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PURPOSE: Currently, markers are lacking that can identify patients with high risk nonmuscle invasive bladder cancer who will fail bacillus Calmette-Guérin treatment. Therefore, we evaluated the prognostic value of T1 substaging in patients with primary high risk nonmuscle invasive bladder cancer. MATERIALS AND METHODS: Patients with primary high risk nonmuscle invasive bladder cancer who received ≥5 bacillus Calmette-Guérin induction instillations were included. All tumors were centrally reviewed, which included T1 substaging (microinvasion vs extensive invasion of the lamina propria). T1 patients were stratified into high risk or highest risk subgroups according to major urology guidelines. Primary end point was bacillus Calmette-Guérin failure, defined as development of a high grade recurrence. Secondary end points were high grade recurrence-free survival, defined as time from primary diagnosis to biopsy-proven high grade recurrence and progression-free survival. Time-to-event analyses were used to predict survival. RESULTS: A total of 264 patients with high risk nonmuscle invasive bladder cancer had tumor invasion of the lamina propria, of which 73% were classified as extensive invasion and 27% as microinvasion. Median followup was 68 months (IQR 43-98) and bacillus Calmette-Guérin failure was more common among patients with extensive vs microinvasive tumors (41% vs 21%, p=0.002). The 3-year high grade recurrence-free survival (defined as bacillus Calmette-Guerin failure) for patients with extensive vs microinvasive tumors was 64% vs 83% (p=0.004). In multivariate analysis, T1 substaging was an independent predictor of high grade recurrence-free survival (HR 3.2, p=0.005) and progression-free survival (HR 3.0, p=0.009). Patients with highest risk/microinvasive disease have an improved progression-free survival as compared to highest risk/T1e disease (p.adj=0.038). CONCLUSIONS: T1 substaging provides important prognostic information on patients with primary high risk nonmuscle invasive bladder cancer treated with bacillus Calmette-Guérin. The risk of bacillus Calmette-Guérin failure is higher in extensive vs microinvasive tumors. Substaging of T1 high risk nonmuscle invasive bladder cancer has the potential to guide treatment decisions on bacillus Calmette-Guérin vs alternative strategies at diagnosis.

INTRODUCTION AND OBJECTIVE:Intravesical Bacillus Calmette-Guerin (BCG) is the recommended treatment option in high-risk non-muscle invasive bladder cancer (HR-NMIBC). However, disease recurrence oc...

Intravesical instillations with Bacillus Calmette-Guérin (BCG) are the recommended treatment in T1 high-grade (HG) bladder cancer (BC) patients. However, even with BCG treatment, 50% of patients develop a HG recurrence or progression to advanced disease. Current risk stratification is insufficient to identify patients at risk of BCG failure. We aimed to identify molecular predictors of BCG failure in T1HG BC patients with the objective to improve clinical decision-making. Primary T1HG BC patients treated with ≥5/6 BCG induction instillations were retrospectively included. RNA-sequencing (50 million paired-end reads, ≥80% tumor) was performed on centrally reviewed tumors from: 1) BCG-naïve tumors and recurrent tumors from patients that failed BCG therapy (BCG non-responders), matched to an equal number of 2) patients who had an ongoing complete response until study inclusion (BCG responders). Endpoints were HG recurrence-free survival defined as BCG-failure (RFS) and progression-free survival (PFS), assessed by survival analyses. BCG-failure was defined as development of a biopsy-proven HG recurrence or progression to muscle-muscle invasion. Using RNA-seq, we sought to identify genes, pathways and signatures that stratified patients with respect to these endpoints. 132 BCG-naïve T1HG tumors were sequenced and 45 post-BCG tumors. Median follow-up for all patients was 75 months (IQR 48-106), 99 months for n=63 BCG-responders (IQR 74-120) and 49 months for n=69 BCG-non-responders (IQR 25-79). Three molecular subtypes were identified: BCG1 (32%), BCG2 (40%) and BCG3 (28%). BCG3 patients had a significantly worse RFS (HR 2.4 p Citation Format: Florus C. De Jong, Teemu D. Laajala, Robert F. Hoedemaeker, Sébastien Rinaldetti, Jolien T. Mensink, Angelique C. Van der Made, Deric K. Van der Schoot, Egbert R. Boevé, Ellen C. Zwarthoff, Joost L. Boormans, Dan Theodorescu, James C. Costello, Tahlita C. Zuiverloon. Transcriptomic analysis of BCG-treated T1HG bladder cancer patients identifies an EMT-basal subgroup with immune suppressive characteristics at high risk of BCG-failure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 614.

Intravesical instillations with Bacillus Calmette-Guérin (BCG) is the recommended treatment for T1 high-grade (HG) bladder cancer (BC) patients. Unfortunately, risk stratification is insufficient to identify patients at risk of BCG treatment failure. Another challenge is the worldwide BCG-shortage, which emphasizes the need for alternative therapeutic strategies. Thus, we aimed to investigate molecular signal transduction pathway activities using Philips' OncoSignal consumer-ready test in BCG treated T1HG BC in order to identify differentially expressed pathways that may predict clinical outcome or provide a rationale for alternative therapeutic strategies. Primary T1HG BC patients treated with ≥5/6 BCG induction instillations were retrospectively included. RNA-sequencing (50 million paired-end reads, containing ≥80% tumor) was performed on: 1) BCG-naïve tumors from patients with complete response to BCG at study inclusion (BCG-responders) and 2) BCG-naïve tumors with matching muscle-invasive bladder cancer (MIBC) recurrences during BCG therapy (BCG-failures). Philips OncoSignal analysis was performed to quantify functional signal transduction pathway activities. Molecular subtyping was performed using non-muscle invasive and muscle-invasive classifiers. Clinical and molecular subtyping results were combined with Philips OncoSignal to explore differences between BCG responders and BCG failures and between molecular subtypes. OncoSignal was performed in 20 tumors: 14 BCG-naïve (7 BCG-responders vs 7 BCG-failures) and 6 MIBC recurrences. Median follow-up for BCG-responders was 99 months (IQR 74-120); median follow-up for BCG-failures was 49 months (IQR 25-79), with a median time to progression of 14 months (IQR 10-41). Based on pilot data, MAPK and TGFβ pathway activity was significantly higher in tumors from BCG failures vs BCG-responders (both p Citation Format: Florus C. De Jong, Teemu D. Laajala, Robert F. Hoedemaeker, Sébastien Rinaldetti, Jolien T. Mensink, Angelique C. Van Der Made, Deric K. Van der Schoot, Egbert R. Boevé, Ellen C. Zwarthoff, Joost L. Boormans, Dan Theodorescu, James C. Costello, Tahlita C. Zuiverloon. Differential pathway analyses of BCG-treated T1HG bladder cancer using Philips OncoSignal: A pilot study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 615.

Objective: Fibroblast growth factor receptor 3 (FGFR3) is a potentially actionable target in bladder cancer (BC). FGFR3 mutations are associated with favorable prognosis in non-muscle invasive (NMI) BC and MIBC. Overexpression of FGFR3 was reported in up to 40% of FGFR3 wild-type MIBC. p53 alterations rarely coincide with FGFR3 mutations. We analyzed FGFR3 mutations and protein-expression of FGFR3 and p53 and assessed their prognostic value in a multicenter, multilaboratory setting. Methods: We included 1,000 cN0M0, chemotherapy-naive patients who underwent radical cystectomy (RC) with pelvic node dissection. Specimens were reviewed by eight uropathologists. At seven laboratories, FGFR3 mutation status was examined using PCR-SNaPshot. p53 and FGFR3 expression were determined by immunohistochemistry (IHC). FGFR3 mutation status, p53 and FGFR3 protein expression were correlated to each other, clinicopathologic parameters, and disease-specific survival (DSS). Results: FGFR3 mutations were found in 107/1,000 RCs (11%), of which 67 were S249C. Overexpression of FGFR3 was found in 279/1,000 (28%) of tumors. p53 overexpression (cut-off>10%) was found in 638/926 (69%) of available cases. Among FGFR3 mutant tumors, 73% had FGFR3 overexpression. Among FGFR3 wild-type tumors, 22% had FGFR3 overexpression. FGFR3 mutations were associated with lower pT-stage (P Conclusions: FGFR3 mutations identified patients with favorable BC with fewer p53 alterations at RC. FGFR3 overexpression was not associated with DSS in patients with FGFR3 wild-type tumors. Our results suggest that FGFR3 mutations (driver effect) have a distinct functional role than FGFR3 overexpression (passenger effect). Hence, patients with FGFR3 mutations may be more likely to benefit from anti-FGFR3 therapy than patients with only overexpression of FGFR3. Citation Format: Bas van Rhijn, Laura Mertens, Roman Mayr, Peter Bostrom, Mirari Marques, Geert van Leenders, Stefanie Gotz, Michiel van der Heijden, Michael Jewett, Francisco Real, Robert Stohr, Alexandre Zlotta, Markus Eckstein, Yanish Soorojebally, Max Burger, Wolfgang Otto, Francois Radvanyi, Damien Pouessel, Theo van der Kwast, Nuria Malats, Arndt Hartmann, Yves Allory, Deric van der Schoot, Ellen Zwarthoff, Tahlita Zuiverloon. FGFR3 mutations and their relation to FGFR3 expression and clinical outcome in a large radical cystectomy cohort: Implications for anti-FGFR3 bladder cancer treatment? [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B23.

Introduction: High-risk non-muscle invasive bladder cancer (HR-NMIBC) patients represent a challenging group as they have the highest risk of treatment failure despite transurethral tumor resection (TUR) and adjuvant intravesical Bacillus Calmette-Guérin (BCG) instillations. Treatment failure is associated with an increased risk of progression and unnecessary exposure to toxicity of BCG, while continuing BCG shortage demands selective use of limited resources. The current risk stratification is insufficient at predicting BCG failure in HR-NMIBC patients. Therefore, we aim to investigate whether pathologic depth of tumor invasion (i.e., T1 substaging) is able to improve patient stratification. Methods: HR-NMIBC patients who received a TUR and at least induction BCG (5 of 6 instillations) were included at four European centers between 2000−2016. Clinicopathologic data were collected and all diagnostic TURs, re-TURs, and subsequent TURs of tumor recurrences were reviewed, which included T1 substaging (micro vs. extensive [pT1e]). Primary endpoint was BCG failure according to EAU guidelines. Progression was defined as muscle-invasive and/or metastatic disease. Logistic regression analysis and Cox regression models were used to identify predictive markers of BCG failure on diagnostic TUR and first recurrence. Results: N=513 HR-NMIBC patients were included: median age 70 years, 78% men. Median follow-up was 52 months. In total, 316 (62%) patients had pT1 disease, 144 (28%) pTa, and 53 (10%) pTis. BCG failure occurred in 28% (18% progression, 6% metastasis). Median time to progression was 18 months. Strongest predictors of BCG failure on diagnostic TUR were pT1e substaging (HR: 2.1; 95% CI 1.1–4.0; p=0.023), concomitant carcinoma in situ (CIS) (HR: 3.0; 95% CI 1.5–5.7; p=0.003), and lymphovascular invasion (LVI) (HR: 3.3, 95% CI 1.0–11, p=0.05). pT1e substaging combined with either concomitant CIS or LVI increased the risk of BCG failure (HR: 3.6; 95% CI 1.8–6.9; p Conclusion: Substaging has the potential to improve the current risk stratification model by identification of HR-NMIBC patients at the highest risk of BCG failure and is specifically able to identify patients at high risk of progression. Substaging can be performed by every pathologist with minimal additional training required. Combined with other pathologic markers, substaging can be used as a stratification tool for early cystectomy or to include patients in clinical trials. Citation Format: Florus C. de Jong, Robert F. Hoedemaeker, Jolien T.M. Mensink, Vebjørn Kvikstad, Egbert R. Boevé, Deric K.E. van der Schoot, Ellen C. Zwarthoff, Tahlita C.M. Zuiverloon. Pathologic T1 substaging improves the identification of high-risk non-muscle invasive bladder cancer patients at risk of BCG failure [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B06.