AVANZANDO EN LA APLICACIÓN DE BIOPSIA LÍQUIDA EN CÁNCER DE … · AVANZANDO EN LA APLICACIÓN DE...

AVANZANDO EN LA APLICACIÓN DE BIOPSIA LÍQUIDA EN CÁNCER DE VEJIGA -

IMPROVING THE APPLICATION OF LIQUID BIOPSY FOR BLADDER CANCER

Urbano Anido Herranz Department of Medical Oncology | University Clinical Hospital of

Santiago de Compostela (CHUS) Traslational Medical Oncology (ONCOMET) | Health Research

Institute (IDIS) E-mail: [email protected]

Twitter: @urbano_anido

mailto:[email protected]

DISCLOSURE

1 CONSULTANT OR ADVISORY BOARD

2 GRANT OR TRAVEL SUPPORT

3 HONORARIA

4 PARTICIPATION IN CLINICAL TRIALS

Pfizer, Novartis, Bayer, Ipsen, EUSA, Sanofi, AAA

BMS, Pfizer, Novartis, Bayer, Ipsen, Sanofi, Pierre Fabre, Roche, Astellas, Rovi

BMS, Bayer, Ipsen, Novartis, Janssen, Astellas, AAA, Kyowa Kirin, Lilly, Pfizer, EUSA, Eisai, Merck

Pfizer, Astra Zeneca, MSD, Astellas, Janssen, Ipsen, Clovis, Roche, Bayer, BMS

NMIBC(CVSIM) (Tis, Ta, T1) ≈51-75% 1-4

MIBC (T2, T3a, T3b)

≈30-42% 1,4

Metastatic disease (T4)

≈4% 1,5

Uréteres

Uretra

1. Howlader N, et al. (eds). SEER Cancer Statistics Review 1975–2013; 2. NCCN Guidelines – Bladder Cancer v1.2017; 3. Sharma S, et al. Am Fam Physician 2009;80:717-23. 4. Kaufman DS, et al. Lancet 2009;374:239-49.

Staging and diagnosis

Survival

73.0% 78.1% 78.0%

1975–1977 1985–1989 2009

5-years survival at diagnosis1

1. SEER Stat Fact Sheets

50% of patients treated with radical intention will develop metastases and die by urothelial carcinoma

Mutational heterogeneity in cancer

Lawrence MS, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214-8

DNA repair alterations

Mouw WK. DNA Repair Pathway Alterations in Bladder Cancer. Cancers (Basel). 2017;9(4).

BRCA1 and ERCC1 in BC

Font A, Taron M, Gago JL, Costa C, Sánchez JJ, Carrato C, et al. BRCA1 mRNA expression and outcome to neoadjuvant cisplatin-based chemotherapy in bladder cancer. Annals of Oncology. 2011 Jan;22(1):139–44. Bellmunt J, Paz-Ares L, Cuello M, Cecere F, Albiol S, Guillem V, et al. Gene expression of ERCC1 as a novel prognostic marker in advanced bladder cancer patients receiving cisplatin-based chemotherapy. Ann Oncol. 2006 Nov 2;18(3):522–8.

BRCA1 ERCC1

Somatic ERCC2 Mutations

Van Allen EM, Mouw KW, Kim P, Iyer G, Wagle N, Al-Ahmadie H, et al. Somatic ERCC2 Mutations Correlate with Cisplatin Sensitivity in Muscle-Invasive Urothelial Carcinoma.

Cancer Discovery. 2014 Sep 30;4(10):1140–53.

ERCC2 & neoadyuvant chemotherapy

JAMA Oncol. 2016;2(8):1094-1096. doi:10.1001/jamaoncol.2016.1056

Genomic characterization

Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014 Mar 20;507(7492):315–22.

Molecular classification of urothelial carcinoma: global mRNA classification versus tumour‐cell phenotype classification

The Journal of Pathology, Volume: 242, Issue: 1, Pages: 113-125, First published: 13 February 2017, DOI: (10.1002/path.4886)

Luminal KRT20+, GATA3+, FOXA1+

Basal/Escamoso KRT5,6,14+, GATA3-, FOXA1-

Luminal-Papilar Luminal-Infiltrado Luminal Basal/Escamoso Neuronal

FGFR mut, fus, amp Histología papilar SHH+ CIS bajo

Bajo riesgo NAC* FGFR3 inhibidores

Baja pureza Marcadores TEM miRNA-200 PD-L1, CTLA-4 medio Marcadores miofibroblasto p53 like

Anti-PD-1/PD-L1/ CTLA-4

NAC cisplatino**

UPKs KRT20 sNX31

Terapias diana

Mujeres Diferenciación escamosa Marcadores basales de keratinas PD-L1 y CTLA-4 altos Infiltrado inmune

Anti-PD-1/PD-L1/ CTLA-4

NAC cisplatino

SOX2 DLX6 MSI1 PLEKHG4B E2F3/SOX4 amp Ciclo celular alto

Etopósido-cisplatino y NAC

*Baja probabilidad de respuesta

**Baja tasa de respuesta

Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. Nature Publishing Group; 2014 Mar 20;507(7492):315–22.

Protocol

unpublished

SOGPLA 2016-01. Estudio prospectivo de la utilidad de la biopsia líquida como factor predictor y pronóstico en pacientes con carcinoma urotelial metastásico en progresión tras quimioterapia basada en platino

95 prospectively collected samples

Baseline samples

n=48

3 cycles of therapy samples

n=24

Progression samples

n=17

51 metastatic bladder cancer patients from

18/24 spanish hositals

Patients with Baseline samples +

3 cycles therapy samples

n=16

Patients with Baseline +

3 cycles therapy + Progression

samples n=9

Patients with Baseline samples +

Progression samples

n=9

Patients with Only Baseline

samples

n=9

CTCs was studied in 89 samples from 51 patients

(6 samples were excluded due to technical problems)

unpublished


Recruitment

unpublished


Number of CTCs

There are 52 patients of 18/24 spanish hospitals, and in 23 (44.23%) patients there was no basal CTCs. There were 55.75% of CTC detection. In patients with no basal CTCs (23), only 6 presented lastly CTCs (on progresión) (2, 3, 19, 2, 2 y 1). In 5 patients at the begining Veridex cancels sample in CellSearch because of low volumen.

unpublished


Median of CTCs by cycle

unpublished


Changes in CTCs by cycle and progression

unpublished


Overall survival

Median 10.05 months (CI95% 7.98 – 14.78)

12-months survival 47.5% (CI95% 34.14 – 66.1)

24-months survival 6.17% (CI95% 1.12 – 33.9)

unpublished


By initial number of CTCs

unpublished


By change in CTCs

unpublished


ctDNA in BC

Birkenkamp-Demtroder K, Christensen E, Nordentoft I, Knudsen M, Taber A, Hoyer S, et al. Monitoring Treatment Response and Metastatic Relapse in Advanced Bladder Cancer by Liquid Biopsy Analysis. Eur Urol. 2018;73(4):535-40.

Monitoring ctDNA

Christensen E, Nordentoft I, Vang S, Birkenkamp-Demtroder K, Jensen JB, Agerbaek M, et al. Optimized targeted sequencing of cell-free plasma DNA from bladder cancer patients. Sci Rep. 2018;8(1):1917.

Monitoring ctDNA

Christensen E, Birkenkamp-Demtroder K, Sethi H, Shchegrova S, Salari R, Nordentoft I, et al. Early Detection of Metastatic Relapse and Monitoring of Therapeutic Efficacy by Ultra-Deep Sequencing of Plasma Cell-Free DNA in Patients With Urothelial Bladder Carcinoma. J Clin Oncol. 2019;37(18):1547-57.

Conclusions

• Liquid biopsy, including blood & urine, have several potential applications in BC and could lead to optimized management, early diagnosis and better survival.

• The high somatic mutation rate in BC indicates this cancer is ideally suited for ctDNA both in blood and in urine.

• Preliminary studies have showed ctDNA has a potential role as:

• A marker of aggressiveness in localised disease

• An indicator of early recurrence after radical treatment

• A prognostic biomarker of reduced survival

• Monitorization of treatment response

• The emergence in the clinic of approved molecularly-targeted drugs based on identifiable genomic biomarkers helps to develop the possibility to transfer the use of liquid biopsy from bench to bedside in BC.

• Larger prospective studies, better methods of isolation and knowledge of BC biology are needed.

MUCHAS GRACIAS THANK YOU

Urbano Anido Herranz

Department of Medical Oncology | University Clinical Hospital of Santiago de Compostela (CHUS)

Traslational Medical Oncology (ONCOMET) | Health Research Institute (IDIS)

E-mail: [email protected]

Twitter: @urbano_anido

mailto:[email protected]

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