PD-L1 and HER2 expression are inversely correlated in advanced urothelial cancer
To date, HER2-targeted agents have shown promising anti-tumour activity as monotherapy and in combination with immune checkpoint inhibitors in patients with advanced urothelial cancer. To learn more on the clinical and genomic landscape of HER2 alterations in bladder cancer and the relationship between HER2 and PD-L1 expression, a retrospective analysis was performed. Results of this study demonstrated an inverse correlation between HER2 immunohistochemistry expression and PD-L1 combined positive score and can provide a foundation for further trials in HER2-directed therapies for advanced bladder cancer.
Although bladder cancer has a relatively high rate of human epidermal growth factor receptor 2 (HER2) alterations, the association between HER2 mutation/amplification, HER2 and PD-L1 immunohistochemistry expression and associations with clinical outcomes for advanced bladder cancer has not been studied.
The aims of the current retrospective study by David Aggen et al. were to define the prevalence of ERBB2 alteration in advanced urothelial cancer and the association with HER2 expression by immunohistochemistry (IHC) and to understand heterogeneity of HER2 expression and the relationship between HER2 and PD-L1 expression.
Methods
Tumour samples from 2,692 unique patients with advanced urothelial cancer were retrospectively analysed and HER2 IHC was performed on a subset of 202 patients. For PD-L1 IHC expression, the combined tumour and immune cell PD-L1 expression score (CPS) was used. HER2 IHC expression was categorised as 0, 1+, 2+ or 3+. Furthermore, ERBB2 alteration – defined as pathogenic mutation and/or amplification – was compared from genomic profiling with MSK-IMPACT® using next-generation sequencing. Pairwise associations were studied between PD-L1 and HER2 expression and ERBB2 alteration in all patients with urothelial bladder cancer, and their associations with progression-free survival (PFS) and overall survival (OS) in patients with muscle-invasive bladder cancer (MIBC).
Results
Among the 202 patients with HER2 IHC, 188 had MSK IMPACT and 168 had PD-L1 CPS available. Of these 202 patients, 38 (18%) were HER2 negative, 60 (30%) HER2 1+, 68 (34%) HER2 2+, and 36 (18%) HER2 3+. The prevalence of ERBB2 alterations was 20%. The PD-L1 CPS score was inversely associated with the level of HER2 expression (p< 0.001). For example, HER2 0 tumours by IHC had a median PD-L1 CPS score of 50, while the median PD-L1 CPS score for HER2 2+ and 3+ tumours were 7 and 4, respectively. In contrast, no association was found between the PD-L1 CPS score and ERBB2 alteration (p= 0.735). ERBB2-altered tumours by NGS were strongly correlated with high-level HER2 expression by IHC (p< 0.001). However, in the HER2 2+ and 3+ group, HER2 NGS alone would miss up to 70% of tumours with high HER2 expression, highlighting the importance of using IHC to define patients with HER2 expression.
In patients with MIBC, ERBB2 alteration and the level of HER2 IHC expression (0 or 1+ vs. 2+ or 3+) were not associated with PFS (p= 0.5 and p= 0.4, respectively) or OS (p= 0.84 and p= 0.94, respectively).
Conclusions
ERBB2 alterations were identified by MSK IMPACT in approximately 20% of urothelial cancers and in this cohort, HER2 2+ or 3+ expression was present in 52% of tumours. This retrospective study shows an inverse correlation between the level of HER2 IHC expression and PD-L1 CPS score in patients with urothelial bladder cancer. According to the researchers, these results support further investigation of HER2-targeted agents and underscore the need for standardisation of HER2 expression assessment by immunohistochemistry in patients with advanced urothelial cancer.
Reference
Aggen DH, et al. HER2 and PD-L1 immunohistochemistry (IHC) expression, and HER2 genomic alterations: associations and clinical outcomes for advanced bladder cancer. Presented at ASCO GU 2024; Abstract 538.
