The human epidermal growth factor receptor family, including HER1, HER2, HER3, and HER4, is increasingly being explored as a therapeutic target in urothelial carcinoma. While HER2-directed antibody-drug conjugates have already shown clinical activity, the expression patterns and potential relevance of other HER receptors remain less well characterized.
The analysis showed that HER receptors are broadly expressed and frequently co-expressed in advanced urothelial carcinoma, providing a biological rationale for the continued development of HER-directed antibody-drug conjugates beyond HER2.
On August 4, 2026, the article titled “HER1–HER4 expression and co-expression in advanced urothelial carcinoma” was published in ESMO Open.
Authors: S. Coca Membribes, D.M. Berney, L. Beltran, E. Nally, F. Jackson-Spence, B. Szabados, S. Mariathasan, T. Powles, and C. Ackerman.
Looking Beyond HER2 in Urothelial Carcinoma
The HER family consists of HER1, also known as EGFR, HER2, HER3, and HER4. These receptors are involved in oncogenic signaling and therapeutic resistance across several tumor types. HER1 and HER2 have previously been shown to be frequently expressed in urothelial carcinoma. Earlier attempts to target these receptors using tyrosine kinase inhibitors, however, did not produce meaningful improvements in randomized trials.
More recently, HER2 has re-emerged as an important therapeutic target with the development of antibody-drug conjugates. Disitamab vedotin has demonstrated antitumor activity across different levels of HER2 expression, while trastuzumab deruxtecan has also established HER2 as an actionable target in selected tumors.
At the same time, HER3-directed and HER1/HER3-bispecific ADCs are under clinical evaluation in urothelial carcinoma. As ADC development moves beyond HER2, detailed characterization of HER1–HER4 expression is needed to inform patient selection and guide the design of future targeted treatments.
The LaMB Trial Biomarker Population
The current study used tumor samples collected through the prospective randomized phase II-III LaMB trial, NCT00949455. The original study evaluated maintenance lapatinib, a dual HER1/HER2 inhibitor, versus placebo in patients with metastatic urothelial carcinoma whose tumors were HER1- or HER2-positive (IHC 2+ or 3+) and who had experienced clinical benefit after four to six cycles of platinum-based chemotherapy.
The present analysis focused on the screening population to reduce selection bias. A total of 446 tumors were assessable for HER1 and HER2 expression. Because of limitations in available tissue and funding, HER3 and HER4 were evaluated in smaller subsets, including 77 tumors for HER3 and 79 for HER4.
Protein expression was assessed by immunohistochemistry. Scores of 1+, 2+, or 3+ were classified as positive, while IHC 3+ was considered high expression. RNA profiling was additionally available for 170 patients, allowing the investigators to examine gene expression and associations with luminal and basal molecular subtypes.
The primary objective was to characterize HER3 and HER4 expression together with co-expression across the HER family. Associations with response to first-line chemotherapy and overall survival were exploratory.
HER Receptors Are Commonly Expressed
Expression of all four HER receptors was frequent. HER1 was positive in 89% of tumors, HER2 in 80%, HER3 in 77%, and HER4 in 75%. High expression, defined as IHC 3+, was less common. HER1 showed high expression in 34% of tumors, compared with 12% for HER2, 26% for HER3, and 29% for HER4.
Among the 77 patients with complete IHC data for all four receptors, 75 patients, or 97%, expressed at least one HER receptor. Among those 75 HER-positive tumors, 46, or 61%, co-expressed all four receptors. High-level co-expression was substantially less frequent. Among 53 tumors included in the high-expression co-expression analysis, only 1 tumor, or 2%, showed IHC 3+ expression of all four receptors.
HER1 was also the receptor most frequently seen as an isolated high-expression finding, occurring in 20 of 53 tumors, or 37%. Isolated high HER2 and HER3 expression was less common, occurring in 9% and 5%, respectively.
HER3 Emerges as a Common Target
One of the clinically relevant findings was the frequency of HER3 expression. HER3 was detected in 77% of evaluated tumors, including high IHC 3+ expression in 26%. HER1 and HER3 co-expression, with or without expression of other HER receptors, was identified in 73% of patients.
These findings are particularly relevant as HER3-directed and HER1/HER3-bispecific ADCs continue to move through clinical development in urothelial carcinoma.
The authors highlighted izalontamab brengitecan, an EGFR/HER3-bispecific ADC currently being evaluated in advanced urothelial cancer. However, they also emphasized that data linking HER1/HER3 expression levels with response to this ADC remain unavailable.
Different Patterns in Luminal and Basal Tumors
HER expression also differed according to molecular subtype. HER2 expression was enriched in luminal tumors, while HER3 expression was enriched in basal tumors.
Among the molecularly characterized samples, HER2 positivity was observed in 93% of luminal tumors compared with 67% of basal tumors, with P < 0.001. HER3 expression was higher in basal tumors than in luminal tumors, at 95% versus 77%, with P = 0.02.
High HER1 expression was also more frequent in basal than luminal tumors, with P = 0.03. No significant difference between the molecular groups was observed for HER4 expression.
Importantly, no molecular subtype showed exclusive enrichment for a single HER receptor. According to the investigators, these findings do not support restricting HER-targeted ADC development to one molecular subtype alone.
HER Expression and Platinum Chemotherapy Response
The study also explored associations between HER expression and response to platinum chemotherapy. When high IHC expression was compared with receptor-negative tumors, patients with high HER3 and HER4 expression had higher overall response rates, whereas those with high HER1 expression had lower response rates. These associations reached P < 0.05.
Notably, the associations differed when overall receptor positivity, defined as IHC 1–3+, was considered. HER1 positivity correlated with better chemotherapy response, whereas HER3 and HER4 positivity correlated with poorer response. Co-expression of HER1/HER3, HER2/HER4, and HER3/HER4 was also associated with higher response rates in exploratory analyses. Among basal tumors, HER2-positive disease was associated with higher response rates, with P = 0.05. The authors cautioned that these outcome analyses were exploratory and that several of the evaluated subsets were relatively small.
No Clear Association With Overall Survival
Despite the high prevalence of HER expression, no significant association between HER1–HER4 expression and overall survival was identified. The hazard ratios for overall survival comparing receptor expression with non-expression were 1.08 for HER1, 0.87 for HER2, 0.87 for HER3, and 0.80 for HER4, with confidence intervals crossing 1 for each receptor.
The absence of a significant association was also consistent across the RNA analyses. Patients with luminal tumors had longer overall survival than those with basal tumors, although the difference was at the statistical boundary with P = 0.05.
The authors also noted an important limitation when interpreting the prognostic analyses: all patients received chemotherapy. The study therefore cannot definitively establish the true prognostic value of HER expression.
What the Findings Mean for HER-Directed ADC Development
The study provides a detailed picture of HER1–HER4 expression in advanced urothelial carcinoma at a time when ADC development is rapidly moving beyond HER2.
Rather than showing expression confined to a single receptor, the analysis demonstrated broad and overlapping HER expression, with most tumors expressing at least one receptor and frequent co-expression across the family.
HER3 was particularly common, supporting the biological rationale for ongoing studies of HER3-directed treatments. Frequent HER1/HER3 co-expression also provides a rationale for bispecific approaches targeting both receptors.
At the same time, the investigators emphasized that receptor expression alone has not yet been shown to predict benefit from these ADCs. Whether higher receptor expression correlates with increased response to ADCs remains uncertain, and whether outcomes are improved in HER1/HER3 double-positive tumors remains to be determined.
Study Limitations
The study benefited from prospective tissue collection within a randomized clinical trial and IHC evaluation by a single genitourinary pathologist. However, HER3 and HER4 analyses were not prespecified in the original clinical protocol and were available only for relatively small subsets of patients. Many of the analyses examining clinical outcomes were therefore underpowered and exploratory.
The study also lacked information on whether individual samples originated from primary tumors or metastatic sites, which may be relevant because HER expression could vary according to disease location.
Finally, DNA alterations in HER family genes were not evaluated. The analysis instead focused on protein and RNA expression, which the investigators considered more directly relevant to the development of HER-targeted ADCs.
Expanding the HER Landscape in Urothelial Cancer
This analysis shows that HER biology in advanced urothelial carcinoma extends well beyond HER2. HER1, HER2, HER3, and HER4 were each detected in the majority of evaluated tumors, while simultaneous expression of multiple HER receptors was common. HER3 expression and HER1/HER3 co-expression were particularly frequent, providing additional biological support for ongoing HER3-directed and bispecific ADC development.
However, HER receptor expression was not associated with overall survival, and its role as a predictive biomarker for emerging HER-directed ADCs remains unresolved.
As these agents move through clinical development, prospective studies linking receptor expression and co-expression patterns with treatment response will be important to determine whether HER profiling can eventually guide treatment selection in advanced urothelial carcinoma.
The full article is available in ESMO Open.
Find more videos on OncoDaily YouTube TV.