BASES BIOLÓGICAS DEL CÁNCER DE...

BASES BIOLÓGICAS DEL CÁNCER DE PRÓSTATA

Rebeca Lozano Mejorada

Unidad de Investigación Clínica en Cáncer de Próstata, CNIO

Unidad de Investigación Tumores Genitourinarios, CNIO-IBIMA

TIMELINE PROSTATE CANCER

1940s 1996

ADT

2004 2010 2011 2012 2013 2014 2017 2018

Docetaxel TAX327

SWOG 9916

Mitoxantrone CALGB 9182

Sipuleucel T IMPACT

Cabazitaxel TROPIC

Abiraterone COU-AA-301

Enzalutamide AFFIRM

Abiraterone COU-AA-302

Enzalutamide PREVAIL

Radium-223 ALSYMPCA

Enzalutamide PROSPER

Apalutamide SPARTAN

Docetaxel CHAARTED STAMPEDE

Abiraterone LATITUDE

STAMPEDE

2015 2016

PROSTATE CANCER

Data: Journal of the National Cancer Institute; Chart: Chris Canipe / Axios

Localized

disease

Biochemical

and/or local

relapse

Metastatic

disease

Castration -

Resistant Death

90%

Curative

treatment (different options)

Salvage

treatment

and /or ADT

Castration and other

hormone treatments Chemotherapy

NATURAL HISTORY OF PROSTATE CANCER

Cortesía Dr Olmos

MOLECULAR TAXONOMY

• Comprehensive molecular profiling of 333 Primary Prostate Cancer

• 74% of Primary PCa had at least one identifiable driving event.

TCGA, Cell, 2015

HIGHLY HETEROGENEUS DISEASE

MOLECULAR TAXONOMY

Shaw AT, Nat Rev Clin Oncol, 2017

Clonal vs Polyclonal origin of Prostate Cancer

MOLECULAR TAXONOMY

Espiritu SMG, Cell, 2018

• The phylogenies of 293 localized prostate cancers linked to clinical outcome data.

• 97% intermediate-risk by NCCN criteria (treatment naïve).

• 41% had only clonal mutations (monoclonal)

• 59% multiple subclones (polyclonal) were detected

• Clonality is a separate entity to current prognostic factors.

MOLECULAR TAXONOMY

Espiritu SMG, Cell, 2018

• Patients with monoclonal tumours have remarkably good outcome.

• Clonality not only characterizes tumours more likely to relapse after definitive local therapy, but also those more likely to metastasize.

MOLECULAR TAXONOMY

Robinson D, Cell, 2015

• Integrative clinical sequencing of 150 mCRPC.

• 90% of mCRPC harbour clinically actionable molecular alterations.

MOLECULAR TAXONOMY

Armenia J, Nature Genetics, 2018

Comparison of primary and metastatic tumours

• WES from 1.013 prostate cancers (680 Primary and 333 metastatic)

MOLECULAR TAXONOMY

Armenia J, Nature Genetics, 2018

• Significantly mutated genes (SMGs) following a long tail distribution.

• 70 of this SMGs not previously implicated in Prostate Cancer

HIGHLY HETEROGENEUS DISEASE

PROSTATE SPECIFIC MEMBRANE ANTIGEN (PSMA)

• PSMA is a transmembrane type II glycoprotein.

• Overexpressed 100 to 1000-fold in 95% of prostate cancer cells (low expression in normal tissues).

• PSMA-ligand complex is internalized into the cell.

Diagnostic potential Impact on treatment

Haberkorn U, Clin Cancer Res, 2016


• Higher diagnostic efficacy

• Detection of recurrent disease after Radical Prostatectomy:

Very low PSA values (0,2-0,5 ng/mL) 55%

Low PSA values (>0,5-1,0 ng/mL) 74%

Perera M, Eur Urol, 2016 Han S, Eur Urol, 2018

Rauscher I, Eur Urol, 2018


Change in management

54% of patients

Perera M, Eur Urol, 2016 Han S, Eur Urol, 2018

Rauscher I, Eur Urol, 2018


• Lutetium-177-PSMA (LuPSMA)

• Short-range beta-particle emitter (1mm)

N = 30 patients (heavily pre-treated)

≥50% PSA response 57% patients

Effective for pain palliation

Well tolerated

Hofman MS, Lancet Oncol, 2018

• Retrospective studies suggest that this alterations are associated with more aggressive disease and shorter survival from diagnosis of PCa.

• Germline and somatic DDR defects have been correlated with the response to platinum and PARPi. However, conflicting data are available with regards to currently approved therapies for mCRPC.

DNA REPAIR PATHWAY

Cheng, Eur Urol, 2016; Mateo, NEJM, 2015; Annala, Eur Urol, 2017; Hussain, JCO, 2017; Antonarakis, Euro Urol, 2018;

Mateo, Eur Urol, 2018; Robinson, Cell, 2015; Pritcard, NEJM, 2016; Castro E, JCO, 2013

• Recently, NGS studies have identified germline mutations in DNA repair genes in 8-12% of patients with metastatic prostate cancer.

DNA REPAIR PATHWAY

Annala, Eur Urol, 2017;; Antonarakis, Euro Urol, 2018; Mateo, Eur Urol, 2018;

¿POBLACIÓN ESPAÑOLA?

DNA REPAIR PATHWAY

PROREPAIR STUDY: 419 mCRPC

1st line 2nd line 3rd line

mCRPC

Prospective Follow-up

Death

4th line

•Treatment according to physician’s choice.

* Follow-up established by protocol: 3-4 weekly PSA, 12-16 weeks imaging re-evaluation

Rubinstein, J Chron Dis, 1981

PRIMARY OBJECTIVE

-To assess the impact of germline mutations in ATM, BRCA1, BRCA2, and PALB2 on

cause-specific survival (CSS) from diagnosis of mCRPC.

DNA REPAIR PATHWAY

Castro E, ESMO 2017

419 eligible patients

Patients were screened for germline mutations in a panel of 107 DDR genes.

Pathogenic mutations were confirmed by a second method (Sanger sequencing, MLPA)

DNA REPAIR PATHWAY

Castro E, ESMO 2017

ATM, BRCA2, BRCA1, PALB2: 6.1% (14 BRCA2, 8 ATM, 4 BRCA1, 0 PALB2)

Prevalence of gDDR: 16.2%

DNA REPAIR PATHWAY

Non Carriers gDDR+ P Value

(gDDR+ vs Non-

Carriers)

ATM, BRCA1,

BRCA2

P value

(ATM,BRCA1/2, vs

No ATM,BRCA1/2)

BRCA2

carriers

P value (BRCA2 vs No

BRCA2)

Age at mCRPC (yrs)

- Median (range)

71.8

(46.6-93.8)

69.3

(50.7-86.6)

0.11

67.1

(52.1-86.6)

0.31

68.9

(52.1-77.6) 0.20

PSA at mCRPC (ng/dl)

- Median (range)

27.5

(0.03-1980)

24.81

(0.93.756)

0.806

29.4

(2.20-580)

0.61

51.6

(2.20-580)

0.30

Progression to mCRPC

• Only PSA

• Radiological

220 (62.7%)

131 (37.3%)

36 (52.9%)

32 (47.1%)

0.13

10 (38.5%)

16 (61.5%)

0.02

4 (28.6%)

10 (71.4%)

0.01

Metastasis sites

• Nodal

• Bone

• Visceral

166 (47.3%)

289 (82.3%)

32 (9.1%)

31 (45.6%)

60 (88.2%)

10 (14.7%)

0.90

0.29

0.18

15 (57.7%)

24 (92.3%)

3 (11.5%)

0.31

0.20

0.74

9 (64.3%)

13 (92.9%)

3 (21.4%)

0.27

0.33

0.16

Performance Status

• ECOG 0

• ECOG 1

• ECOG 2

1178 (50.7%)

144 (41%)

29 (8.3%)

25 (36.8%)

40 (58.8%)

3 (4.4%)

0.225

8 (30.8%)

15 (57.7%)

3 (11.5%)

0.07

5 (28.6%)

7 (50%)

2 (14.3%)

0.24

Elevated ALP (>ULN) 150 (42.7%) 29 (42.6%) 1.0 13 (50%) 0.54 9 (64.3%) 0.11

Elevated LDH (>ULN) 114 (32.9%) 23 (34.3%) 0.89 10 (40%) 0.51 6 (42.9%) 0.56

Haemoglobin <10 g/dl 18 (5.1%) 2 (2.9%) 0.75 2 (7.7%) 0.36 2 (14.3%) 0.14

Albumin <3.5 g/dl 23 (6.6%) 4 (6.1%) 1.0 1 (3.8%) 0.56 1 (7.1%) 0.93

• Patients' characteristics at mCRPC

DNA REPAIR PATHWAY

• Treatments for mCRPC (40 months median follow-up)

Non

Carriers gDDR+

P value (gDDR+ vs Non-

Carriers)

ATM, BRCA1,

BRCA2

P value

(ATM,BRCA1/2,

vs

No ATM,BRCA1/2)

BRCA2

carriers

P value (BRCA2 vs No

BRCA2)

Treatment lines for mCRPC

•Total no lines

•SPT lines

3 (1-9)

2 (1-5)

3 (1-7)

2 (1-5)

0.48

0.55

3 (1-6)

2 (1-5)

0.60

0.87

3 (1-5)

2 (1-3)

0.38

0.80

Survival Prolonguing Therapies

•Abiraterone

•Enzalutamida

•Docetaxel

•Cabazitaxel

•Radium-23

257 (73.2%)

107 (30.5%)

265 (75.5%)

107 (30.5%)

61 (17.4%)

45 (66.2%)

19 (27.9%)

51 (75%)

25 (36.8%)

8 (11.8%)

0.24

0.67

0.93

0.31

0.25

16 (61.5%)

8 (30.8%)

21 (80.8%)

10 (38.5%)

3 (11.5%)

0.22

0.94

0.51

0.43

0.6

9 (64.3%)

4 (28.6%)

12 (85.7%)

4 (28.6%)

1 (7.1%)

0.55

1.0

0.36

1.0

0.48

No SPT

• Ketokonazole

• Steroids

• Estrogens

• Ciclofosfamide

• Mitroxantrone

• Platium-based chemotherapy

• PARP inhibitors

15 (4.3%)

49 (14%)

9 (2.6%)

38 (10.8%)

23 (6.6%)

19 (5.4%)

4 (1.1%)

1 (1.5%)

9(13.2%)

5 (7.4%)

9 (13.2%)

2 (2.9%)

5 (7.4%)

0

0.49

0.87

0.06

0.53

0.40

0.57

1.0

0

2 (7.7%)

1 (3.8%)

4(15.4%)

1 (3.8%)

4 (15.4%)

0

0.6

0.56

0.60

0.51

1.0

0.05

1.0

0

0

0

2 (14.3%)

0

2 (14.3%)

0

1.0

0.23

1.0

0.66

1.0

0.19

1.0

DNA REPAIR PATHWAY

• Cause Specific Survival from mCRPC

DNA REPAIR PATHWAY

Prognostic factors in UVA for CSS

from mCRPC MVA HR (95%CI) p-value

Germline BRCA2 mutations

0·0325 Carrier vs non-carrier 2·11 (1·06-4·18)

Median Time to mCRPC since

ADT

0.0018 <28 vs ≥28 months 1.52 (1.17-1.98)

Median age at mCRPC

0·0965 ≤71·4 vs 71·4 years 1·26 (0·96-1·64)

ECOG performance status (PS) 0·0004

ECOG 1 vs ECOG 0 1·29 (0·97-1·72) 0·0798

ECOG 2 vs ECOG 0 2·52 (1·60-3·97) <0·0001

Median PSA at mCRPC

0·5277 ≤27·5 vs >27·5 ng/dL 1·09 (0·83-1·43)

Serum Alkaline Phosphatase

0·2844 Elevated (>ULN) vs Normal (≤ULN ) 1·16 (0·88-0·284)

Serum Lactate dehidrogenase

(LDH)

<0·0001 Elevated (>ULN) vs Normal (≤ULN ) 1·85 (1·40-2·44)

Haemoglobin

0·0270 <10 vs ≥10 g/dL 1·85 (1·07-3·18)

Serum albumin

0·0009 <3·5 vs ≥3·5 g/dL 2·18 (1·38-3·46)

gBRCA2 is an independent prognostic factor for CSS from mCRPC

DNA REPAIR PATHWAY

• Response rates to taxanes and Androgen Signalling Inhibitor (ASI)

Outcomes gDDR

P value Carriers Non-carriers

Response to first taxane

PSA50 response rate (95%CI) 42·2% (27·8-56·7) 51·2% (45-57·4) 0·2678

ORR rate (95%CI) 25·0% (12·8-37·25) 13·9% (9·5-18·3) 0·0532

Response to first abi/enza

PSA50 response rate (95%CI) 53·8% (40·3-67·4) 52·3% (46·5-58·1) 0·8353

ORR rate (95%CI) 9·5% (0-2·7) 10·1% (6·7-22·2) 1.000

Outcomes ATM/BRCA1/ BRCA2/PALB2

P value Carriers Non-Carriers



ORR rate (95%CI) 30·0% (10·0-40·4) 14·7% (10·4-18·9) 0·1026


PSA50 response rate (95%CI) 44·4% (21·5-67·4) 53% (47·5-58·5) 0·4810

ORR rate (95%CI) 9·5% (0-2·7) 10·1% (6·7-22·2) 1.000

Outcomes BRCA2 carriers




ORR rate (95%CI) 36·4% (7·9-64·8) 14·9% (10·7-19·1) 0·0764


PSA50 response rate (95%CI) 30% (1·6-58·4) 53·2% (47·8-58·6) 0·2020

ORR rate (95%CI) 16·7% (0-37·8) 9·8% (6·5-13·1) 0·3430

DNA REPAIR PATHWAY

• Time to progression on taxanes and ASI

Outcomes gDDR



TTPP median, months (95%CI) 6·1 (4·4-7·9) 6·2 (5·7-6·7) 0·8486

PFS median, months (95%CI) 7·5 (5·87-9·2) 7·3 (6·7-7·9) 0·9663




Outcomes ATM/BRCA1/ BRCA2/PALB2

P value Carriers Non-Carriers







Outcomes BRCA2 carriers








DNA REPAIR PATHWAY

ASIs Taxane Taxane ASIs

SUBANALYSIS: mCRPC outcomes according to BRCA2 status and treatment sequence

CONCLUSIONES

El cáncer de próstata es una enfermedad muy heterogénea, sin embargo, los avances acontecidos en la biología molecular nos están permitiendo obtener un mejor conocimiento y clasificación de esta entidad.

Importancia de los eventos policlonales en la evolución pronóstica del cáncer de próstata.

PSMA es una proteína transmembrana con prometedores resultados tanto en diagnóstico como en tratamiento.

Importancia de vía “DNA repair” en cáncer de próstata. Implicaciones terapéuticas y de screening genético.

PROREPAIR-B es el primer estudio que reporta prevalencia de mutaciones germinales en genes reparadores del ADN en una cohorte de pacientes con CPRCm mediterráneos.

Diferentes alteraciones en genes reparadores del ADN pueden tener diferente impacto en pacientes con CPRCm (BRCA2 peor pronóstico).

AGRADECIMIENTOS

PROREPAIR study investigators

Prostate Cancer Team at CNIO& IBIMA lead

by David Olmos & Elena Castro

Nuria Romero

Leticia Rivera

Gala Grau

Ylenia Cendón

Lorena Magraner

Visiting Researchers

Adriana Rosero

Ignacio Moreno

Isabel Santos

Collaborators at CNIO

Alicia Barroso

Ana Osorio

Antonio López

Berta Nasarre

Paz Nombela

Teresa Garcés

Vanessa Cañadilla

F. López-Campos

A.Gutierrez-Pecharromán

Jacobo Rogado

M. García-Ferrón

M. Ruiz-Vico

Noemí Hernández

INGEMM Pablo Lapunzina

Ángela del Pozo

Elena Vallespín

J.C. Silla-Castro

Kristina Ibáñez

Univ. of Washington Mallory Beightol

Colin Pritchard

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