Molecular subtyping and immune-gene signatures identify a subset of early bladder tumors as candidates for single-agent immune-checkpoint inhibition.

Published on Jul 21, 2021in Urologic Oncology-seminars and Original Investigations2.882
· DOI :10.1016/J.UROLONC.2021.06.011
Andrea Necchi13
Estimated H-index: 13
(UniSR: Vita-Salute San Raffaele University),
Daniele Raggi19
Estimated H-index: 19
(University of Milan)
+ 8 AuthorsYair Lotan107
Estimated H-index: 107
(UTSW: University of Texas Southwestern Medical Center)
Sources
Abstract
Abstract null null Purpose null Clinical high-grade (HG) T1 non-muscle invasive bladder cancer (NMIBC) represents a significant risk to patients, but these patients are not typically offered neoadjuvant therapies, including immune therapy. In this study, we determine whether patients with HG clinical T1 or T2 bladder urothelial carcinoma (UC) have profiles that predict the potential effectiveness of immune-checkpoint inhibitors (ICI). null null null Materials and Methods null Data from transurethral resection of bladder tumor (TURBT) specimens from 2 studies was evaluated. The molecular upstaging (MOL) cohort included HG cT1N0M0 (n = 87) and cT2N0M0 (n = 119) bladder UC who underwent radical cystectomy (RC) without any neoadjuvant therapy. The PURE-01 cohort (n = 102) was used as ICI-treated reference. Specimen collection and sample processing were conducted using a clinical-grade whole-transcriptome assay (Decipher). Immune-signatures scores and molecular subtyping were evaluated. Kaplan-Meier curves and log-rank tests were used for exploratory analyses of recurrence-free survival (RFS) and overall survival (OS). null null null Results null In both the PURE-01 and MOL cohorts, the Immune190 signature, stratified by subtype, showed the highest scores in basal-type, but also in luminal-infiltrated tumors, but the lowest scores in the luminal tumors. However, in HG cT1 tumors the Immune190 scores were the lowest for luminal papillary tumors (Consensus, TCGA) and luminal tumors (GSC), with less distinct differences between other subtypes. RFS was significantly longer for luminal vs non-luminal tumors in MOL (P = 0.04) but not in PURE-01 (P = 0.8). In the MOL cohort, OS was inferior in HG cT1 tumors for Immune190-high vs low tumors (median split, P = 0.042). null null null Conclusion null We identified a population of cT1-T2N0M0 tumors in the MOL cohort that shared molecular features with tumors included in PURE-01. These profiles suggest that treatment with ICI could be proposed to more selected HG cT1N0M0 tumors, identified with a gene expression assay.
📖 Papers frequently viewed together
14 Authors (Yair Lotan, ..., Ewan A. Gibb)
25 Citations
23 Citations
12 Citations
References25
Newest
#1Sia Viborg Lindskrog (AU: Aarhus University)H-Index: 3
#2Frederik Prip (AU: Aarhus University)H-Index: 2
Last. Lars Dyrskjøt (AU: Aarhus University)H-Index: 60
view all 47 authors...
The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond establishe...
9 CitationsSource
#1Arjun Vasant BalarH-Index: 20
#2Ashish M. Kamat (University of Texas MD Anderson Cancer Center)H-Index: 76
Last. Ronald de Wit (Erasmus University Medical Center)H-Index: 21
view all 17 authors...
451Background: Pembrolizumab (pembro) was approved in January 2020 for treatment of HR NMIBC based on interim results from 96 patients (pts) in the open-label, single-arm, multicenter, phase II KEY...
3 CitationsSource
#1Marco Bandini (UniSR: Vita-Salute San Raffaele University)H-Index: 24
#2Ewan A. GibbH-Index: 27
Last. Andrea NecchiH-Index: 13
view all 17 authors...
Abstract Background Initial studies of preoperative checkpoint inhibition before radical cystectomy (RC) have shown promising pathologic complete responses. We aimed to analyze the survival outcomes of patients enrolled in PURE-01 study (NCT02736266). Patients and methods We report the results of the secondary endpoints of PURE-01 in the final population of 143 patients. In particular, we report the event-free survival (EFS) outcomes, defined as the time from the first cycle of pembrolizumab to ...
17 CitationsSource
#1A. Gordon RobertsonH-Index: 32
#2Clarice S. Groeneveld (Curie Institute)H-Index: 6
Last. Joshua J. Meeks (NU: Northwestern University)H-Index: 44
view all 17 authors...
Abstract Stage T1 bladder cancers have the highest progression and recurrence rates of all non–muscle-invasive bladder cancers (NMIBCs). Most T1 cancers are treated with bacillus Calmette-Guerin (BCG), but many will progress or recur, and some T1 patients will die from bladder cancer. Particularly aggressive tumors could be treated with early cystectomy. To better understand the molecular heterogeneity of T1 cancers, we performed transcriptome profiling and unsupervised clustering, and identifie...
21 CitationsSource
#1Andrea NecchiH-Index: 35
#2Daniele RaggiH-Index: 19
Last. Ewan A. GibbH-Index: 27
view all 26 authors...
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...
47 CitationsSource
#1Peter C. Black (UBC: University of British Columbia)H-Index: 51
#2Catherine M. Tangen (Fred Hutchinson Cancer Research Center)H-Index: 63
Last. Ian M. ThompsonH-Index: 110
view all 16 authors...
5022Background: Radical cystectomy (RC) is the standard of care for patients with BCG-unresponsive high risk non-muscle invasive bladder cancer (NMIBC), but many patients are unfit for surgery or e...
22 CitationsSource
#1Andrea NecchiH-Index: 35
#2Daniele RaggiH-Index: 19
Last. Ewan A. GibbH-Index: 27
view all 21 authors...
Abstract In the PURE-01 study, patients with muscle-invasive bladder cancer (MIBC) who achieved a pathological complete response (CR; ypT0N0) had tumor features suggesting that pre-existing immunity may promote response. We focused on fibroblast growth factor receptor-3 (FGFR3) genomic alterations (GAs) as potential tumor resistance features. The primary endpoint of our study was CR. FGFR3 GAs were assessed via comprehensive genomic profiling of sequenced DNA (N = 112), a transcriptome-based FGF...
8 CitationsSource
#1Andrea NecchiH-Index: 35
#2Daniele RaggiH-Index: 19
Last. Francesco Montorsi (UniSR: Vita-Salute San Raffaele University)H-Index: 138
view all 24 authors...
Abstract Background Patients with predominant variant histology (VH) of bladder tumors, defined as involving >50 % of the tumor specimens, are typically excluded from clinical trials, and for these patients, the efficacy of standard chemotherapy is limited. Objective To evaluate the activity of preoperative pembrolizumab in patients with muscle-invasive bladder carcinoma (MIBC) and VH, enrolled in PURE-01 study (NCT02736266). Design, setting, and participants In the open-label, single-arm, phase...
101 CitationsSource
#1Aurélie KamounH-Index: 3
Last. John N. Weinstein (University of Texas MD Anderson Cancer Center)H-Index: 127
view all 42 authors...
Abstract Background Muscle-invasive bladder cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, but the diversity of their subtype sets impedes their clinical application. Objective To achieve an international consensus on MIBC molecular subtypes that reconciles the published classification schemes. Design, setting, and participants We used 1750 MIBC transcriptomic profiles from 16 published datasets and two a...
237 CitationsSource
#1Joep J. de Jong (EUR: Erasmus University Rotterdam)H-Index: 7
#2Yang LiuH-Index: 79
Last. Ewan A. GibbH-Index: 27
view all 12 authors...
Background:Urothelial carcinoma (UC) of the luminal molecular subtype is associated with lower rates of pathological upstaging from clinical stage T1-T2 to non-organ confined (NOC; ≥pT3 and/or pN+)...
2 CitationsSource
Cited By0
Newest