Muscle-invasive Urothelial Cancer Patients Research Articles

Integrated multiomics analysis and machine learning refine molecular subtypes and prognosis for muscle-invasive urothelial cancer

Muscle-invasive urothelial cancer (MUC), characterized by high aggressiveness and significant heterogeneity, is currently lacking highly precise individualized treatment options. We used a computational pipeline to synthesize multiomics data from MUC patients using 10 clustering algorithms, which were then combined with 10 machine learning algorithms toidentify molecular subgroups of high resolution and develop a robust consensus machine learning-driven signature (CMLS). Through multiomics clustering, we identified three cancer subtypes (CSs) that are related to prognosis, with CS2 exhibiting the most favorable prognostic outcome. Subsequent screening enabled identification of 12 hub genes that constitute a CMLS with robust predictive power for prognosis. The low-CMLS group exhibited a more favorable prognosis and greater responsiveness to immunotherapy and was more likely to exhibit the "hot tumor" phenotype. The high-CMLS group had a poor prognosis and lower likelihood of benefitting from immunotherapy, but dasatinib and romidepsin may serve as promising treatments for them. Comprehensive analysis of multiomics data can offer important insights and further refine the molecular classification of MUC. Identification of CMLS represents a valuable tool for early prediction of patient prognosis and for screening potential candidates likely to benefit from immunotherapy, with broad implications for clinical practice.

Urothelial cancer proteomics provides both prognostic and functional information

Traditionally, bladder cancer has been classified based on histology features. Recently, some works have proposed a molecular classification of invasive bladder tumors. To determine whether proteomics can define molecular subtypes of muscle invasive urothelial cancer (MIUC) and allow evaluating the status of biological processes and its clinical value. 58 MIUC patients who underwent curative surgical resection at our institution between 2006 and 2012 were included. Proteome was evaluated by high-throughput proteomics in routinely archive FFPE tumor tissue. New molecular subgroups were defined. Functional structure and individual proteins prognostic value were evaluated and correlated with clinicopathologic parameters. 1,453 proteins were quantified, leading to two MIUC molecular subgroups. A protein-based functional structure was defined, including several nodes with specific biological activity. The functional structure showed differences between subtypes in metabolism, focal adhesion, RNA and splicing nodes. Focal adhesion node has prognostic value in the whole population. A 6-protein prognostic signature, associated with higher risk of relapse (5 year DFS 70% versus 20%) was defined. Additionally, we identified two MIUC subtypes groups. Prognostic information provided by pathologic characteristics is not enough to understand MIUC behavior. Proteomics analysis may enhance our understanding of prognostic and classification. These findings can lead to improving diagnosis and treatment selection in these patients.

Fibroblast Growth Factor Receptor 1 Overexpression Is Associated with Poor Survival in Patients with Resected Muscle Invasive Urothelial Carcinoma.

PurposeTo examine the usefulness of various receptor tyrosine kinase expressions as prognostic markers and therapeutic targets in muscle invasive urothelial cancer (UC) patients.Materials and MethodsWe retrospectively analyzed the data of 98 patients with muscle invasive UC who underwent radical cystectomy between 2005 and 2010 in Yonsei Cancer Center. Using formalin fixed paraffin embedded tissues of primary tumors, immunohistochemical staining was done for human epidermal growth factor receptor 2 (HER2), fibroblast growth factor receptor 1 (FGFR1), and fibroblast growth factor receptor 3 (FGFR3).ResultsThere were 41 (41.8%), 44 (44.9%), and 14 (14.2%) patients who have over-expressed HER2, FGFR1, and FGFR3, respectively. In univariate analysis, significantly shorter median time to recurrence (TTR) (12.9 months vs. 49.0 months; p=0.008) and overall survival (OS) (22.3 months vs. 52.7 months; p=0.006) was found in patients with FGFR1 overexpression. By contrast, there was no difference in TTR or OS according to the HER2 and FGFR3 expression status. FGFR1 remained as a significant prognostic factor for OS with hazard ratio of 2.23 (95% confidence interval: 1.27–3.90, p=0.006) in multivariate analysis.ConclusionOur result showed that FGFR1 expression, but not FGFR3, is an adverse prognostic factor in muscle invasive UC patients after radical cystectomy. FGFR1 might be feasible for prognosis prediction and a potential therapeutic target after thorough validation in muscle invasive UC.

Efficacy of neo-adjuvant gemcitabine plus cisplatin (GC) in muscle-invasive urothelial cancer (UC)

5077 Background: Neoadjuvant chemotherapy with methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) plus radical cystectomy (RC) improves survival over cystectomy alone in urothelial cancer (UC); survival is greatest for patients achieving either pT0 or = pT1 after chemotherapy. GC is less toxic and achieves a similar response and survival to MVAC in metastatic UC, but is untested as neoadjuvant therapy. This study compared GC-induced pathological response in the bladder to that seen with neoadjuvant MVAC in an historic control series (1983–88) at our center (JCO 12:1394, 1994). Methods: We retrospectively reviewed records from muscle-invasive UC patients who received neoadjuvant chemotherapy from 11/2000 to 5/2006; 43 received GC (planned 4 cycles) followed by RC. Post-chemotherapy pathologic response was compared to neoadjuvant MVAC pts (planned 4 cycles) but whose post-chemotherapy surgery varied by surgeon’s discretion. 34 of 111 MVAC patients underwent post-chemotherapy RC and an additional 21 patients underwent partial cystectomy (PC). Pathologic outcomes of the GC cohort were compared to MVAC patients that underwent either RC (n=34) or to either RC or PC (n=55). IRB approval was obtained. Results: Baseline characteristics and treatment results were similar for both groups. The median time from start of GC chemotherapy to RC was 141 days (IQ range 123–155). Start of MVAC to RC (n=34) was 95 days (IQ range 76–163) and to either RC or PC (n=55) was 119 days (IQ range 89–175). Achieving = pT1 was similar for GC (15/43; 35%, 95% CI 21–51%) and MVAC followed by RC (6/34; 18%, 95% CI 7–35) or MVAC followed by either RC or PC (20/55; 36%, 95% CI 24–50). Achieving pT0 for GC patients (11/43; 26%, 95% CI 14–41) was also similar to MVAC plus RC (5/34; 15%, 95% CI 5–31) and MVAC plus either RC or PC (15/55; 27%, 95% CI 16–41). Conclusions: Neoadjuvant GC is similar to MVAC in both pathologic response in the bladder and time to cystectomy. The efficacy and tolerance of neoadjuvant GC warrants further study to assess overall survival. No significant financial relationships to disclose.