Furthermore, single-agent treatment studies with neoadjuvant ICI such as pembrolizumab and atezolizumab have also been reported with promising results. In context, the PURE-01 trial evaluated systemic neoadjuvant pembrolizumab for cT2-4N0M0 muscle-invasive bladder cancer (MIBC) patients in a phase II study, reporting N=134 patients undergoing radical cystectomy surgery with a pathological complete response rate of 36.8%, which is like the rate observed for clinical guideline-recommended therapy involving neoadjuvant chemotherapy (NAC).1 The question remains on how to improve response rates by selecting patients who would receive the most benefit from immune therapy.
Notably, previous biomarker evaluations among the PURE-01 trial revealed a promising role for molecular tumor subtypes classified by Decipher Bladder, a clinical-grade, transcriptome-wide molecular diagnostic test for clinical decision-making in bladder cancer (Necchi et al., Eur Urol 2020).2 Molecular subtyping found neuroendocrine-like tumors universally had the worst survival outcomes, while patients with MIBC classified as claudin-low molecular subtype remained free from progression within the first two years of follow-up.
In the present study, we further analyzed whole-transcriptome profiles from the PURE-01 trial and provided a detailed characterization of relapsing patients to identify distinct gene expression patterns for novel biomarker discovery within a cohort of N=102 PURE-01 patients with complete molecular data and updated follow-up data. With a median follow-up of 27.5 months, 19 patients experienced disease relapse. Interestingly, the identification of molecular subtypes associated with relapsing patients at the time of TURBT showed the NE-like subtype was highly represented among relapsing patients (11%), potentially explaining the unfavorable outcomes for some patients. Furthermore, within the subgroup of patients with tumors classified as claudin-low subtype, only one patient developed disease relapse during follow-up.
Differential gene expression revealed genes such as KRT20 (a gene associated with luminal bladder tumors) and H19 (associated with neuroendocrine disease in multiple tumor types) were enriched in relapsing patients, while immune-associated gene transcripts including CXCL11 or CC5 were higher in patients that did not experience relapse. KRT20 has been reported as one of the biomarker genes for luminal bladder cancer, a molecular subtype harboring lower levels of immune- and stromal infiltration. In our study, baseline KRT20 gene expression was higher in patients relapsing after neoadjuvant ICI therapy. It is these luminal MIBC that appear to have more favorable disease and have similar outcomes with immediate radical cystectomy (RC) or neoadjuvant therapy followed by RC. These tumors have therefore been suggested to be potential candidates who could avoid neoadjuvant chemotherapy.
Recently, Hamidi et al. showed in an analysis of 2,803 bladder cancer tumors from four randomized trials of atezolizumab found similar findings that basal and immune infiltrated tumors experienced the greatest benefits from immune checkpoint inhibition.3 Notably, the basal and immune subtypes that showed benefit from atezolizumab in multiple clinical scenarios are biologically remarkably similar to the claudin-low subtype we found to be associated with clinical benefit in our study. In addition, the Hamidi study also found luminal tumors did not have an overall survival benefit from the addition of PD-L1 inhibition.
To conclude, the present study may support future neoadjuvant therapeutic decision-making based on molecular subtypes in the primary tumor, leveraging tumor biology for personalized medicine. While the number of systemic therapeutic options is emerging, standardized biomarker approaches are encouraged to select the right therapy for the right patient, potentially supporting the cost-effectiveness of neoadjuvant therapy applications. While the clinical and biological behavior of bladder cancer is complex and heterogeneous, future biomarker efforts from clinical trials using molecular subtyping approaches could clarify the clinical impact of tumor heterogeneity with respect to innovative targeted therapies or immunotherapies. As such, results of ongoing trials, such as GUSTO4 are eagerly awaited.
Written by: Joep J. de Jong,1 Elai Davicioni,2 & Andrea Necchi3,4
- Erasmus University Medical Center, Rotterdam, The Netherlands
- Veracyte Inc.
- Department of Medical Oncology, IRCCS San Raffaele Hospital, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
- Basile G, Bandini M, Gibb EA, Ross JS, Raggi D, Marandino L, Costa de Padua T, Crupi E, Colombo R, Colecchia M, Lucianò R, Nocera L, Moschini M, Briganti A, Montorsi F, Necchi A. Neoadjuvant Pembrolizumab and Radical Cystectomy in Patients with Muscle-Invasive Urothelial Bladder Cancer: 3-Year Median Follow-Up Update of PURE-01 Trial. Clin Cancer Res. 2022 Dec 1;28(23):5107-5114. doi: 10.1158/1078-0432.CCR-22-2158.
- Necchi A, Raggi D, Gallina A, Bandini M, de Jong JJ, Marandino L, Briganti A, Montorsi F, Davicioni E, Lotan Y, Gibb EA. Molecular subtyping and immune-gene signatures identify a subset of early bladder tumors as candidates for single-agent immune-checkpoint inhibition. Urol Oncol. 2021 Oct;39(10):734.e11-734.e17. doi: 10.1016/j.urolonc.2021.06.011. Epub 2021 Jul 21.
- Hamidi H, Senbabaoglu Y, Beig N, Roels J, Manuel C, Guan X, Koeppen H, Assaf ZJ, Nabet BY, Waddell A, Yuen K, Maund S, Sokol E, Giltnane JM, Schedlbauer A, Fuentes E, Cowan JD, Kadel EE 3rd, Degaonkar V, Andreev-Drakhlin A, Williams P, Carter C, Gupta S, Steinberg E, Loriot Y, Bellmunt J, Grivas P, Rosenberg J, van der Heijden MS, Galsky MD, Powles T, Mariathasan S, Banchereau R. Molecular heterogeneity in urothelial carcinoma and determinants of clinical benefit to PD-L1 blockade. Cancer Cell. 2024 Dec 9;42(12):2098-2112.e4. doi: 10.1016/j.ccell.2024.10.016. Epub 2024 Nov 21.
- Verification of molecular subtyping of bladder cancer in the GU Griffin J, Down J, Quayle LA, Heath PR, Gibb EA, Davicioni E, Liu Y, Zhao X, Swain J, Wang D, Hussain S, Crabb S, Catto JWF; the GUSTO Trial Management Group. Verification of molecular subtyping of bladder cancer in the GUSTO clinical trial. J Pathol Clin Res. 2024 Feb 1;10(2):e12363. doi: 10.1002/2056-4538.12363.