Editor's Note: In recent years, HER2-targeted antibody–drug conjugates (ADCs), including disitamab vedotin, have demonstrated significant clinical value in the treatment of urothelial carcinoma (UC). However, HER2 expression in UC exhibits spatiotemporal heterogeneity. Bladder carcinoma in situ (CIS), in particular, is characterized by its occult presentation, high malignancy, and substantial risk of progression to invasive carcinoma. A standardized HER2 testing workflow for CIS is currently lacking, highlighting the need for further investigation. To address this challenge, a research team led by Professor Dawei Tian and Professor Jianing Guo of the Second Hospital of Tianjin Medical University conducted a clinical study whose findings were selected for presentation at the annual congress of the European Society for Medical Oncology (ESMO) [1], providing new evidence in this field. Oncology Frontier – UroStream invited both professors to discuss the clinical value of HER2, the characteristics of HER2 expression in CIS, the potential of disitamab vedotin in UC, and the implications of their findings for HER2 testing and clinical management.Oncology Frontier – UroStream: With updates to UC treatment guidelines and continued advances in clinical research, HER2 has become an important therapeutic target in this field. To begin, what is the clinical value of HER2 as a target in non-muscle-invasive bladder cancer (NMIBC)?
Professor Dawei Tian: HER2 is an important factor influencing tumor prognosis and progression and has become a major therapeutic target in malignancies such as breast and gastrointestinal cancers. In UC, however, HER2 only began to attract increasing attention from urologists in 2022, with the emergence of HER2-targeted ADCs such as disitamab vedotin. In recent years, multiple clinical studies have further confirmed the importance of HER2 in UC diagnosis and treatment.
In NMIBC, studies have found that HER2 expression is closely associated with disease progression. HER2 overexpression is an important risk factor for progression from NMIBC to muscle-invasive disease. It may also affect the efficacy of standard intravesical bacillus Calmette–Guérin (BCG) therapy in intermediate- and high-risk NMIBC, reducing the benefit patients derive from treatment [2]. HER2 has therefore emerged as an important factor affecting prognosis, disease outcomes, and treatment efficacy in NMIBC.
HER2 expression is also highly relevant in muscle-invasive bladder cancer (MIBC). Studies have shown that HER2 positivity is common among patients with MIBC and is significantly associated with tumor diameter greater than 3 cm, multifocal tumors, high tumor grade, and pelvic lymph node metastasis [3].
Overall, our current understanding of HER2 as a target in UC is derived largely from retrospective studies. Large-scale, multicenter prospective studies are still needed. Nevertheless, drawing on established experience with anti-HER2 therapies in other solid tumors and considering the available clinical evidence, the medical community has reached a broad consensus that HER2 expression level is an independent factor affecting prognosis in patients with UC.
Oncology Frontier – UroStream: Your team’s latest study analyzing HER2 expression in bladder CIS has been selected for this year’s ESMO Congress, providing new evidence to inform clinical practice. Based on your research findings and clinical experience, how should HER2 testing in bladder CIS be standardized? What specific considerations are needed compared with testing in invasive UC?
Professor Jianing Guo: For patients with UC, HER2 immunohistochemistry (IHC) can provide important information to guide precision-treatment decisions and prognostic assessment. Our study suggests [1] that HER2 expression in bladder CIS does not always correspond to that in conventional invasive carcinoma. In some patients, HER2 expression in the CIS component is even higher than in the invasive component. HER2 status may also be associated with the risks of tumor recurrence and malignant progression in patients with CIS, making it an important reference for prognostic assessment and individualized treatment selection.
Based on these findings, several aspects deserve attention in clinical practice.
First, multiple-site sampling is recommended. HER2 protein expression should be assessed in samples from the primary tumor, recurrent lesions, and metastatic lesions.
Second, tumor regions near the superficial epithelial mucosa may be prioritized for assessment. In addition, tissue blocks containing histological subtypes associated with more prominent HER2 overexpression—such as micropapillary, plasmacytoid, and glandular-differentiation variants—may be prioritized for testing.
Third, biopsy specimens should be submitted for testing promptly after collection.
These measures may improve the detection rate of HER2 protein expression and give more patients the opportunity to receive HER2-targeted ADC treatment, including disitamab vedotin, potentially improving survival outcomes.
For interpretation, HER2 assessment in CIS may refer to the Expert Consensus on HER2 Immunohistochemical Testing in Urothelial Carcinoma (2026 Edition) [2]. One point is particularly important: although HER2 in bladder CIS is interpreted according to the criteria used for invasive carcinoma, the pathology report should explicitly identify the result as the HER2 status of a non-invasive carcinoma component. This helps prevent clinicians from mistakenly interpreting it as the HER2 status of invasive disease.
If a tumor contains both invasive and non-invasive components and their HER2 scores differ, the IHC scores for each component should be reported separately. This will help clinicians develop more precise, individualized treatment plans.
Oncology Frontier – UroStream: HER2-targeted ADCs such as disitamab vedotin are already available in clinical practice. What benefits can these agents offer patients with CIS and other forms of UC? In your clinical practice, how can these drugs be used to benefit more patients?
Professor Dawei Tian: Disitamab vedotin is an innovative drug developed in China. Compared with similar drugs that are more expensive internationally, it enables ordinary patients to access precision-targeted therapy, demonstrating the clinical value of China’s domestic pharmaceutical innovation.
Since receiving approval for a UC indication in 2022, disitamab vedotin has been investigated in multiple clinical studies spanning several stages of UC treatment. The RC48-C016 study was even published in The New England Journal of Medicine, one of the world’s leading medical journals [4], marking a potentially practice-changing advance.
The study results showed that the median overall survival (OS) with conventional gemcitabine–cisplatin (GC) chemotherapy for advanced UC was 16.9 months, whereas the disitamab vedotin combination regimen increased median OS to 31.5 months—nearly doubling survival. These results are highly encouraging.
Furthermore, nearly 40% of patients receiving conventional chemotherapy may be unable to continue treatment because they cannot tolerate adverse effects. Patients with advanced disease can consequently face a situation in which few treatment options remain. The innovative disitamab vedotin regimen helps address this challenge by reducing adverse effects while maintaining good treatment tolerability, offering renewed hope for longer survival to patients with advanced UC expressing HER2.
For patients with high-risk or very-high-risk NMIBC, intravesical BCG has traditionally been a principal treatment option. However, this approach has not fully met clinical needs.
On the one hand, adverse effects can be substantial. Approximately 15% of patients may be unable to tolerate treatment because of urinary frequency, urgency, dysuria, hematuria, or the risk of infection. On the other hand, BCG is a biological product with limited manufacturing capacity, and its clinical availability is further constrained by cost. In addition, outcomes with BCG are often suboptimal in patients with HER2-positive NMIBC.
Against this background, several major clinical centers in China are actively exploring new treatment strategies, including adding disitamab vedotin to standard intravesical BCG. Preliminary results from investigator-initiated trials (IITs) suggest that regimens incorporating disitamab vedotin can prolong PFS and reduce recurrence risk in patients with high-risk or very-high-risk NMIBC, with acceptable safety and good tolerability.
Overall, having high-quality anticancer drugs developed domestically is a great advantage for China. These treatments can alleviate suffering and prolong survival—a privilege for clinicians and a major benefit for patients.
Oncology Frontier – UroStream: What implications does HER2 expression heterogeneity in NMIBC have for clinical pathology testing and future research into targeted therapies? Looking ahead, how can artificial intelligence and other assistive technologies improve the accuracy and reproducibility of HER2 interpretation, ultimately translating into clinical benefits for patients?
Professor Jianing Guo: As Professor Tian has noted, HER2 has important prognostic significance and therapeutic value as a target in UC. We therefore recommend routine HER2 protein expression testing for patients with intermediate- and high-risk NMIBC to identify those who may benefit from anti-HER2 ADC treatment. Routine HER2 fluorescence in situ hybridization (FISH) testing is not currently recommended. This approach can meet clinical decision-making needs while helping conserve healthcare resources.
Given the pronounced spatiotemporal heterogeneity of HER2 expression in UC, our findings suggest that testing only a single lesion or focusing exclusively on the invasive component may fail to capture the full HER2 expression profile. Clinical sampling should therefore emphasize multiple sites, with HER2 testing recommended for primary, recurrent, and metastatic lesions.
As long as HER2 expression is present, treatment with disitamab vedotin may offer patients a survival benefit. Further research is needed to clarify the pathological and mechanistic differences between CIS and invasive carcinoma, thereby providing a stronger evidence base for HER2-targeted ADC treatment. Moreover, the finding that HER2 expression in some CIS samples exceeds that in the invasive component provides a rationale for further investigation of HER2-targeted ADCs in this setting.
In clinical practice, pathology and urology departments should jointly establish which specimen types are appropriate for HER2 testing and agree on standardized submission procedures. This will facilitate information sharing and ensure consistent specimen handling and testing quality. For cases with atypical HER2 expression or marked heterogeneity, interpretation by a pathologist in the presence of the clinical team can help clinicians better understand the implications of the report.
In addition, computer-based image analysis and artificial intelligence can support IHC interpretation, reduce human error, and improve accuracy and reproducibility. However, the final results must still be confirmed by a pathologist.
Study Overview
English Title: A Single Center Clinical Study: The Heterogeneity of HER-2 Expression in Urothelial Carcinoma in Situ of the Bladder
Chinese Title: A Single-Center Clinical Study of HER2 Expression Heterogeneity in Bladder Urothelial Carcinoma In Situ
Study Objective
Bladder CIS is a major clinical challenge because of its occult presentation, high malignancy, and substantial risk of progression to invasive carcinoma. Routine clinical HER2 testing has primarily focused on invasive UC, and no unified testing standard has been established for the HER2 expression characteristics of bladder CIS.
Against this background, the study aimed to investigate HER2 expression heterogeneity in bladder CIS and provide clinical evidence to optimize individualized targeted-treatment strategies for patients with this condition.
Study Methods
This retrospective clinical study collected clinicopathological data from patients with bladder UC treated between 2022 and 2025. A total of 42 cases of invasive UC accompanied by urothelial CIS were included. HER2 IHC testing was performed using a standardized restaining protocol, and HER2 expression was assessed separately in the invasive carcinoma and CIS components.
Study Results
The study analyzed 42 patients with UC accompanied by CIS, including 11 patients with MIBC and 31 with NMIBC.
HER2 expression was positive in the invasive carcinoma component in 37 patients (88.1%) and in the corresponding CIS component in 39 patients (92.9%).
A comparison of the two components showed that HER2 expression was upregulated to varying degrees in the CIS component relative to the invasive component in 40.5% of cases (17/42). Expression remained unchanged in 45.2% of cases (19/42), while downregulation was observed in only 14.3% (6/42).
The difference in HER2 expression levels between the invasive carcinoma and CIS components was statistically significant (P=0.042).
Study Conclusions
This study provides preliminary evidence that HER2 expression varies among cases of bladder CIS and that HER2 expression characteristics differ to some extent between CIS and invasive UC. These findings suggest that HER2 expression heterogeneity may occur during the progression of bladder UC.
Routine HER2 testing of bladder CIS lesions is therefore important. It may help further refine the molecular classification of high-risk bladder cancer and provide a basis for individualized treatment strategies for patients with high-risk bladder CIS.
Professor Dawei Tian
Professor Jianing Guo
