• Pathology

Background:

• Antibody-drug-conjugates (ADCs) targeting HER2 have increased interest in ERBB2 alterations in bladder cancer.
• Limited data exists on ERBB2 copy number alterations (CNAs) frequency across bladder cancer subtypes and nodal metastases.
• The impact of ERBB2 amplification on protein expression requires further investigation.

Purpose of the Study:

• To determine the frequency of ERBB2 CNAs and protein expression in primary bladder cancer subtypes.
• To analyze ERBB2 amplification in regional nodal metastases and its concordance with primary tumors.
• To assess the relationship between ERBB2 amplification and protein expression.

Main Methods:

• Tissue microarrays (TMAs) from 820 primary bladder cancers and 209 nodal metastases were analyzed.
• ERBB2 copy numbers were assessed using fluorescence in situ hybridization (FISH).
• Protein expression was evaluated by immunohistochemistry (IHC); ERBB2 ploidy was compared to NECTIN4 ploidy in a subset.

Main Results:

• ERBB2 amplification was found in 7.4% of primary bladder cancers, with varying frequencies across subtypes (e.g., 19% in micropapillary carcinoma).
• Amplification was present in 12.4% of nodal metastases, showing concordance with primary tumors (kappa=0.61).
• ERBB2 amplification significantly correlated with increased protein expression in both primary and nodal tumors (p<0.0001), with higher expression in metastases.

Conclusions:

• ERBB2 amplification frequency differs by bladder cancer subtype and leads to elevated protein expression.
• Nodal metastases exhibit a higher prevalence of ERBB2 amplification and protein expression compared to primary tumors.
• Co-amplification of ERBB2 and NECTIN4 was observed in a small subset of cases, suggesting potential therapeutic targets.