Circulating and Urine Tumor DNA Dynamics Predict Minimal Residual Disease and Guide Adjuvant Therapy in Locally Advanced Upper Tract Urothelial Carcinoma

Shanghai Jiao Tong University

Status

Enrolling

Conditions

Muscle Invasive Upper Tract Urothelial Carcinoma

Treatments

Drug: Adjuvant chemotherapy

Drug: adjuvant immunotherapy

Study type

Observational

Funder types

Other

Identifiers

NCT05595408

CURATE-UTUC

Details and patient eligibility

About

In our study, the ultra-deep sequencing of circulating tumor DNA (ctDNA) and urine tumor DNA (utDNA) were performed to assess whether ctDNA and utDNA can be used as predictive biomarkers for the detection of minimal residual disease (MRD) and early diagnosis of UTUC recurrence, and explored the role of ctDNA and utDNA detection of MRD in the prediction of adjuvant therapy efficacy and prognostic evaluation.

Full description

60% of Upper Urinary Tract Urothelial Carcinoma (UTUC) patients with muscle-invasive disease at diagnosis, which progresses rapidly, aggressively, and has a poor prognosis. Up to 30-40% of the patients may develop bladder recurrance after radical nephroureterectomy for primary upper tract urothelial carcinoma.

Minimal residual disease (MRD) refers to the small number of malignant cells that remain after curative treatments (curative intent surgical resection, radiotherapy, and/or chemotherapy). MRD is common in patients with blood cancer, and is known to be associated with recurrence and poor prognosis. Recent studies also reported that MRD-negative in postoperative solid tumors such as colorectal/colon cancer and muscle-invasive bladder cancer is associated with better survival outcomes. However, the clinical values of MRD monitoring for adjuvant therapy in postoperative UTUC remain inadequate.

A total of 103 patients with stage II-IV UTUC will be recruited in this clinical trial. The following plasma samples, urine samples and tumor tissues will be collected from each patient including T0 (preoperatively, 2[1-3] days before surgery), T1 (28±3 days postoperatively), T2 (within 7 days after cycle 2 adjuvant therapy), T3 (end-of-treatment), and quarterly/semi-annually during surveillance (T4-T6) until recurrence/24 months. In addition, demographic and tumor characteristics of the patients will be collected for subsequent analysis, including age, sex, tumor stage, pathological stage, disease couse time, etc. Tumor tissues and matched peripheral blood were collected before treatment and WES was used ctDNA detection techniques. For each patient, we selected up to 30 clonal somatic mutations for personalized, tumor informed ctDNA assay design.Statistical analyses will be performed to analyze the survival outcomes and to explore the clinical value of MRD monitoring for adjuvant therapy in postoperative UTUC.

Sample Size Calculation:

The initial target sample size of 103 patients was calculated to detect a hazard ratio (HR) of 3.0 in extravesical recurrence-free survival (RFS) between ctDNA-positive and ctDNA-negative groups at postoperative month 1 (T1), assuming a 24-month extravesical recurrence rate of 30% (derived from the POUT trial's 29% 3-year recurrence in the chemotherapy arm, adjusted upward for UTUC-specific risk and contemporary immunotherapy use based on CheckMate 274 subgroup data), with 80% power at a two-sided α=0.05 using a Cox proportional hazards model, and accounting for a 12% dropout rate. Following a pre-specified interim analysis of the first 51 patients with sufficient follow-up, we observed 15 extravesical recurrences with a projected 24-month rate of 49% based on early Kaplan-Meier trajectory, and an unexpectedly strong association between T1 ctDNA positivity and recurrence (HR 8.7, P<0.001). Given the substantially higher event rate and effect size than initially projected, the Data and Safety Monitoring Board (DSMB) approved a reduction in the target sample size to 84 patients while maintaining ≥80% statistical power for the primary endpoint. Final enrollment reached 84 patients, and post-hoc power analysis using the observed effect size (HR=8.7) and event rate (29 extravesical recurrences in 84 patients) confirmed >98.7% power for the primary analysis of T1 ctDNA-stratified extravesical RFS.

Enrollment

84 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

pathological comfirmed T2-4 or N+ and M0 upper tract urothelial carcinoma
Male or female aged ≥18 years old who are willing to sign the informed consent form
have no distant metastasis
have an ECOG 0 to 2
upper tract urothelial carcinoma patients received radical nephroureterectomy
have no multiple primary carcinoma
received adjuvant chemotherapy or immunotherapy after surgery within 12 weeks
≥2 postoperative liquid biopsy assessments (T1 and T2)

Exclusion criteria

a prior history of bladder or synchronous bladder cancer
Pregnant or lactating women, or patients who are fertile but do not take contraceptive measures;
Severe infection;
Severe heart disease;
Uncontrollable neurological or mental disorders;
Severe diabetes mellitus;
Patients with severe autoimmune diseases.
Neoadjuvant therapy exposure
No bilateral UTUC
Surveillance time < month
<2 postoperative MRD surveillance assessments