Alvin C. Goh

Background: Urothelial cancer typically affects older adults, yet early-onset urothelial cancer (age 45 years and younger) cases are rising and remain poorly characterized. We hypothesized that early-onset urothelial cancer exhibits distinct clinical and genomic features that reflect a different biological etiology from standard-onset urothelial cancer. Methods: We compared clinical, pathologic, and genomic characteristics of patients with early-onset urothelial cancer vs standard-onset urothelial cancer evaluated at Memorial Sloan Kettering Cancer Center from 2000 through 2024. Clinical data included 9221 patients, with tumor and germline genomic profiling by Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay in 2753 patients. Results: Early-onset urothelial cancer accounted for 335 of 9221 (3.6%) patients. Early-onset urothelial cancer patients were more likely never-smokers (43% vs 26%, P < .001), female (30% vs 25%, P = .034), and of Asian race (7.4% vs 3.1%, P < .001). Early-onset urothelial cancer tumors were more often low-grade (41% vs 23%, P < .001) and of pure nonurothelial histology (4.0% vs 1.7%, P = .003). Early-onset urothelial cancer showed marked enrichment for HRAS mutations, independent of histologic subtype, and HRAS-mutated tumors had reduced APOBEC-associated mutation signatures. Germline pathogenic variants were detected in 21.0% of early-onset vs 17.2% of standard-onset urothelial cancer patients (P = .43), driven mostly by mismatch repair and MUTYH gene alterations. Rare cases of somatic mosaicism in HRAS and ERCC2 were observed in patients with very early-onset disease. Conclusions: Early-onset urothelial cancer represents a biologically distinct subset characterized by HRAS-driven oncogenesis, reduced APOBEC mutagenesis, frequent germline variants, and, rarely, somatic mosaicism. These findings suggest developmental or genetic mechanisms underlying early-onset urothelial cancer and supporting age- and biology-informed approaches to risk assessment, genetic counseling, and targeted therapy development.

Purpose:To determine whether carcinoma in situ (CIS) is a sufficient measure of minimal residual disease (MRD) in non–muscle-invasive bladder cancer (NMIBC) and evaluate alternative measures of MRD.Experimental Design:We evaluated the concordance of CIS on transurethral resection of bladder tumor (TURBT) and radical cystectomy (RC) to determine eradication rates of clinical CIS (cCIS) by TURBT alone and rates of occult pathologic CIS (pCIS) seen only in RC specimens. We studied a prospective cohort of patients with BCG-naïve high-grade NMIBC to evaluate pretreatment urinary cytology and urinary tumor (ut)DNA as alternative biomarkers.Results:Eradication of CIS was seen in 20% of patients (78/383). Positive urinary cytology, but not cCIS, was associated with pCIS. In our prospective cohort (n = 173), abnormal pre-BCG urine cytology, but not pre-BCG cCIS, had worse high-grade recurrence-free survival [HG-RFS; hazard ratio, 3.56; 95% confidence interval (CI), 1.74–7.31, P < 0.001]. The median follow-up was 1.8 years (95% CI, 1.3–2.2). Among those with utDNA available, 84% (56/67) had sufficient DNA for genomic profiling. The 2-year HG-RFS rate in patients without an oncogenic alteration (n = 17) in their pre-BCG urine was 100% versus 60% (95% CI, 46%–78%) in patients with detectable oncogenic alterations (n = 38; P = 0.004). Area under the curve values for predicting 2-year HG-RFS were 0.52 for cCIS, 0.68 for cytology, and 0.74 for utDNA.Conclusions:We found ∼20% eradication of cCIS from TURBT alone. cCIS was a poor metric of MRD, performing worse than abnormal pretreatment urinary cytology and utDNA. These urine biomarkers are more objective MRD measures than cCIS for NMIBC risk stratification and treatment assessment.

Plasma cell-free DNA sequencing data

Representativeness of Study Participants

Purpose: To determine whether carcinoma in situ (CIS) is a sufficient measure of minimal residual disease (MRD) in non–muscle-invasive bladder cancer (NMIBC) and evaluate alternative measures of MRD. Experimental Design: We evaluated the concordance of CIS on transurethral resection of bladder tumor (TURBT) and radical cystectomy (RC) to determine eradication rates of clinical CIS (cCIS) by TURBT alone and rates of occult pathologic CIS (pCIS) seen only in RC specimens. We studied a prospective cohort of patients with BCG-naïve high-grade NMIBC to evaluate pretreatment urinary cytology and urinary tumor (ut)DNA as alternative biomarkers. Results: Eradication of CIS was seen in 20% of patients (78/383). Positive urinary cytology, but not cCIS, was associated with pCIS. In our prospective cohort (n = 173), abnormal pre-BCG urine cytology, but not pre-BCG cCIS, had worse high-grade recurrence-free survival [HG-RFS; hazard ratio, 3.56; 95% confidence interval (CI), 1.74–7.31, P < 0.001]. The median follow-up was 1.8 years (95% CI, 1.3–2.2). Among those with utDNA available, 84% (56/67) had sufficient DNA for genomic profiling. The 2-year HG-RFS rate in patients without an oncogenic alteration (n = 17) in their pre-BCG urine was 100% versus 60% (95% CI, 46%–78%) in patients with detectable oncogenic alterations (n = 38; P = 0.004). Area under the curve values for predicting 2-year HG-RFS were 0.52 for cCIS, 0.68 for cytology, and 0.74 for utDNA. Conclusions: We found ∼20% eradication of cCIS from TURBT alone. cCIS was a poor metric of MRD, performing worse than abnormal pretreatment urinary cytology and utDNA. These urine biomarkers are more objective MRD measures than cCIS for NMIBC risk stratification and treatment assessment.

Supplementary Table 3. Summary of Grade 3 to 5 Treatment-emergent Adverse Events