Adanma Ayanambakkam, MD, University of Oklahoma

In this interview, Adanma Ayanambakkam, MD, discusses his study on the use of circulating tumor DNA (ctDNA) clearance as a biomarker in renal cell carcinoma (RCC), highlighting findings from a single-institution retrospective study and its potential implications for disease monitoring and treatment planning.

Adanma Ayanambakkam, MD: My name is Adanma Ayanambakkam. I'm an assistant professor at the University of Oklahoma at Stevenson Cancer Center, and I'm a genitourinary medical oncologist here at Stevenson. Thank you for the opportunity to talk about my project of interest, which is circulating tumor DNA (ctDNA) clearance in renal cell carcinoma (RCC).

Could you provide an overview of the trial design and key objectives in evaluating ctDNA clearance as a biomarker for RCC?

Dr Ayanambakkam: CtDNA-based molecular residual disease detection has been a promising prognostic biomarker in multiple solid tumors, such as lung cancer, bladder cancer, and colon cancer, but there is limited and conflicting data in RCC. We know that, for some reason, RCC has greater variability in what we call "shed rates" in ctDNA, and they're influenced by multiple factors like disease biology, clear cell versus non-clear cell, the burden of disease, and also the timing of ctDNA collection. Our study aimed to assess the utility of longitudinal ctDNA monitoring in both localized nonmetastatic and metastatic RCC.

In our study, we had about 72 patients with a total of around 300 ctDNA samples. This was a single-institution retrospective study that analyzed these patients from 2022 to 2025. We used the commercially validated Signatera ctDNA assay, which is a bespoke, tumor-informed multiplex- polymerase chain reaction (PCR)–next-generation sequencing (NGS) assay. It's designed to detect minimal residual disease (MRD) and to track the ctDNA volumes and mean tumor molecules per milliliter (mL).

How the ctDNA testing is done is Signatera identifies 16 unique tumor-specific mutations from the tumor biopsy, and then they are targeted using a highly specific multiplex PCR approach, which allows for an ultrasensitive ctDNA detection and longitudinal monitoring assay. We collected clinical data based on pathological subtype, tumor stage, grade, presence of clear cell versus non-clear cell, and radiographic response.

The researchers were not blinded to ctDNA, and none of the treatment decisions were made based on ctDNA results. We looked at ctDNA dynamics and we categorized them into 3 variables: (1) ctDNA clearance, defined as transition from ctDNA-positive to ctDNA-negative status; (2) ctDNA decrease or increase in levels during longitudinal monitoring; and (3) Cox regression analysis to determine certain associations within ctDNA and median time to progression or relapse-free survival.

What were the most significant findings regarding ctDNA clearance and its correlation with treatment outcomes in RCC patients?

Dr Ayanambakkam: In our cohort, what we found was that in the nonmetastatic or localized RCC cohort, we had 34 patients with nonmetastatic RCC, all of whom underwent a nephrectomy. We had median follow-up of around 14 months, with a range of 15 to 49 months. 94% of our patients—32 of 34—remained relapsed-free at the time of follow-up, and all of these patients had undetectable ctDNA postsurgery. In the 6% of patients (2 of 34) who had relapsed—1 at 2 months and 1 at 12 months—both had detectable ctDNA prior to radiographic recurrence. One of them did not have ctDNA clearance at any time point, and another patient had ctDNA clearance for about 10 months before which developing positive ctDNA, which was before they had radiographic relapse.

In the patients with metastatic RCC, we had 38 patients with a median follow-up of 17 months. 74% of these patients had ongoing disease response, while 26% had progression of disease. Among those patients who had ongoing responses radiographically (28 patients), 90% (25 of 28) achieved ctDNA clearance.

Three patients did not have ctDNA clearance, but all three had reduction in the ctDNA levels. Two patients had more than a 50% reduction in the mean tumor molecules per mL, and one patient had less than a 50% reduction in mean tumor molecules per mL. In the 10 patients who had progression of disease, 70% (7 of 10) had rising undetectable ctDNA prior to radiographic progression.

There were three patients who had undetectable ctDNA despite having radiographic progression. One patient had an isolated brain metastasis, one patient had lung metastases, and one patient had a small adrenal metastasis, which was 2 cm biopsy-proven.

The sensitivity of ctDNA testing in our cohort was 100% in the patients with localized RCC and 70% in the patients with metastatic RCC. The specificity was 100% in the patients with localized RCC and about 93.3% in the patients with metastatic RCC. Overall, this does reaffirm what we have found out in other studies and single-institution studies as well.

In your view, how might these findings influence treatment planning and patient monitoring strategies for RCC?

Dr Ayanambakkam: It's still in the early stage, and we will need prospective trials to implement all of these potential opportunities. However, this finding does highlight that there's potential for ctDNA in both the nonmetastatic and in the metastatic settings.

In the nonmetastatic setting, there is a potential for early relapse detection in nonmetastatic RCC. Our data suggest that ctDNA could potentially serve as an early relapse predictor in patients with localized RCC. Almost all of our patients who remained relapse-free—94% of them—had undetectable ctDNA postsurgery or postnephrectomy, and all those patients who relapsed postnephrectomy had detectable ctDNA before radiographic evidence of progression.

This suggests that postsurgical ctDNA monitoring could help identify high-risk patients earlier. There are currently ongoing trials that are looking at ctDNA-based escalation or de-escalation of therapy in the adjuvant setting. This would be informative for how we can tailor and personalize treatment approaches for our patients.

In the metastatic setting, ctDNA has an ability to be used for treatment response monitoring. For example, in 28 of the 38 patients who had a response, 90% achieved ctDNA clearance. All the other patients had some sort of ctDNA reduction. Here, it seems that ctDNA dynamics are important when compared to ctDNA clearance as well.

But in ctDNA as an early predictor of disease progression, it's important to understand that 10 patients had progression, 70% had detectable ctDNA or rising ctDNA before radiographic progression. It's also important to highlight that in some patients, such as those with isolated brain metastases or low-volume oligometastatic disease, ctDNA might not be able to detect progression, and there may be limitations in some of these metastatic patterns that are there.

This does translate to having some clinical implications in RCC management, either in the postsurgical surveillance setting or in real-time disease monitoring in the metastatic RCC setting. Hopefully, it will help identify early identification of disease progression in the metastatic RCC and nonmetastatic RCC setting.

How did ctDNA clearance differ between localized and metastatic RCC cases?

Dr Ayanambakkam: In nonmetastatic or localized RCC, the ctDNA clearance was very binary. Either patients had full clearance and they were able to achieve ctDNA clearance, or they did not have ctDNA clearance and they had detectable ctDNA.

All those who had ctDNA clearance remained progression-free, and all those who had detectable ctDNA or rising ctDNA had progression of disease. However, in the metastatic cohort, we know that the ctDNA clearance was not always binary. There were patients who had response in ctDNA, who had decrease in ctDNA levels, and those who had persistent or increasing ctDNA levels.

The majority of these patients were able to achieve ctDNA clearance, and they had ongoing responses radiographically, with 90% of patients who were able to achieve ctDNA clearance. But it is important to understand that there were some patients—about 10% of patients with radiographic response—who still did not clear their ctDNA completely but exhibited significant reductions in ctDNA levels. One of these had less than 50% reduction, and two of them had more than a 50% reduction in ctDNA. So, even partial ctDNA reduction might be meaningful in metastatic disease, and we might not be able to achieve ctDNA clearance. This could also be an indicator of the burden of disease in the metastatic setting when compared to the nonmetastatic setting.

Unlike the nonmetastatic RCC cohort ctDNA, where it was an early predictor of recurrence, in the metastatic RCC cohort, ctDNA levels fluctuated with treatment response. Thus, in this setting, serial monitoring of ctDNA might be important for interpretation.

How do you see ctDNA clearance evolving in clinical practice—would it complement or replace other diagnostic tools?

Dr Ayanambakkam: So, ctDNA clearance is an evolving biomarker in RCC. It holds promise as an early indicator of disease relapse and maybe even treatment response monitoring in both the localized and the metastatic setting.

But it's important to understand that there are limitations, and so ctDNA is probably going to be a compliment to other diagnostic tools, such as the radiographic response monitoring that we currently use. Maybe we'll be able to identify those patients who might need to scan a little bit earlier or those who can delay their scans ,and change how the disease is being monitored or even maybe change treatment.

These data are more retrospective. There are inherent challenges to retrospective, single-institution data. This does coincide with data that has been released by Dr Arnab Basu and his colleagues, and also other publications in the RCC setting, but it's important that we have prospective randomized clinical trials that will validate the role of ctDNA and how it can be incorporated into standard practice.

There are no standardized guidelines on how and when ctDNA testing can be done, and there are multiple platforms which can be used to assess ctDNA. So, it's important to understand the limitations of each methodology of ctDNA assessment and also standardize guidelines through these prospective, randomized trials, which will hopefully shape the way ctDNA is being used in the RCC setting.