Basal/squamous and Mixed subtype bladder cancers present poor outcomes after neoadjuvant chemotherapy in the VESPER trial.
Bladder cancer
basal subtype
intra-tumor heterogeneity
molecular subtype
neoadjuvant chemotherapy
prognosis
Journal
Annals of oncology : official journal of the European Society for Medical Oncology
ISSN: 1569-8041
Titre abrégé: Ann Oncol
Pays: England
ID NLM: 9007735
Informations de publication
Date de publication:
17 Sep 2024
17 Sep 2024
Historique:
received:
06
02
2024
revised:
19
07
2024
accepted:
10
09
2024
medline:
20
9
2024
pubmed:
20
9
2024
entrez:
19
9
2024
Statut:
aheadofprint
Résumé
Neoadjuvant chemotherapy (NAC) is the standard treatment for muscle-invasive bladder cancer (MIBC), yet 40% of patients progress, emphasizing the need for biomarkers predictive for response or chemoresistance. Gene expression-based subtypes may serve as biomarkers, though which subtypes will respond, notably when it comes to the basal subtype, remains contentious. This post-hoc study analyzed 300 NAC-treated patients enrolled in the GETUG/AFU VESPER trial, with transurethral diagnostic FFPE which underwent pathological review prior to being sequenced. "Mixed" subtype was defined for tumors displaying at least two different Consensus molecular subtypes in separate regions. We evaluated the association between molecular subtypes and outcome after NAC. Tumours with remaining tissue at cystectomy (n=83) were compared with pre-treatment tumours. Cases were classified Basal/squamous (Ba/Sq) (n=84), Luminal Unstable (n=57), Stroma-rich (n=53), Mixed (n=48), Luminal Papillary (n=39), Luminal Non-Specific (n=18) and Neuroendocrine-like (n=1), with 30/48 Mixed cases including a Ba/Sq component. Compared with other molecular subtypes in a multivariate Cox model, Ba/Sq (Pure or Mixed) patients had an increased hazard ratio of progression free survival (HR:2.0, 95% CI 1.36-3.0). Mixed tumors were associated with decreased metabolic activity that could account for chemoresistance. Ba/Sq and Mixed non-responders mostly maintained their subtype at cystectomy and have fewer myeloid dendritic cells after NAC. Tumors classified luminal papillary at TURBT exhibited an increase of T CD4+ and macrophage signatures after NAC. Other subtypes did not show significant immune changes after NAC. Our study design relied on detailed pathological review, which precluded evaluating the Mixed subtype in published datasets. Furthermore, the sample size for post-NAC analyses constrained the statistical power of these findings. Our findings underscore the importance of recognizing intra-tumor heterogeneity in MIBC, its role in chemoresistance associated with Ba/Sq subtype and provide valuable insights that could help future treatment development and improve patient outcomes.
Sections du résumé
BACKGROUND
BACKGROUND
Neoadjuvant chemotherapy (NAC) is the standard treatment for muscle-invasive bladder cancer (MIBC), yet 40% of patients progress, emphasizing the need for biomarkers predictive for response or chemoresistance. Gene expression-based subtypes may serve as biomarkers, though which subtypes will respond, notably when it comes to the basal subtype, remains contentious.
PATIENTS AND METHODS
METHODS
This post-hoc study analyzed 300 NAC-treated patients enrolled in the GETUG/AFU VESPER trial, with transurethral diagnostic FFPE which underwent pathological review prior to being sequenced. "Mixed" subtype was defined for tumors displaying at least two different Consensus molecular subtypes in separate regions. We evaluated the association between molecular subtypes and outcome after NAC. Tumours with remaining tissue at cystectomy (n=83) were compared with pre-treatment tumours.
RESULTS
RESULTS
Cases were classified Basal/squamous (Ba/Sq) (n=84), Luminal Unstable (n=57), Stroma-rich (n=53), Mixed (n=48), Luminal Papillary (n=39), Luminal Non-Specific (n=18) and Neuroendocrine-like (n=1), with 30/48 Mixed cases including a Ba/Sq component. Compared with other molecular subtypes in a multivariate Cox model, Ba/Sq (Pure or Mixed) patients had an increased hazard ratio of progression free survival (HR:2.0, 95% CI 1.36-3.0). Mixed tumors were associated with decreased metabolic activity that could account for chemoresistance. Ba/Sq and Mixed non-responders mostly maintained their subtype at cystectomy and have fewer myeloid dendritic cells after NAC. Tumors classified luminal papillary at TURBT exhibited an increase of T CD4+ and macrophage signatures after NAC. Other subtypes did not show significant immune changes after NAC. Our study design relied on detailed pathological review, which precluded evaluating the Mixed subtype in published datasets. Furthermore, the sample size for post-NAC analyses constrained the statistical power of these findings.
CONCLUSIONS
CONCLUSIONS
Our findings underscore the importance of recognizing intra-tumor heterogeneity in MIBC, its role in chemoresistance associated with Ba/Sq subtype and provide valuable insights that could help future treatment development and improve patient outcomes.
Identifiants
pubmed: 39299443
pii: S0923-7534(24)04016-X
doi: 10.1016/j.annonc.2024.09.008
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Investigateurs
G Pignot
(G)
Jp Fendler
(J)
L Guy
(L)
G Verhoest
(G)
N Mottet
(N)
A Doerfler
(A)
S Abadie-Lacourtoisie
(S)
A Azzouzi
(A)
P Mongiat
(P)
L Geoffrois
(L)
P Eschwege
(P)
F Di Fiore
(F)
G Roubaud
(G)
Jl Hoepffner
(J)
P Barthelemy
(P)
H Lang
(H)
E Voog
(E)
E Mandron
(E)
Jm Tourani
(J)
C Serrrate
(C)
A Colau
(A)
C Saldana
(C)
A De La Taille
(A)
T Nguyen
(T)
F Kleinclauss
(F)
Y Loriot
(Y)
J Irani
(J)
Jc Eymard
(J)
S Larre
(S)
O Huillard
(O)
M Zerbib
(M)
F Rolland
(F)
J Rigaud
(J)
N Houede
(N)
S Droupy
(S)
G Malouf
(G)
M Roupret
(M)
S Vieillot
(S)
N Letang
(N)
T Lharidon
(T)
N Gaschignard
(N)
W Hilgers
(W)
Jl Davin
(J)
Informations de copyright
Copyright © 2024 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.