Introduction

In contrast to cancers of the breast and stomach, targeting Her2 has not yet demonstrated anti-tumor activity in muscle-invasive bladder cancer (MIBC). We hypothesized that an integrated approach to Her2 characterization in MIBC may better guide patient prioritization for targeted therapy.

Methods

We investigated Her2 alterations on different biological levels (DNA, RNA and protein) in pre-chemotherapy MIBC of 127 patients who recieved at least 3 cycles of neoadjuvant chemotherapy prior to radical cystectomy (NAC cohort). The findings were underlined in the The Cancer Genome Atlas (TCGA) bladder dataset (n=407). Moreover, the signifcance of Her2 was analysed between the recently identified molecular subtypes (TCGA clusters).

Results

In the NAC cohort, FISH revealed that 16/83 tumors harbored ERBB2 amplification, while 24/127 had high Her2 protein expression by IHC (i.e. IHC score = 3). Samples with ERBB2 amplification had higher mRNA (p<0.001) and protein expression (p<0.001). However, 6/16 amplified samples had mRNA expression in the 1st tertile, and 10/16 had IHC scores of either 1 (n=5) or 2 (n=5). Interestingly, epigenetic regulation may downregulate Her2 expression. ERBB2 amplified tumors with low mRNA and protein expression showed a high ERBB2 methylation rate (R=-0.62, p<0.001). _x000D_ While the vast majority of ERBB2 amplified tumors (37/41), showed amplification of other known oncogenes (e.g. CCND1, CCDE1), 4 tumors showed ‘exclusively’ ERBB2 amplification._x000D_ In both datasets, Her2 alterations were most frequent in TCGA cluster I. None of the Her2 alterations harbored prognostic information in the TCGA dataset. In the NAC dataset, Her2 was a marker of unfavourable outcome in tumors assigned to TCGA cluster I.

Conclusions

Assessment of Her2 alterations on all biological levels provides a more comprehensive insight into Her2, than FISH or/and IHC alone. Failure of previous clinical trials may have confounded by this complex molecular landscape of Her2 alterations in MIBC. Our findings could help to improve patient selection for future clinical trials. Finally, Her2 activity is associated with molecular subtypes and therefore, future biomarker studies should take molecular subtypes into account.

Funding

none