BCANTT 2025: Tracking and Tackling an Increasing Trend in Young-Onset Bladder/Urothelial Cancer

(UroToday.com) The Bladder Cancer Advocacy Network (BCAN) Bladder Cancer Think Tank 2025, held in Washington D.C., United States, was host to the Breakout Session: Tracking and Tackling an Increasing Trend in Young-Onset Bladder/Urothelial Cancer. Dr. Shilpa Gupta and Dr. Ashish Kamat co-chaired the breakout session Tracking and Tackling an Increasing Trend in Young-Onset Bladder/Urothelial Cancer. They invited Dr. Mario Fernández, Melanie Pepin, and Kristen Watts to tackle this very important subject.

Dr. Kamat opened the session by emphasizing that among the 40 most common cancers in young adults (ages 15–39), invasive bladder cancer ranked 11th between 2000 and 2011. He cited findings from a SEER database analysis, which included 2,772 patients diagnosed from 2000 to 2016. Of these, 71% had Ta/Tis disease, 20% had T1–T2N0M0 disease, and 7% presented with regional or distant metastases. Most cases (61%) were low-grade, while 4.5% exhibited histologic variants.⁸

At the BCAN 2024 Think Tank, it was noted that this working group previously agreed to define young-onset bladder cancer as diagnosis at ≤50 years old, a threshold that helps standardize research despite earlier studies variably using cutoffs between 15–39 or 25–39 years. Building on this consensus, investigators reviewed the MD Anderson Cancer Center experience from August 2016 to August 2024. Among 260 patients diagnosed at age ≤50, the median age was 43 years (range 36–47), and 74% were male. Germline testing was performed in 13% of patients. At diagnosis, 81% had NMIBC and 19% had MIBC. Encouragingly, cancer-specific survival exceeded 86% at 10 years. However, female patients exhibited significantly worse survival, underscoring the need to further explore sex-based disparities in outcomes.

Dr. Kamat highlighted that, according to their data at MD Anderson, long-term survival for young-onset bladder cancer patients is generally favorable; however, outcomes are notably worse in females, even after adjusting for tumor stage and grade. While most patients were eligible for platinum-based neoadjuvant chemotherapy, the pathologic complete response rate remained modest at 33%. Among those undergoing cystectomy, more than half elected to receive an orthotopic urinary diversion, highlighting a preference for continent reconstruction in this younger population.

In a comparative analysis of patients undergoing BCG therapy, individuals with young-onset bladder cancer (YOBC) demonstrated significantly improved overall survival (OS) and progression-free survival (PFS) compared to those with later-onset disease (HR 3.3, 95% CI 1.1–10.5, p=0.0396). Notably, YOBC cases were more frequently categorized within the intermediate-risk NMIBC group per EAU criteria. These findings underscore that survival outcomes after BCG are generally more favorable in patients diagnosed with YOBC.

Dr. Gupta highlighted ongoing efforts from the BCAN Think Tank 2024 to better understand and define YOBC. These included the establishment of a YOBC Working Group, consensus on an age cutoff of ≤50 years, institutional reviews of YOBC trends, and the initiation of surveys targeting both patients and providers. The patient survey, still in progress, has enrolled 88 individuals with YOBC, nearly equally divided between men and women, predominantly Caucasian, and mostly privately insured. Notably, a substantial number of respondents (15 women and 19 men) reported not undergoing tumor genetic testing, underscoring a continued gap in personalized genomic evaluation. 

Dr. Gupta also presented findings from Dr. Basnet’s evaluation of 9,411 urothelial carcinoma cases that underwent comprehensive genomic profiling (CGP), identifying 291 patients (3.1%) diagnosed with clinically advanced urothelial bladder cancer (CAUBC) under age 50. Compared with their older counterparts (CAUBC >50), younger patients had fewer genomic alterations per tumor (7 vs 8; p<0.0001) and demonstrated distinct ancestry distributions. African and admixed American ancestries were significantly more represented among younger cases, while European ancestry was more prevalent among older patients.

Biomarker analysis revealed that high microsatellite instability (MSI-H) was rare in both groups, while tumor mutational burden (TMB >10 mutations/Mb) and APOBEC signatures were significantly more common in the older cohort (35% vs 28.5%, p=0.048; and 32.5% vs 26%, p=0.041, respectively). These results underscore potential age-related differences in tumor biology and ancestry-related genomic landscapes in advanced bladder cancer.

In clinically advanced urothelial bladder cancer, certain genomic alterations appeared more frequently in patients under 50 years of age, including HRAS (5% vs 2%), CCND1 (16.2% vs 13%), and PTEN (6.5% vs 4.5%), although none of these differences reached statistical significance. Importantly, the overall prevalence of targetable or potentially targetable genomic alterations was comparable between younger and older patients.

Current evidence highlights a lack of published consensus regarding the clinical behavior and outcomes in YOBC. Immune checkpoint inhibitor response biomarkers, including tumor mutational burden (TMB) and PD-L1, are less frequently elevated in this population. Comprehensive genomic profiling in YOUBC reveals a distinct pattern of biomarker and genomic alteration distribution, with potential implications for therapy selection and trial design tailored to younger patients. Efforts are underway to expand this work through the BCAN–IBCG initiative focused on YOBC.

Dr. Gupta emphasized several next steps to advance the understanding of YOBC, including the creation of a multi-institutional database with shared clinical, pathological, and genomic data to assess treatment outcomes across disease stages. She also underscored the importance of leveraging national and international cancer registries such as SEER, NCDB, and the Canadian Cancer Registry to analyze population-level trends. Finally, a deeper dive into genomic data through platforms like Foundation Medicine and TCGA, as well as collaboration through the IBCG YOBC initiative, will help guide future directions. 

The bladder cancer incidence in Latin America in 2022 was 23,641 new cases, with age-standardized incidence rates of 7.3 per 100,000 for men and 2.4 per 100,000 for women. Despite lower incidence compared to high-HDI regions like Europe and North America, the 5-year prevalence remains substantial at over 105,000 cases. In Chile, 1,635 new cases of bladder cancer were diagnosed this year, with a 7.2 and 2.7/100,000 ASR for men and women, respectively. Notably, the 5-year prevalence was 5,224 cases.

We know that underdeveloped regions, many of which fall into earlier stages of the smoking epidemic, remain key targets of the tobacco industry. As illustrated in this figure, Latin America is currently in Stage 3, characterized by rising rates of female smoking and increasing smoking-attributable mortality, particularly among men, as illustrated below. Combined with an aging population, these trends raise concern for a potential surge in tobacco-related diseases, including bladder cancer, in the coming decades.¹

Dr. Fernández noted that bladder cancer incidence in Latin America is projected to rise sharply by 85% by the year 2040. This expected increase, shown alongside similar trends in other low- and middle-income regions, underscores the urgent need for enhanced prevention strategies, early detection infrastructure, and access to care across the region.

For this, Dr. Fernández emphasized the importance of contextualizing cancer burden within the realities of healthcare investment. In 2021, health expenditure per capita in Latin America was under $770 USD, significantly lower than in high-income regions, highlighting a major barrier to addressing the anticipated rise in bladder cancer incidence. While basic cancer care is often covered, access to high-cost drugs and advanced technologies remains limited. Moreover, there are no population-level cancer prevention programs, and screening or genetic risk assessments are rarely offered or reimbursed by most health insurance plans across the region.

In terms of young-onset bladder cancer (YOBC) in Chile, data from 2017–2025 show that patients ≤50 years old (n=37) tended to present with more favorable disease characteristics compared to older patients (>50 years, n=302). Younger patients were more likely to have single tumors (81.1%), low-grade histology (73.0%), smaller tumor size (<3cm in 67.6%), and non-invasive cTa stage (76.5%). Notably, no patients under 50 had muscle-invasive disease (cT2), and only 5.6% had associated carcinoma in situ (CIS). 

Moreover, among patients with non–muscle-invasive bladder cancer (NMIBC), younger individuals (≤50 years) in Chile were more likely to present with low- or intermediate-risk disease compared to older patients. Only 32.4% of younger patients were classified as high risk, versus nearly 58% of those >50 years. Importantly, cancer-specific survival (CSS) in the younger cohort was 100%, reinforcing that YOBC in this setting is typically associated with less aggressive behavior and good outcomes.

Dr. Fernández also addressed arsenic as a well-established environmental carcinogen, particularly relevant in regions like northern Chile, where both deep and superficial water sources contain high levels of naturally occurring arsenic. Chronic exposure has been linked to increased incidence and cancer-specific mortality from bladder cancer, upper tract urothelial cancer, lung cancer, and renal cell carcinoma. Notably, studies in the Atacama Desert population have identified genetic adaptation signatures to arsenic exposure, shaped by natural selection before and after European admixture, highlighting the long-standing and biologically impactful nature of this environmental risk.

Alarmingly, over 100 million people worldwide are at risk of exposure to arsenic through contaminated drinking water. In Chile alone, an estimated 437,000 individuals are currently exposed to groundwater arsenic concentrations ranging from 900 to 1,040 µg/L, far exceeding the WHO guideline limit of 50 µg/L. Furthermore, between 1958 and 1970, up to 200,000 inhabitants in Chile, Antofagasta, were exposed to drinking water containing arsenic levels up to 17 times above recommended limits.

Antofagasta offers a unique setting for studying the long-term health effects of arsenic exposure due to its extremely dry environment, limited sources of drinking water, and the availability of detailed arsenic concentration records dating back to the 1950s. This combination of environmental stability and historical data has allowed researchers to clearly link periods of high arsenic exposure to bladder cancer mortality.

Notably, in a study led by Dr Fernandez, bladder cancer mortality rates in Antofagasta have shown a striking upward trend, with a clear divergence from national averages beginning in the 1970s reflecting the latency period following peak arsenic exposure in the 1950s–60s. Mortality rates peaked at 28.4 per 100,000 for men and 18.7 per 100,000 for women in recent years.² This applies both to men and women as illustrated below.

Dr. Fernández noted that bladder cancer mortality in the arsenic-exposed region of northern Chile remained markedly elevated even 40 years after high exposures ceased, particularly among individuals under 50 years of age. Between 2001 and 2010, men aged 40–49 had a 13-fold higher mortality risk (RR 13.0, 95% CI 7.94–21.4), and women aged 50–59 had a nearly 10-fold higher risk (RR 9.58, 95% CI 6.83–15.7) compared to the rest of Chile. These findings raise the possibility that early-life arsenic exposure may have long-lasting effects, potentially initiating biological changes that increase cancer susceptibility decades later.

Moreover, a landmark case-control study published demonstrated increased lung and bladder cancer incidence in adults following in utero and early-life arsenic exposure. Conducted in Northern Chile, the study included all bladder cancer cases diagnosed between 2007 and 2010 and assessed lifetime residential histories including where the patient’s mother lived during pregnancy to estimate arsenic exposure during critical developmental windows. The findings reinforce the concept that early-life arsenic exposure can have lasting carcinogenic effects, manifesting decades later in adulthood.³

Bladder cancer incidence markedly increased following early-life exposure to high levels of arsenic in drinking water, with effects persisting for up to 40 years after exposure ceased (1958–1970). Individuals exposed to concentrations >800 µg/L only in utero or during childhood had an adjusted odds ratio (OR) of 8.11 (95% CI: 4.31–15.25) for developing bladder cancer, compared to an OR of 4.71 (95% CI: 2.61–8.48) among those exposed only as adults, as illustrated below. This nearly twofold difference underscores the profound and lasting susceptibility to carcinogenic effects from early-life arsenic exposure, suggesting that humans may be especially vulnerable to lifelong health consequences stemming from exposure during critical developmental periods.

In a genome-wide association study of a high-risk, arsenic-exposed population in Northern Chile (Antofagasta), investigators identified several genetic variants associated with the presence of bladder urothelial carcinoma. Similarly, in the New England Bladder Cancer Study, variants near genes involved in folate metabolism and oxidative stress response, including MTHFR, GSTZ1, GSTM1, and AS3MT, were highlighted as potential modifiers of bladder cancer risk in arsenic-exposed individuals. While genome-wide gene-environment interaction analyses revealed no statistically significant interactions, these findings suggest that inherited differences in arsenic and xenobiotic metabolism pathways may help identify individuals most susceptible to carcinogenic effects.

Another important finding was that the age at death from bladder cancer was significantly lower in males from Antofagasta compared to the rest of Chile, as shown below. Moreover, in a comparative analysis of patients from Antofagasta and Santiago, multivariable modeling identified arsenic exposure as the sole independent predictor of aggressive disease features. Specifically, it was associated with significantly increased odds of high-grade tumors (OR 4.31; 95% CI: 1.71–10.86) and locally advanced stage at diagnosis (T3–T4; OR 10.23; 95% CI: 1.12–93.12).⁴

Dr. Fernandez’s closing take-home messages were:

• Bladder cancer incidence is rising across Latin America, placing growing strain on healthcare systems.
• A distinct subtype of arsenic-related bladder cancer is emerging in high-exposure regions.
• This disease pattern is notably aggressive.
• Long-term consequences of arsenic exposure persist effects remain evident even 40 years after the peak exposure period ended.
• Early-life exposure, particularly in individuals under age 50, appears to drive much of this aggressive disease phenotype.

Melanie Pepin began her presentation by sharing her personal journey as a bladder cancer survivor and framing the importance of germline genetic insights in this context. She explained that Cancer-Associated Pathogenic Variants (CAPVs), including alterations in oncogenes, tumor suppressors, and DNA repair genes, are inherited and constitutional, distinguishing them from somatic mutations acquired over a lifetime. CAPVs may influence not only the location and timing of somatic mutations but also the pace of tumor progression. She emphasized that the cancer risk conferred by germline variants can vary significantly depending on the specific gene involved.

CAPVs are typically inherited in an autosomal dominant fashion (as illustrated below) but often show reduced penetrance, meaning not all carriers develop cancer. CAPVs may increase the likelihood of developing a second, new primary cancer, especially in carriers of specific genes. Importantly, identifying these variants has implications not only for patients but also for their families. Genetic testing may help detect relatives at risk and enable early cancer screening, potentially saving lives. Moreover, CAPVs are more commonly seen in patients diagnosed at a younger-than-average age, raising the question of whether this pattern can be confirmed specifically in bladder cancer cohorts.

She went on to review the medical literature regarding bladder cancer in younger individuals, beginning with a systematic review. This analysis included 18 publications from 1998 to 2016, all focused on patients younger than 45 years. The review addressed study type, histologic subtype, overall survival, recurrence rates, and key clinical findings. Strikingly, none of the studies reported germline genetic testing results. Instead, the most recent publications emphasized only tumor molecular profiling.⁵ Ms. Pepin noted that the emphasis on germline testing in bladder cancer has emerged only recently (around 2017), highlighting a critical gap in earlier research and a missed opportunity to identify inherited cancer risk in younger patients.

Across studies of germline variants in individuals with bladder cancer, there is significant heterogeneity in both clinical and genomic methodology. Patient diagnoses span non–muscle-invasive (NMIBC), muscle-invasive (MIBC), and upper tract (UT) disease, with tumor grade also varying across cohorts. Additionally, the type of genetic testing employed differs substantially: some studies rely on targeted cancer gene panels focusing on selected genes and splice regions (often following initial exome sequencing), while others perform whole-exome sequencing (WES) to capture all protein-coding DNA. A subset of analyses incorporates tumor-normal testing, which compares somatic and germline DNA to clarify variant origin and relevance.

Ms. Pepin highlighted a 2018 study that sequenced 54 DNA repair genes in 98 patients with bladder cancer. The findings revealed that 10% of patients harbored a pathogenic or likely pathogenic (P/LP) germline variant, with the prevalence increasing to 15% in those with muscle-invasive disease. Notably, the frequency of P/LP variants was three times higher in individuals diagnosed before age 45, with 28.6% of early-onset cases carrying such variants compared to only 8.8% of older patients, underscoring the importance of considering germline testing in younger patients.⁶

Ms. Pepin summarized findings across CAPV studies in bladder cancer, showing that younger individuals tend to have a higher prevalence of pathogenic or likely pathogenic variants. Patients under 42 had significantly more variants (p<0.01), and 10% of cases occurred in individuals younger than 45. In high-grade tumors, no significant difference was found in those under 55. Among those evaluated for cancer syndromes, the median age was 60 (p<0.0001), and patients with pathogenic variants were younger (68 vs. 70 years; p<0.01).

In a prospective multisite study evaluating germline variants across genitourinary cancers, including bladder cancer, 106 patients with bladder cancer underwent universal germline testing with a panel of 80 genes. Among them, 14.2% had a positive result, 44.3% had variants of uncertain significance (VUS), and 41.5% tested negative. Of those with positive findings, approximately 62.6% had moderate or high-penetrance variants, including alterations in CHEK2, ATM, BRIP1, MSH2, and HOXB13 as illustrated below.⁷

Ms. Pepin noted that multiple studies support a higher frequency of CAPVs in younger individuals with bladder cancer. She emphasized the need for prospective studies specifically focusing on this population. Key considerations for the future include whether the observed frequency of germline mutations is increasing, potentially due to rising rates of de novo variants as well as the growing ability to interpret variants of uncertain significance (VUS), identify novel cancer-associated genes, and apply advanced testing technologies. She advocated for a more integrated approach that combines germline insights with common bladder cancer–associated variants and environmental risk factors.

ASCO guidelines recommend germline genetic testing in bladder cancer patients who meet specific criteria:

• Those with a personal or family history of Lynch-associated cancers
• Those with a pathogenic variant identified in their tumor tissue
• Patients diagnosed with bladder cancer at a young age (e.g., <50 years).

While testing has historically been selective, growing evidence and updated guidelines support an expanded approach, potentially including universal testing, especially considering emerging targeted therapies and the risk of missing germline mutations through tumor-only sequencing.

Ms. Pepin highlighted the ATM likely pathogenic variant (c.875C>T; p.Pro292Leu), which is associated with a moderate increase in bladder cancer risk. Carriers should be counseled about an elevated risk of breast cancer, warranting alternating breast MRI and mammography every 6 months. There is also an increased risk of prostate cancer and a roughly 10% lifetime risk of pancreatic cancer by age 80. These findings highlight the importance of incorporating personalized surveillance strategies based on gene-specific risk. 

While guidelines increasingly support an expanded approach to germline testing, potentially including universal testing for young bladder cancer patients, several tools are available to help personalize care in the interim. These include Ancestry.com for familial connections, FORCE (Facing Hereditary Cancer Empowered) for patient support and education, ConnectMyVariant.com for tracing shared variants across families, and FindAGeneticCounselor.NSGC.org for locating certified genetic counselors.

Ms. Pepin concluded by sharing her personal journey with genetic testing, underscoring both its potential and current limitations. Following her own efforts to initiate testing, a likely pathogenic variant in the ATM gene was identified not only in her case but also in her mother and a healthy niece. However, despite this significant finding, only one of her siblings has undergone testing to date. This highlights persistent barriers to the broad implementation of personalized genetic testing, even when clinically meaningful variants are discovered within families.

Kristen Watts, a bladder cancer survivor, shared her journey after being diagnosed at age 21. Her symptoms began with anemia and syncope, but it took up to five months before she was referred to a urologist. Initial imaging showed a small bladder mass, and repeat ultrasound revealed a 5 cm lesion. She underwent cystoscopy and TURBT, which showed non–muscle-invasive bladder cancer (NMIBC), requiring a re-resection. She was offered and received BCG induction, followed by another TURBT and maintenance BCG (1 instillation every 3 weeks), but ultimately experienced BCG intolerance. She continues with cystoscopic surveillance every three months and has developed chronic bladder pain syndrome, though the cancer has not recurred. 

Presented by:

Co-Chairs: Shilpa Gupta, MD, Cleveland Clinic, Cleveland, OH. Ashish Kamat, MD, MBBS, MD Anderson Cancer Center, Houston, TX.

• Mario Fernández, MD, Clínica Alemana Universidad del Desarrollo, Santiago de Chile, Chile.
• Melanie Pepin, MS, CGC, Bladder Cancer Survivor, Genetic Counselor
• Kristen Watts, BCAN Patient Advocate

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 Bladder Cancer Advocacy Network (BCAN) Bladder Cancer Think Tank 2025 held in Washington D.C., United States, between July 30^th and August 1^st.

Reference:

1. Ploeg M, Aben KK, Kiemeney LA. The present and future burden of urinary bladder cancer in the world. World J Urol. 2009 Jun;27(3):289-93. doi: 10.1007/s00345-009-0383-3. Epub 2009 Feb 15. PMID: 19219610; PMCID: PMC2694323.
2. Fernández MI, López JF, Vivaldi B, Coz F. Long-term impact of arsenic in drinking water on bladder cancer health care and mortality rates 20 years after end of exposure. J Urol. 2012 Mar;187(3):856-61. doi: 10.1016/j.juro.2011.10.157. Epub 2012 Jan 15. PMID: 22248521.
3. Steinmaus C, Ferreccio C, Acevedo J, Yuan Y, Liaw J, Durán V, Cuevas S, García J, Meza R, Valdés R, Valdés G, Benítez H, VanderLinde V, Villagra V, Cantor KP, Moore LE, Perez SG, Smith AH. Increased lung and bladder cancer incidence in adults after in utero and early-life arsenic exposure. Cancer Epidemiol Biomarkers Prev. 2014 Aug;23(8):1529–38. doi:10.1158/1055-9965.EPI-14-0185.
4. Fernández MI, Valdebenito P, Delgado I, Segebre J, Chaparro E, Fuentealba D, Castillo M, Vial C, Barroso JP, Ziegler A, Bustamante A. Impact of arsenic exposure on clinicopathological characteristics of bladder cancer: A comparative study between patients from an arsenic-exposed region and nonexposed reference sites. Urol Oncol. 2020 Feb;38(2):40.e1-40.e7. doi: 10.1016/j.urolonc.2019.09.013. Epub 2019 Oct 18. PMID: 31630994.
5. Bourgi A, Vincentelli A, Rusch E, Bruyère F. Youth matters: a systematic review of the molecular and clinical landscape of bladder cancer in young adults. World J Urol. 2025 May 22;43(1):321. doi: 10.1007/s00345-025-05698-y. PMID: 40405006.
6. Na R, Wu Y, Jiang G, Yu H, Lin X, Wang M, Conran CA, Fantus RJ, Zhang N, Liu S, Helfand BT, Zheng SL, Isaacs WB, Ding Q, Shen Z, Xu J. Germline mutations in DNA repair genes are associated with bladder cancer risk and unfavourable prognosis. BJU Int. 2018 Nov;122(5):808-813. doi: 10.1111/bju.14370. Epub 2018 Jun 4. PMID: 29727914.
7. Choudry MM, Durant AM, Edmonds VS, Warren CJ, Kunze KL, Golafshar MA, Nielsen SM, Esplin ED, Andrews JR, Samadder NJ, Tyson MD. Germline Pathogenic Variants Identified in Patients With Genitourinary Malignancies Undergoing Universal Testing: A Multisite Single-Institution Prospective Study. J Urol. 2024 Oct;212(4):590-599. doi: 10.1097/JU.0000000000004089. Epub 2024 Jun 11. PMID: 38860938.
8. Palumbo C, Pecoraro A, Rosiello G, Luzzago S, Deuker M, Stolzenbach F, Tian Z, Shariat SF, Simeone C, Briganti A, Saad F, Berruti A, Antonelli A, Karakiewicz PI. Bladder cancer incidence rates and trends in young adults aged 20-39 years. Urol Oncol. 2020 Dec;38(12):934.e11-934.e19. doi: 10.1016/j.urolonc.2020.06.009. Epub 2020 Jul 9. PMID: 32653412.