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CÁNCER DE VEJIGA:
Escenario Actual y Futuro Próximo
Javier Puente, MD, PhD
Hospital Universitario Clinico San Carlos
Medical Oncology Department
Complutense University
Associate Professor of Medicine
Average number of new cases per year and age-specific in UK (2010)
FDA-Approved drugs for Genitourinary tumors in the past
7 years
No major treatment advances in 20 years
2nd LINE T4bN0M0 or TxN2-3 or M1 Progression after 1st line platinum treatment Stratify: -Center -Refractory vs Non-refractory
R A N D O M I S E
VFL+BSC (PS 0: 320 mg/m2, q3w; PS 0 with previous pelvic
irradiation and PS 1: 280 mg/m2)
BSC with treatment upon progression permitted
Bellmunt J, JCO 2009
N: 370 N:
253
N: 117
2:1
Primary Endpoint: OS Secondary Endpoints: ORR, PFS, DCR, QoL, CB
Bellmunt J, JCO 2009
Phase III trial of vinflunine+BSC vs BSC: Results in OS: ITT and Eligible population
IDENTIFY PATIENTS (SUBGROUPS)
UROTHELIAL CARCINOMA
INMUNO-THERAPY
TREATMENT RESPONSE
GENE SIGNATURE
MOLECULAR TARGETS
Clinical Prognostic factors in the first and second line can
distinguish outcomes
Pathologic response to NAC strongly predicts RFS
and OS
Petrelli et al. Eur Urol 2013
Predictors of platinum-chemotherapy response
Font A, et al. J Clin Oncol 2012; 30
Predictors of platinum-chemotherapy response
A panel of three markers Hyper-and Hypomethylated in urine
sediments accurately predicts bladder cancer recurrence
Sheng-Fang Su et al. Clin Cancer Res 2014; 20(7): 1979-90
A panel of three markers Hyper-and Hypomethylated in urine
sediments accurately predicts bladder cancer recurrence
Sheng-Fang Su et al. Clin Cancer Res 2014; 20(7): 1979-90
Gene expression signature for MVAC response in
Japanese patients
MVAC signature compared to COXEN (Co-expression
extrapolation) signature derived from NCI-60 cell lines
SWOG-TRIAL: COXEN-directed neoadjuvant chemotherapy. Prospective
validation of the COXEN biomarker to predict pT0/pT1
Immuno-Oncology: blocking CTLA-4 and PD-1 pathways
with monoclonal antibodies
Tumour cell
- - -
CTLA-4 pathway blockade PD-1 pathway blockade
Anti-CTLA-4
Anti-PD-1/PD-L1
+ + +
Anti-PD-1
- - -
- - -
Periphery Tumour microenvironment
T cell activation (cytokines, lysis, proliferation,
migration to tumour)
Dendritic cell + + +
CTLA-4 = cytotoxic T-lymphocyte antigen-4; PD-1 = programmed cell death 1; PD-L1/2 = PD ligand 1/2; TCR = T cell receptor.
Adapted from Wolchock J, et al. Oral presentation at ASCO 2013 (Abstract 9012).
T cell T cell
+ + + CD28 B7
B7
MHC TCR
TCR MHC
PD-L1 PD-1
PD-L2 PD-1
CTLA-4
MPDL3280A (anti-PDL1) treatments leads to clinical activiy
in metastatic bladder cancer
Powles T, et al. Nature 2014
MPDL3280A (anti-PDL1) treatments leads to clinical activity
in metastatic bladder cancer
Powles T, et al. Nature 2014
Pembrolizumab in Urothelial Cohort: KEYNOTE-012
Plimack E, et al. ESMO 2014
Pembrolizumab in Urothelial Cohort: KEYNOTE-012
Pembrolizumab in Urothelial Cohort: KEYNOTE-012
Plimack E, et al. ESMO 2014
Phase III trials in second-line urothelial cancer with
inmunotherapy
Cancer Genomics 2015
- Cancers emerge from genomic errors
- Sequencing technology is now at the bedside
- Clinical computational biology: - Computational algorithms to analize and interpret genomic data from
patients samples
- Designing clinical research towards precision medicine:
- PHENOTYPE TO GENOTYPE
- Analyzing exceptional responses of therapies
- GENOTYPE TO PHENOTYPE
- Matching mutations with drugs
Comparasion of mutation frequencies in NMI vs M1
Comparasion of mutation in HGT1 micropapillary,
Ta/T1 cohort and M1 TCGA
Bladder cancer is a moleculary heterogeneous disease
Nature 2014
Bladder cancer is a moleculary heterogeneous disease
Nature 2014
Cancer Genomics 2015
Prevalence and Co-Occurrence of Actionable Genomic
Alterations in High-grade Bladder Cancer
Iyer et al. JCO 2013
- Integrative analysis to identify ACTIONABLE
DRUG TARGETS:
- Genomic alterations clinically validated
- Alterations for which a selective inhibitor is
under investigation
DNA copy number alterations (CNAs) were
define.
Prevalence and Co-Occurrence of Actionable Genomic
Alterations in High-grade Bladder Cancer
Iyer et al. JCO 2013
Prevalence and Co-Occurrence of Actionable Genomic
Alterations in High-grade Bladder Cancer
RTK/RAS/RAF Signalling Pathway
Iyer et al. JCO 2013
Prevalence and Co-Occurrence of Actionable Genomic
Alterations in High-grade Bladder Cancer
G1-S Cell Cycle Regulatory Pathway
Phase II trial of Palbociclib (PD-0332991) in patients with
Metastatic Urothelial Cancer (UC) after failure of first-
line chemotherapy
Iyer et al. JCO 2013
Prevalence and Co-Occurrence of Actionable Genomic
Alterations in High-grade Bladder Cancer
PI3K/Akt Pathway
A phase II study of XL184/Cabozantinib in patients with advanced
urothelial carcinoma (NCT01688999)
Apolo A, ASCO 2013
Phase II study of BKM120 in advanced urothelial carcinoma
Apolo A, ASCO 2013
Molecular Allocation Trial Design (MSKCC) in platinum pre-treated
patients
CONCLUSIONS
- Bladder cancer is a targetable disease (has a high mutation rate)
- >60% of patients have actionable alterations.
- Genes involved in cell cycle control, chromatin regulation, and receptor tyrosine and PI3K-mTOR signalling pathways are commonly mutated.
- Prospective genotyping can identify patients with targetable alterations and stratify them for appropriate clinical trials.
- Critical to move the field forward and individualize patient care.
THANK YOU Dr. Javier Puente Vázquez
Servicio Oncología Médica
Hospital Universitario Clínico San Carlos
