Detecting Molecular Relapse After Immunotherapy in Urothelial Carcinoma and Renal Cell Carcinoma Using ctDNA

In this video interview, Lingbin Meng, MD, PhD, assistant professor, The Ohio State University Comprehensive Cancer Center, discusses her study on using circulating tumor DNA (ctDNA) to detect early molecular relapse in patients with urothelial carcinoma and renal cell carcinoma following immunotherapy. Presented at ASCO GU, the research highlights how ctDNA may guide personalized surveillance and treatment decisions for this patient group. Dr Meng also addresses the clinical, technical, and economic challenges to its broader adoption.

Please introduce yourself by stating your name, title, organization, and relevant professional experience.

Lingbin Meng, MD: Hi, everyone. My name is Lingbin Meng, and I am an assistant professor of medical oncology at The Ohio State University Comprehensive Cancer Center. I specialize in treating genital urinary malignancy, including prostate, bladder, kidney, and testicular cancer. My primary interest lies in clinical trial design and translational research with a focus on biomarkers and immunotherapy.

Can you briefly summarize your study and its key takeaways?

Dr Meng: We presented a poster at ASCO GU on our study comparing circulating DNA surveillance with traditional imaging to detect relapse or progression in 36 patients with urothelial carcinoma (UC) and renal cell carcinoma (RCC) who completed immunotherapy. The study found that circulating tumor DNA (ctDNA) surveillance detected recurrences earlier than imaging in a significant number of patients with metastatic UC and RCC, with a median lead time of 22 weeks.

The ctDNA was highly concordant with the radiographic progression in 8 out of the 9 patients. About 98% who became ctDNA positive during the surveillance show radiographic progression. Conversely, none of the 27 patients who were ctDNA negative showed any image progression. One patient with metastatic RCC became ctDNA positive without image progression, illustrating the molecular relapse in image blind spots.

So, to conclude, our study found that ctDNA is a highly sensitive early warning biomarker that can uncover relapse months before scan and has the potential to reshape post-immunotherapy surveillance pathways.

How do you envision ctDNA testing being integrated into current post-treatment surveillance pathways, and what clinical decisions could it inform ahead of imaging?

Dr Meng: ctDNA could be integrated as a regular monitor along with standard imaging for patients post-immunotherapy, particularly in the metastatic setting. However, it cannot replace the traditional scan. Currently, I'm treating metastatic UC and RCC most of the time. I find that ctDNA could be a helpful tool to guide us on how to treat patients. For example, it can help us individualize the scan interval or trigger the early image if we find a positive ctDNA result indicating molecular relapse early that warranted earlier surveillance with the CT or PET scan to localize the disease recurrence. It can also help guide us on how to deescalate or escalate the treatment in advanced settings.

Currently we have several trials, including IMvigor011 and the ctMoniTR Proect, trying to investigate whether we can use ctDNA—positive or negative—as a biomarker to deescalate or escalate the therapy for muscle-invasive bladder cancer post-cystectomy. That will be interesting to know in the future.

One patient in your study had a positive ctDNA result without radiographic progression. How should clinicians interpret isolated ctDNA positivity, and what safeguards might be necessary to avoid overtreatment?

Dr Meng: In our study, one patient with metastatic RCC had a ctDNA positive at 0.15 but did not show radiographic progression. So, interpreting those isolated ctDNA positives requires careful consideration. While our study shows higher concordance, this case highlighted that ctDNA positivity might not always intermediately correlate with image-detectable disease. It could indicate that very early molecular disease not yet visible or it could be a false-positive reading.

So, how can we overcome this? It's challenge to avoid over-treating. I always confirm the ctDNA positivity with the serial testing rather than just a single reading. Besides, it's always important to correlate it with the patient’s clinical picture or traditional scan to help us make a decision.

Clinicians should confirm the persistently rising circulating levels or, at least, correlate with patients' clinical change or additional imaging information. Close monitoring and repeated testing are important to distinguish the true molecular relapse from the potentially false-positive reading.

Were there any specific patient characteristics—such as tumor type, disease stage, or initial ctDNA levels—that correlated more strongly with relapse risk or ctDNA dynamics? Could this help refine patient selection for ctDNA surveillance?

Disease stage appeared to be a significant factor, although our sample size is relatively small. But we observed that patients with metastatic UC and metastatic RCC are more likely to develop ctDNA positivity compared to those with localized disease, which suggests that more than once the tumor burden may have been correlated with higher ctDNA shedding and early molecular detection.

By the time we have the molecular relapse, which means ctDNA becoming positive, the level could be variant when the patient has imaging progression. When the patient has imaging progression, the ctDNA level could range from 0.08 up to 136. So, you don't want to miss that, even if the ctDNA has a very low expression.

What do you see as the biggest barriers—technical, clinical, or economic—to widespread adoption of ctDNA surveillance in urologic oncology?

Dr Meng: We face a lot of barriers. Clinically, we need large-scale studies to validate these findings. We also need standardized ctDNA surveillance protocols, especially for treating those isolated patients who are ctDNA positive without imaging progression. Should we do something or not?

As I mentioned before, we want to know whether we can deescalate or escalate the treatment for patients who need adjuvant therapy or not, especially for muscle-invasive bladder cancer. I'm eager to know whether ctDNA could be used as a biomarker to guide the treatment for the adjuvant setting.

We also face many technical barriers because the sensitivity and the specificity of the assays across different types of solid tumors can be a lot. Currently, we have tests such as Guardant 360, FoundationOne, etc. How can we standardize interpretations from different reports?

Another big challenge is, how can we distinguish the tumor-derived alteration from clonal hematopoiesis of intermediate potential (CHIP), which can lead to a false-positive finding. As we know, the CHIP-related mutation, especially in genes such as DNMT3A or TET2, may appear in the plasma without reflecting the active tumor, so careful bioinformatic infiltering paired with white blood cell sequencing is needed to enhance the ctDNA's clinical accuracy.

Last, but not least, is the economic barrier. Currently the procedure is free for patients because it is mostly in an experiment or a trial phase; it’s either covered by the research or by patients’ health insurance. Down the road, if the ctDNA helps with the early detection and intervention and improves the long-term outcome, it may reduce the cost associated with treating more than once for relapse of disease.

To summarize, the second surveillance shows strong potential to detect relapse earlier than imaging in patients with UC and RCC. In the future, more robust prospective validation and careful integration into clinical workflow will be essential.