ASCO GU 2025: Capturing What You Cannot See: How Can ctDNA Be Used to Improve Clinical Staging for Upper Tract Disease?

(UroToday.com) The 2025 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between February 13th and 15th 2025, was host to the Panning for Gold: The Role of ctDNA as a Biomarker for Bladder Cancer Session. Dr. Roger Li discussed how can ctDNA be used to improve clinical staging for Upper Tract Disease?

Dr. Roger Li began his presentation by emphasizing the aggressive nature of upper tract urothelial carcinoma (UTUC) at presentation. He highlighted that 70% of UTUC cases are high-grade, and 60% present at ≥T2 stage. The 5-year cancer-specific survival (CSS) rate for UTUC at ≥T2 stage ranges from 21% to 59%, which is quite low, underscoring the aggressive nature of this disease and the need for it to be treated accordingly. Dr. Li also discussed the issue of inaccurate cancer staging, referencing data showing that 46% of cases are under-staged by ureteroscopy. (1) This under-staging leads to missed opportunities for administering systemic therapies, which could improve patient outcomes by addressing micrometastatic disease and reducing the risk of recurrence.

Accurate risk stratification prior to radical nephroureterectomy remains a challenge in upper-tract urothelial carcinoma (UTUC). As a result, various tools, including preoperative nomograms, have been developed and should be incorporated into the current standard of care. One notable nomogram is the one reported by Petros et al., which utilizes a combination of preoperative patient, imaging, endoscopic, and laboratory values. This nomogram has proven to be an accurate tool for predicting locally advanced, non-organ confined UTUC. (2) It can help more effectively select patients for preoperative systemic chemotherapy and facilitate clinical trial enrollment. The variables that this nomogram uses are shown below:

However, the evidence for neoadjuvant systemic chemotherapy in patients with upper-tract urothelial carcinoma (UTUC) is limited to phase II clinical trials. One such trial is a prospective phase II study led by Vitaly Margulis, in which 30 patients received four cycles of neoadjuvant chemotherapy with accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (aMVAC) for those with baseline creatinine clearance greater than 50 mL per minute, or gemcitabine and carboplatin for those with creatinine clearance between 30 and 50 mL per minute.(3) This study showed a 14% pathological complete response (pCR) rate. A similar prospective phase II study used split-dose gemcitabine and cisplatin as neoadjuvant chemotherapy, demonstrating a 63% pathological response rate and a 19% complete pathological response (ypT0N0) rate. However, it is important to note that none of these studies included comparator groups. (4) 

In the context of bladder cancer, where there is an opportunity for a layered treatment approach using neoadjuvant systemic therapy followed by radical cystectomy (RC), next-generation sequencing (NGS) biomarkers may be considered to identify patients who will benefit most from neoadjuvant chemotherapy (NAC). In fact, data from a 2019 study demonstrate the potential feasibility of this approach. Specifically, if patients tested negative for circulating tumor DNA (ctDNA) prior to starting neoadjuvant chemotherapy, their cancer-related outcomes following surgery were excellent. (Figure below) (5) This raises the question of whether NAC chemotherapy is truly necessary for this cohort of patients and sets the stage to answer the question if ctDNA can be used for prognosis and staging in high risk UTUC?  

A study led by Dr. Heather Huelster evaluated 32 patients diagnosed with high-risk upper-tract urothelial carcinoma (UTUC) who underwent upfront nephroureterectomy or ureterectomy. Plasma cell-free DNA was prospectively collected from chemotherapy-naïve, high-risk UTUC patients. Of the 32 patients, 30 samples passed quality control, and at least one ctDNA variant was detected in 70% of cases. In this study they used the 152-gene PredicineCare^TM agnostic panel. A pan-cancer next-generation sequencing (NGS) assay that detects genomic alterations to inform patient care and guide clinical trial decisions. The assay covers 152 core loci, addressing 81% of commonly altered genes in upper-tract urothelial carcinoma (UTUC). Targeted sequencing is performed on matching plasma and surgical UTUC samples. (6) 

Dr Huelster and colleagues found that matching alterations are common in patients with invasive UTUC with a Median TMB – 7.2 mutations/Mb, one hypermutated tumor 52% detected plasma ctDNA corroborated alterations in matching tumor samples. Notably, 88% of those alterations detected in tissue were not detected in plasma as shown in the Oncoplot below and in the Venn diagram showing overall mutational concordance between tumor tissue and plasma cfDNA. (6)

A significantly higher median number of alterations were observed in the plasma of muscle-invasive/non-organ confined (MI/NOC) patients compared to non-muscle invasive (NMI) patients (p < 0.0001), but no such difference was seen in tumor tissue (p = 0.5). However, alterations were more frequently found in the TERT promoter (63%), TP53 (40%), MYC (37%), FGFR3 (33%), and CDKN2A (30%).

Notably, Dr. Li highlighted that the presence of preoperative ctDNA was a poor prognostic factor. Among the patients with detectable ctDNA, nearly 50% experienced disease progression, 27% died from UTUC, and one patient (9%) died from unknown causes. In contrast, only one patient with negative ctDNA suffered disease progression and death. (6)

Future directions for ctDNA in the preoperative setting involve assaying circulating or urinary cell-free DNA through NGS after UTUC diagnosis. This approach aims to improve accurate staging and assist in selecting between upfront surgery or neoadjuvant chemotherapy, as illustrated in the graphic below.

Dr Li, concluded his presentation with the following key takeaways:

• Neoadjuvant cisplatin-based chemotherapy has demonstrated benefit in high-risk UTUC
• Preoperative ctDNA may be used for treatment selection
• Plasma ctDNA recapitulates tumor alterations found in tissue. However, this is found more commonly in patients with advanced disease
• Preoperative ctDNA was found to be prognostic of the patient’s postoperative course. Can cTDNA be used for treatment selection?

Presented by: Roger Li, MD, Urologic Oncologist at the H. Lee Moffitt Cancer Center and Research Institute.Tampa, FL, United States.

Written by: Julian Chavarriaga, MD – Urologic Oncologist at Cancer Treatment and Research Center (CTIC) via Society of Urologic Oncology (SUO) Fellow at The University of Toronto. @chavarriagaj on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025. 

References:

1. Petros FG, Li R, Matin SF. Endoscopic Approaches to Upper Tract Urothelial Carcinoma. Urol Clin North Am. 2018 May;45(2):267-286. doi: 10.1016/j.ucl.2017.12.009. Epub 2018 Feb 21. PMID: 29650142.
2. Petros FG, Qiao W, Singla N, Clinton TN, Robyak H, Raman JD, Margulis V, Matin SF. Preoperative multiplex nomogram for prediction of high-risk nonorgan-confined upper-tract urothelial carcinoma. Urol Oncol. 2019 Apr;37(4):292.e1-292.e9. doi: 10.1016/j.urolonc.2018.12.002. Epub 2018 Dec 22. PMID: 30584035.
3. Margulis V, Puligandla M, Trabulsi EJ, Plimack ER, Kessler ER, Matin SF, Godoy G, Alva A, Hahn NM, Carducci MA, Hoffman-Censits J; Collaborators. Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by Extirpative Surgery in Patients with High Grade Upper Tract Urothelial Carcinoma. J Urol. 2020 Apr;203(4):690-698. doi: 10.1097/JU.0000000000000644. Epub 2019 Nov 8. PMID: 31702432; PMCID: PMC7735436.
4. Coleman JA, Yip W, Wong NC, Sjoberg DD, Bochner BH, Dalbagni G, Donat SM, Herr HW, Cha EK, Donahue TF, Pietzak EJ, Hakimi AA, Kim K, Al-Ahmadie HA, Vargas HA, Alvim RG, Ghafoor S, Benfante NE, Meraney AM, Shichman SJ, Kamradt JM, Nair SG, Baccala AA Jr, Palyca P, Lash BW, Rizvi MA, Swanson SK, Muina AF, Apolo AB, Iyer G, Rosenberg JE, Teo MY, Bajorin DF. Multicenter Phase II Clinical Trial of Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy for Patients With High-Grade Upper Tract Urothelial Carcinoma. J Clin Oncol. 2023 Mar 10;41(8):1618-1625. doi: 10.1200/JCO.22.00763. Epub 2023 Jan 5. PMID: 36603175; PMCID: PMC10043554.
5. Christensen E, Birkenkamp-Demtröder K, Sethi H, Shchegrova S, Salari R, Nordentoft I, Wu HT, Knudsen M, Lamy P, Lindskrog SV, Taber A, Balcioglu M, Vang S, Assaf Z, Sharma S, Tin AS, Srinivasan R, Hafez D, Reinert T, Navarro S, Olson A, Ram R, Dashner S, Rabinowitz M, Billings P, Sigurjonsson S, Andersen CL, Swenerton R, Aleshin A, Zimmermann B, Agerbæk M, Lin CJ, Jensen JB, Dyrskjøt L. Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma. J Clin Oncol. 2019 Jun 20;37(18):1547-1557. doi: 10.1200/JCO.18.02052. Epub 2019 May 6. PMID: 31059311.
6. Huelster HL, Gould B, Schiftan EA, Camperlengo L, Davaro F, Rose KM, Soupir AC, Jia S, Zheng T, Sexton WJ, Pow-Sang J, Spiess PE, Daniel Grass G, Wang L, Wang X, Vosoughi A, Necchi A, Meeks JJ, Faltas BM, Du P, Li R. Novel Use of Circulating Tumor DNA to Identify Muscle-invasive and Non-organ-confined Upper Tract Urothelial Carcinoma. Eur Urol. 2024 Mar;85(3):283-292. doi: 10.1016/j.eururo.2023.09.017. Epub 2023 Oct 4. PMID: 37802683.