Editor's Note: The ASCO Breakthrough Summit, held from August 8th to 10th in Yokohama, Japan, focused on new technologies in cancer treatment and shared breakthrough advances and research that are driving global cancer treatment forward. The research titled "Preliminary results of an open-label, single-arm, multi-center study on disitamab vedotin (DV) combined with toripalimab and radiotherapy as bladder-preserving therapy in HER2 overexpression muscle-invasive bladder cancer (MIBC; DECIDING study-stage I)" by Dr. Haige Chen and Dr. Ruiyun Zhang from Renji Hospital, Shanghai JiaoTong University School of Medicine, was selected for presentation. Urology Frontier invited Dr. Ruiyun Zhang to discuss the treatment needs of MIBC patients, the DECIDING study results, progress in ctDNA, and the team's ongoing explorations.

Urology Frontier: What unmet treatment needs currently exist for MIBC patients in China?

Dr. Ruiyun Zhang: I am very grateful for the coverage by the well-known oncology specialty media, Urology Frontier. Regarding the treatment needs of MIBC patients in China, first and foremost, there is still a lack of sufficient awareness among both clinicians and patients. The primary demand for most bladder cancer patients in China is bladder preservation, and most clinicians also offer bladder-preserving treatment options. However, through grassroots education and academic exchanges, we have found that not all hospitals at different levels and in different regions are equipped to provide standard bladder-preserving treatments. Some colleagues have misunderstandings, and certain technologies have not yet kept pace with the latest international TMT therapies, immunotherapy, and other advanced treatments. Most patients in China only undergo maximal transurethral resection of bladder tumors (TURBT), and some MIBC patients may receive local bladder instillation therapy, but there is still much room for improvement in this area.

Secondly, as the concept of bladder preservation evolves, TMT therapy and other bladder-preserving strategies are increasingly recommended for MIBC patients internationally. However, these approaches may also lead to treatment-related adverse events and side effects. Therefore, balancing oncological control with toxicity in MIBC patients requires careful consideration by clinicians. In clinical practice, individualized treatment strategies should be developed based on the patient’s level of awareness, cooperation, and follow-up conditions to determine whether bladder-preserving therapy or radical cystectomy is more appropriate, ultimately improving long-term tumor control outcomes.

Thirdly, for patients undergoing bladder-preserving treatment, early detection of tumor progression and monitoring to facilitate timely salvage treatment is currently a hot research direction. Traditional methods, such as cystoscopy, pathological analysis after TURBT, multiparametric MRI combined with urine cytology, can indeed screen for early progression in some patients, but these methods still require the tumor to progress before abnormalities are detected. The frontier of current research involves using new technologies to detect abnormalities before tumor progression occurs. Studies have reported that combining specific molecular markers with traditional MRI imaging techniques can effectively identify early bladder cancer progression. Additionally, new liquid biopsy techniques, such as utDNA and urine DNA methylation testing, show great promise. In the future, bladder-preserving patients could benefit from non-invasive and more precise monitoring for early recurrence and progression by combining traditional monitoring methods with new detection techniques.

Urology Frontier: At the ASCO Breakthrough Summit, you reported on the DECIDING study, further expanding bladder-preserving strategies for MIBC. How effective and safe is this study protocol, and what impact do you believe this research will have on MIBC patients?

Dr. Ruiyun Zhang: It is an honor to represent our team and present the preliminary results of the DECIDING study at this year’s ASCO Breakthrough Summit. For MIBC patients, the most common bladder-preserving treatment strategy is TMT, which involves maximal TURBT followed by concurrent chemoradiotherapy to achieve bladder cancer cure. However, about 40% of MIBC patients are unable to tolerate cisplatin or refuse chemotherapy, and some may experience severe chemotherapy-related adverse events.

Previous results from studies like EV-302, presented at conferences like ESMO and ASCO-GU, demonstrated that the combination of EV and pembrolizumab as first-line treatment provides significant benefits for patients with advanced metastatic urothelial carcinoma. This led us to explore whether this targeted immunotherapy combination strategy could be applied to MIBC patients. The DECIDING study enrolled MIBC patients with high HER2 expression (HER2 IHC 2+ or IHC 3+) who received concurrent radiotherapy with disitamab vedotin combined with toripalimab. As there are currently no relevant data from neoadjuvant studies in mUC and MIBC, this study aims to recruit about 51 patients, with 6 patients in the first phase for DLT safety studies and 45 patients in the second phase as an expansion cohort to evaluate efficacy and safety.

At this conference, we reported the results from the first phase of the study. In terms of safety, the analysis found that the 6 patients tolerated the treatment well. The short-term safety analysis within the 28-day period defined by the study showed that none of the 6 patients experienced dose-limiting toxicity. Although there were treatment-related adverse events during the relatively long follow-up period, most were manageable Grade 1/2 events. In terms of efficacy, the 3-month CR rate in the first phase was relatively high, and at the 12-month follow-up, many patients remained in CR. Although one patient experienced a short-term recurrence, the postoperative outcome was favorable, and the patient is still under continuous follow-up. Overall, the first phase demonstrated good efficacy and safety, and we are now conducting the second phase of the study, looking forward to further progress in collaboration with multiple renowned centers in China, to ultimately benefit domestic MIBC patients.

Urology Frontier: How do you think ctDNA and other biomarkers can be used to optimize MIBC treatment strategies?

Dr. Ruiyun Zhang: Liquid biopsy technology has made significant strides in the field of urothelial carcinoma and bladder cancer. Compared to blood ctDNA or pleural effusion detection in lung cancer, gastrointestinal tumors, and breast cancer, urinary system tumors (especially bladder cancer) can be analyzed using urine tumor DNA (utDNA) for biomarker analysis. Compared to blood ctDNA, utDNA is easier to collect, and several authoritative teams have conducted research on its analysis and application. Our team at Renji Hospital, Shanghai JiaoTong University School of Medicine, has also conducted multiple explorations and found that blood ctDNA in bladder cancer has low sensitivity, sometimes even below the detection limit, while some utDNA shows higher sensitivity and better reflects the characteristics of bladder cancer. It can be applied to early screening, early diagnosis, and early recurrence prediction in bladder cancer patients, including NMIBC and MIBC.

The current research hotspots in urinary tumor DNA for bladder cancer focus on two main directions. The first is to optimize detection processes and reduce testing costs through further research. In the future, there is hope that by optimizing NGS sequencing, multi-site PCR, and methylation detection technologies, the cost of ctDNA testing can be reduced to a level affordable for the general population, making it applicable to early screening in high-risk populations. Secondly, there is still a need to improve the sensitivity of ctDNA detection to identify minimal residual disease (MRD). This research direction targets patients who have undergone bladder-preserving treatment for MIBC. During follow-up, ctDNA detection can help determine the remission status of tumors within the patient. Radical cystectomy with pelvic lymph node dissection is the standard treatment strategy for MIBC as recommended by guidelines, but it only achieves clinical complete remission (cCR). By combining liquid biopsy techniques and deep sequencing, MRD within the patient can be detected with higher sensitivity, allowing for better early recurrence or early progression detection.

In the field of blood ctDNA, researchers may focus more on progressive diseases, such as locally advanced or metastatic muscle-invasive bladder cancer. For patients with advanced urothelial carcinoma, blood ctDNA levels are significantly higher than in early-stage patients. However, due to various reasons, it is difficult to repeatedly sample tumor lesions, and some metastatic lesions are also challenging to obtain. In such cases, biomarkers like ctDNA can play a role. Additionally, ctDNA can be used to screen potential therapeutic targets, providing a basis for subsequent diagnosis and treatment. Finally, some patients may develop acquired resistance during treatment, and ctDNA testing could potentially guide future drug strategies and clinical practice.

Urology Frontier: What other explorations have you and your team conducted to bring more benefits to MIBC patients?

Dr. Ruiyun Zhang: The Urology Department of Renji Hospital, Shanghai JiaoTong University School of Medicine, has a long history. Under the leadership of Professors Huang Yiran, Xue Wei, and Chen Haige, we have conducted long-term research on bladder cancer, aiming to provide one-stop, comprehensive services for patients. Our team has carried out various studies; in the treatment of MIBC, we have modified radical cystectomy and explored more options through cross-disciplinary collaboration between medicine and engineering. Although the standard treatment for MIBC includes pelvic lymph node dissection, it is relatively time-consuming and labor-intensive and may lead to intraoperative and postoperative complications, making precise lymph node dissection challenging. One research hotspot is real-time localization of suspected lymph nodes using bladder cancer-specific targets, enabling targeted lymph node dissection.

Since MIBC is not a localized disease, current treatment strategies emphasize that MIBC patients should undergo surgical treatment after neoadjuvant therapy. Our team has also conducted several explorations in the field of neoadjuvant therapy for MIBC, including ongoing studies on targeted immunotherapy and biomarker-guided neoadjuvant therapy. Through these explorations, we hope to provide more personalized and precise treatment strategies for MIBC patients in the future. Of course, we are also very focused on bladder-preserving treatment options for MIBC patients, which is one of our key research projects.

Additionally, we have conducted clinical research on rare pathological types of bladder cancer, such as bladder neuroendocrine carcinoma and urachal carcinoma. Although bladder neuroendocrine carcinoma accounts for only 0.5% to 1.0% of malignant bladder tumors, and urachal carcinoma even less (only 0.35% to 0.7% of bladder tumors), their malignancy and biological characteristics differ from those of MIBC, necessitating the development of targeted treatment strategies. Renji Hospital and several multi-center collaborations in China are promoting clinical research on these rare types of bladder cancer, hoping to publish results soon and improve clinical practice and long-term outcomes for these patients.

Dr. Haige Chen

• Chief Physician, Doctoral Supervisor
• Senior Visiting Scholar at the University of Leuven, Belgium
• Deputy Director of the Urology Department at Renji Hospital, Shanghai JiaoTong University School of Medicine
• Executive Director of the Urology Department at the South Campus of Renji Hospital, Shanghai JiaoTong University School of Medicine
• Leader of the Bladder Tumor Group at Renji Hospital, Shanghai JiaoTong University School of Medicine
• Academic Positions: Member of the Oncology Group of the Chinese Medical Association Urology Branch Member of the Shanghai Branch of the Chinese Medical Association Urology Branch Deputy Leader of the Oncology Group of the Shanghai Branch of the Chinese Medical Association Urology Branch Member of the Urology Branch of the China Health Promotion Association Member of the Urology Group of the China Equipment Association Endoscopic and Minimally Invasive Technology Branch Member of the International Bladder Cancer Network (IBCN) Founding Member of the China Bladder Cancer Alliance Expert Reviewer for the National Natural Science Foundation Reviewer for journals such as Oncology Letter, BMC Cancer, Urology, etc.

Dr. Ruiyun Zhang

• Attending Physician, Medical Doctor trained in France
• Attending Physician, Urology Department, Renji Hospital
• Head of the Bladder Tumor Clinical Group, West Campus, Renji Hospital
• Quality Control Expert at the National Drug Clinical Trial Institution, Renji Hospital
• Selected for the Shanghai Health Commission’s New Star Talent Program
• Member of the IBCN Committee
• Youth Committee Member of the Disease Prevention and Control Branch of the Chinese Ethnic Health Association
• Member and Corresponding Editor of the Asian Robotic Radical Cystectomy Collaboration Group (ARARC)
• Academic Secretary of the BJUI Chinese Edition Editorial Board
• Reviewer for journals such as Oncology Letters, BMC Cancer, Oncology and Translational Medicine, etc.
• National Champion of the First National Young Urologists Case Competition
• National Champion of the First “Rongchang Cup” National Urothelial Carcinoma Case Presentation Competition