Andrea Necchi1, Daniele Raggi2, Andrea Gallina3, Jeffrey S Ross4, Elena Farè2, Patrizia Giannatempo2, Laura Marandino2, Maurizio Colecchia2, Roberta Lucianò5, Marco Bianchi3, Renzo Colombo3, Andrea Salonia6, Giorgio Gandaglia3, Nicola Fossati3, Marco Bandini3, Filippo Pederzoli3, Umberto Capitanio3, Francesco Montorsi6, Joep J de Jong7, Ryan Dittamore8, Yang Liu8, Elai Davicioni8, Joost L Boormans7, Alberto Briganti6, Peter C Black9, Ewan A Gibb10. 1. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: andrea.necchi@istitutotumori.mi.it. 2. Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 3. Unit of Urology, Division of Experimental Oncology, Urological Research Institute (URI), IRCCS Ospedale San Raffaele, Milan, Italy. 4. Foundation Medicine, Cambridge, MA, USA; Upstate Medical University, New York, NY, USA. 5. Department of Pathology, IRCCS Ospedale San Raffaele, Milan, Italy. 6. Unit of Urology, Division of Experimental Oncology, Urological Research Institute (URI), IRCCS Ospedale San Raffaele, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy. 7. Department of Urology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 8. Decipher Biosciences Inc., Vancouver, British Columbia, Canada. 9. Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. 10. Decipher Biosciences Inc., Vancouver, British Columbia, Canada. Electronic address: ewan.gibb@decipherbio.com.
Abstract
BACKGROUND: The PURE-01 study (NCT02736266) evaluated the use of pembrolizumab before radical cystectomy (RC) in muscle-invasive bladder cancer (MIBC). OBJECTIVE: To evaluate the ability of molecular signatures to predict the pathological complete response (CR: ypT0N0) and progression-free survival (PFS) after pembrolizumab and RC. DESIGN, SETTING, AND PARTICIPANTS: We analyzed the expression data from patients with T2-4aN0M0 MIBC enrolled in the PURE-01 study (N=84) and from patients of a retrospective multicenter cohort treated with cisplatin-based neoadjuvant chemotherapy (NAC; N=140). INTERVENTION: Neoadjuvant pembrolizumab or NAC and RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Immune signatures and molecular subtyping (The Cancer Genome Atlas, consensus model, and genomic subtyping classifier [GSC]) were evaluated in relation to CR and PFS. Multivariable logistic regression analyses for CR were used, adjusting for gender and clinical T stage. RESULTS AND LIMITATIONS: The Immune190 signature was significant for CR on multivariable logistic regression analyses (p= 0.02) in PURE-01, but not in the NAC cohort (p= 0.7). Hallmark signatures for interferon gamma (IFNγ; p= 0.004) and IFNα response (p= 0.006) were also associated with CR for PURE-01, but not for NAC (IFNγ: p= 0.9 and IFNα: p= 0.8). In PURE-01, 93% of patients with the highest Immune190 scores (>1st quartile) had 2-yr PFS versus 79% of those with lower scores; no difference was observed in NAC patients, as well as for the other hallmarks in both groups. The neuroendocrine-like subtype had the worst 2-yr PFS in all three subtyping models (33%) and the GSC claudin-low subtype had the best, with no recurrences in 2 yr. Basal subtypes (across classifications) with higher Immune190 scores showed 100% 2-yr PFS after pembrolizumab therapy (p = 0.04, compared with basal-Immune190 low). Statistical analyses are limited by the small number of events and short follow-up. CONCLUSIONS: Higher RNA-based immune signature scores were significantly associated with CR and numerically improved PFS outcomes after pembrolizumab, but not after NAC. These data emphasize that RNA profiling is a potential tool for personalizing neoadjuvant therapy selection. PATIENT SUMMARY: We used gene expression profiling to evaluate the association between immune gene expression and response to neoadjuvant immunotherapy, compared with standard chemotherapy, in patients with muscle-invasive bladder cancer (MIBC). We found a significant association between immune gene expression and response to pembrolizumab, but not chemotherapy. We conclude that gene expression profiling has the potential to guide personalized neoadjuvant therapy in MIBC.
BACKGROUND: The PURE-01 study (NCT02736266) evaluated the use of pembrolizumab before radical cystectomy (RC) in muscle-invasive bladder cancer (MIBC). OBJECTIVE: To evaluate the ability of molecular signatures to predict the pathological complete response (CR: ypT0N0) and progression-free survival (PFS) after pembrolizumab and RC. DESIGN, SETTING, AND PARTICIPANTS: We analyzed the expression data from patients with T2-4aN0M0 MIBC enrolled in the PURE-01 study (N=84) and from patients of a retrospective multicenter cohort treated with cisplatin-based neoadjuvant chemotherapy (NAC; N=140). INTERVENTION: Neoadjuvant pembrolizumab or NAC and RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Immune signatures and molecular subtyping (The Cancer Genome Atlas, consensus model, and genomic subtyping classifier [GSC]) were evaluated in relation to CR and PFS. Multivariable logistic regression analyses for CR were used, adjusting for gender and clinical T stage. RESULTS AND LIMITATIONS: The Immune190 signature was significant for CR on multivariable logistic regression analyses (p= 0.02) in PURE-01, but not in the NAC cohort (p= 0.7). Hallmark signatures for interferon gamma (IFNγ; p= 0.004) and IFNα response (p= 0.006) were also associated with CR for PURE-01, but not for NAC (IFNγ: p= 0.9 and IFNα: p= 0.8). In PURE-01, 93% of patients with the highest Immune190 scores (>1st quartile) had 2-yr PFS versus 79% of those with lower scores; no difference was observed in NACpatients, as well as for the other hallmarks in both groups. The neuroendocrine-like subtype had the worst 2-yr PFS in all three subtyping models (33%) and the GSC claudin-low subtype had the best, with no recurrences in 2 yr. Basal subtypes (across classifications) with higher Immune190 scores showed 100% 2-yr PFS after pembrolizumab therapy (p = 0.04, compared with basal-Immune190 low). Statistical analyses are limited by the small number of events and short follow-up. CONCLUSIONS: Higher RNA-based immune signature scores were significantly associated with CR and numerically improved PFS outcomes after pembrolizumab, but not after NAC. These data emphasize that RNA profiling is a potential tool for personalizing neoadjuvant therapy selection. PATIENT SUMMARY: We used gene expression profiling to evaluate the association between immune gene expression and response to neoadjuvant immunotherapy, compared with standard chemotherapy, in patients with muscle-invasive bladder cancer (MIBC). We found a significant association between immune gene expression and response to pembrolizumab, but not chemotherapy. We conclude that gene expression profiling has the potential to guide personalized neoadjuvant therapy in MIBC.
Authors: JunJie Yu; WeiPu Mao; Si Sun; Qiang Hu; Can Wang; ZhiPeng Xu; RuiJi Liu; SaiSai Chen; Bin Xu; Ming Chen Journal: Cancer Manag Res Date: 2022-01-05 Impact factor: 3.989
Authors: Anke Richters; Richard P Meijer; Niven Mehra; Joost L Boormans; Antoine G van der Heijden; Michiel S van der Heijden; Lambertus A Kiemeney; Katja K Aben Journal: BMJ Open Date: 2021-05-18 Impact factor: 2.692
Authors: Marco Bandini; Jeffrey S Ross; Daniele Raggi; Andrea Gallina; Maurizio Colecchia; Roberta Lucianò; Patrizia Giannatempo; Elena Farè; Filippo Pederzoli; Marco Bianchi; Renzo Colombo; Giorgio Gandaglia; Nicola Fossati; Laura Marandino; Umberto Capitanio; Federico Deho'; Siraj M Ali; Russell Madison; Jon H Chung; Andrea Salonia; Alberto Briganti; Francesco Montorsi; Andrea Necchi Journal: J Natl Cancer Inst Date: 2021-01-04 Impact factor: 13.506