Cancer de Mama Triple Negativo
Heterogeneidad Tumoral
Rol de Platinos e Inhibidores PARP
Dr. Adrián Agustín Nervo
Cancer de Mama Triple Negativo
5
Triple Negativo
No target
disponible
Herceptin
Lapatinib
Pertuzumab
Pertuzumab
TDM1
TDM1
Tamoxifeno
IA
Fulvestrant
Inhibidores mTor
Inhibidores cDK
Triple Negativo
90% DE LOS BRCA 1 MUTADOS
80-90% SON SIMIL – BASALES
10-15% DE LOS TN SON BRCA1 MUTADOS
Triple Negativo
Característica Clínicas del 3N
• No asociación
consistente con status
nodal o estadio y
evolución
• Patron de Recaída
– Alto riesgo
– ILE corto
– Sitio diferente de los
luminales:
– SNC 30-45%
0.35
0.30
Other (290 of 1421)
Triple negative (61 of 180)
HR
0.25
0.20
0.15
0.10
0.05
0
n
Bone,
%
Soft Tissue, %
Viscera, %
TNBC
79
13
13
74
ER+
123
39
7
54
HER2+
78
7
12
81
Respuesta a la QT Neoadyuvante
•
TNBC often responsive to conventional NAC with good outcome similar to other
subtypes
< pCR = poorer outcome
1.0
Probability of Being Alive
•
98%
94%
P = .24
0.9
88%
0.8
P = .0001
0.7
68%
0.6
0.5
0.4
pCR/non-TNBC
pCR/TNBC
RD/non-TNBC
RD/TNBC
1
2
3
4
5
Yrs After Surgery
6
7
SABCS 2014
T NBC
21 publically available gene expression data sets
587 TNBC
3N
San Antonio Breast Cancer Symposium, December 9-13, 2014
Vanderbilt: subtipos de 3N- TNBCtype
Basal-like 1 and 2
Immunomodulatory
Mesenchymal-like
Mesenchymal Stem-like
Luminal-AR
San Antonio Breast Cancer Symposium, December 9-13, 2014
Lehman et al JCI 2012
Subtipos Moleculares de Cáncer de Mama
3N
Posible origen de los subtipos 3N
Mesenchymal
stem-like
Basal-like
+- mesencyhmal
features
Luminal AR
San Antonio Breast Cancer Symposium, December 9-13, 2014
Lim et al Nat Med 2009
Dos subtipos mayores de 3N
Subtypes split by intrinsic subtype by PAM50
San Antonio Breast Cancer Symposium, December 9-13, 2014
Masuda et al CCR 2013
Vanderbilt: subtipos de 3N
Basal-like 1 and 2
Immunomodulatory
Basal-like
Mesenchymal-like
Mesenchymal Stem-like
Luminal-AR
San Antonio Breast Cancer Symposium, December 9-13, 2014
Luminal
Lehman et al JCI 2012
Significancia Clínica de los subtipos 3N
Luminal AR
Basal-like TNBC
10-15% TNBC
~80% TNBC
San Antonio Breast Cancer Symposium, December 9-13, 2014
Líneas celulares Luminal AR
High expression hormonal driven pathways
Express androgen receptor
Sensitive in vitro to Bicalutamide
San Antonio Breast Cancer Symposium, December 9-13, 2014
Lehman et al JCI 2012
Phase II Trial of Bicalutamide in Patients with Androgen Receptor–
Positive, Estrogen Receptor Negative Metastatic Breast Cancer
(TBCRC 011)
ER/PR negative (<=10% b IHC) but AR positive (>10% IHC)
Bicalutamide 150mg qd
Screened 424 patients 12% AR positive – 28 treated on study
0% Response rate
19% (5/26) stable disease >6 months
Benefit possible in strongly AR positive
Trials with Abiraterone and
Enzalutamide ongoing
San Antonio Breast Cancer Symposium, December 9-13, 2014
Gucalp et al CCR 2013
Significancia Clinica de la expresión genética de los subtipos
35% LAR intermediate grade
Chemotherapy response – possibly lower
pCR in LAR although including RCB-1 no
clear difference
San Antonio Breast Cancer Symposium, December 9-13, 2014
Masuda et al CCR 2013
Significancia Clínica de los subtipos 3N
Luminal AR
Basal-like TNBC
10-15% TNBC
~80% TNBC
Mesenchymal Stemlike
5-10% TNBC
San Antonio Breast Cancer Symposium, December 9-13, 2014
Ca Mama 3N-Mesenchymal stem-like
• Superposición con claudin-low y cáncer de mama metaplásico
• Enriquecido por expresión stem cell-like
• Menor tasa de proliferación que los basal-like
• Frecuente infiltrado inmune
• Niveles intermedios de mutación PIK3CA
San Antonio Breast Cancer Symposium, December 9-13, 2014
Vanderbilt: subtipos de 3N
Basal-like 1 and 2
Immunomodulatory
Mesenchymal-like
Mesenchymal Stem-like
Luminal AR
San Antonio Breast Cancer Symposium, December 9-13, 2014
Lehman et al JCI 2012
3N Predminio Linfocitario
Tumour infiltrating lymphocyctes in breast cancer
Intratumoural
Stromal
San Antonio Breast Cancer Symposium, December 9-13, 2014
Adams et al JCO 2014
3N Predominio Linfocitario
Tumour infiltrating lymphocyctes in breast cancer
Analysis of BIG 02-98 AC-CMF +- docetaxel
TNBC
HER2
ALL
ER pos
pre-trastuzumab
San Antonio Breast Cancer Symposium, December 9-13, 2014
Loi et al JCO 2013
3N Predominio Linfocitario
Tumour infiltrating lymphocyctes in breast cancer
Intra-tumoural TILs
Stromal TILs
San Antonio Breast Cancer Symposium, December 9-13, 2014
Adams et al JCO 2014
Significancia clínica de los subtipos 3N
Luminal AR
Basal-like TNBC
10-15% TNBC
~80% TNBC
Mesenchymal Stemlike
5-10% TNBC
Lymphocyte predominant
San Antonio Breast Cancer Symposium, December 9-13, 2014
Lymphocyte depleted
Vanderbilt: subtypos de 3N
Basal-like 1 DNA repair activated
Basal-like 2 Growth factor receptor
Immunomodulatory
Mesenchymal-like
Mesenchymal Stem-like
Luminal AR
San Antonio Breast Cancer Symposium, December 9-13, 2014
Lehman et al JCI 2012
Y saliendo de las
tinieblas, vamos
a algo más
terrenal
….o no
Targeting the positives in TNBC
Platinums, PARPS and novel approaches to
high risk disease
Andrew Tutt
Director
Breakthrough Breast Cancer Research Centre
London
Triple Negativo: Inestabilidad
TNBCs haveGenómica
highly variable
BRCA1 BRCA2
Mutation
associated
Chromosome
alta heterogeneidad
tumoralstructural instability
pocas mutaciones pasibles de targets
Stable genome- low instability
Unstable genome- high instability
Alexandrov et al Nature 2013
BRCA1 está mutado en ≈15% de pacientes 3N
BRCA1/2 y mecanismos de reparación del ADN
Environmental factors
DNA DAMAGE
(UV, radiation, chemicals)
Normal physiology
Cell death
(DNA replication, ROS)
Chemotherapy
(alkylating agents, antimetabolites)
Radiotherapy
MAJOR DNA REPAIR
PATHWAYS
Single strand breaks
• Nucleotide excision repair
Replication lesions
• Base excision repair
– PARP1
• Base excision repair
• PARP1
Double strand breaks
 Nonhomologous end-joining
 Homologous recombination
– BRCA1/BRCA2
 Fanconi anemia pathway
 Endonuclease-mediated repair
DNA adducts/base damage
• Alkyltransferases
• Nucleotide excision repair
• Base excision repair
– PARP1
Helleday T, et al. Nat Rev Cancer. 2008;8:193-204. O’Shaughnessy J, et al. ASCO 2009. Abstract 3. Reproduced with permission.
Platino
Una Larga historia en Cáncer de Mama……
1988 JCO
Platino e Inhibidores de la PARP
Activo en TNBC BRCA 1
BRCA1 sensibles a agentes
que producen cross-link en el DNA
1. Platinum chemotherapy
Inflicts DNA damage via adducts and
DNA crosslinking
PARP1
PARP inhibitor
PARP1
2. PARP1
upregulations
Base-excision
repair of DNA
damage
3. Inhibition of
PARP1
PARP1 Disables DNA
base-excision
repair
BRCA-1
BRCA-2
Cell Survival
Cell Death
Platino en 3N metastásicos
TNT Trial-Abst S3-01
First Line Advanced TNBC or
BRCA1/BRCA2 Breast Cancer
Correlative Biology
Program
RECIST ORR
TTP
PFS
ORR 2nd line
Toxicity
OS
376 patients
Central ER / PR / HER2
Basal Phenotypes
Germline BRCA1/2
genotype
53BP loss
HR Genome Scar
Somatic BRCA1/2
BRCA1 methylation
Whole Exome NGS
RNA Seq
Recurrent Disease BX
Genome Scars
Reversion Mutations
Whole Exome NGS
RNA Seq
TNT - Trial
TNT-Trial
Abst S3-01
Platino en 3N metastásico
•
•
•
•
Pocos Trials TN específicos ->mayormente subsets
Generalmenteplatinosevaluadosencombinación
Variasdefiniciones de“triple-negativo”
BRCA1/2 mutacionesraramentecaracterizadas
Se
nececitanmásestudiosrandomizadoscomparandoplatinos a
QT standard of care en 1 y 2ºlínea de
tratamientoenenfermedadmetastásica. TNT??
San Antonio Breast Cancer Symposium December 9-13, 2014
Platino en Neoadyuvancia en BRCA1 Mutatados
BRCA1
Mutation
Carriers with
Tumors >2cm
CISPLATIN
75mg/m2
q 3wks IV x 12
wks
Clinical and
Pathological
Response
•N = 25
•median age: 46
Pathological Response 72%
•28% with clinically positive lymph nodes
•22. pts completed 4 cycles of Cisplatin
Gronwald et al ASCO 2009
Platino en Neoadyuvancia
Platino en Neoadyuvancia
Alta pCR con antraciclinas y taxanos en BRCA1/2
mutados
Platino no standard en neo/adyuvancia
Seguimos con nuestro combo
AC x4 – Paclitaxel w
• BRCA1 mutation pCR 46% vs 22% non-carriers
• Is the effect specific to platinum vs standard of care?
• Requires planned subgroup analyses in randomised trials
Arun B et al -- J Clin Oncol 29:3739-3746
PARP
• Rol clave en la reparación del ADN (SSB)
• Utiliza la vía de excisión de bases como reparación
• Se une directamente al sitio de ADN dañado
• Una vez activada, utiliza a NAD como substrato generando múltiples
cadenas de poly(ADP-ribose)
• Recluta otras enzimas reparadoras de ADN
XRCC1 Lig3
PNK
Polß
Inhibidores PARP
• Las células con BRCA-1 and BRCA-2 deficiente son
marcadamente sensibles a inhibidores PARP
• En presencia de un inhibidor PARP , tienen una
marcado déficit en la capacidad de repararse y esto
conduce a la apoptosis
PARP1
PARP inhibitor
PARP1
2. PARP1
upregulations
Base-excision
repair of DNA
damage
1. Platinum chemotherapy
Inflicts DNA damage via
adducts and DNA
crosslinking
3. Inhibition of
PARP1
PARP1 Disables DNA
base-excision
repair
BRCA-1
BRCA-2
Cell Survival
Cell Death
Inhibidores PARP en gBRCA m
400 mg td
100 mg td
Estudios en marcha……
Potent PARP
inhibitor at MTD as
continuous
exposure
gBRCA1 / BRCA2
Carriers
Advanced
anthracycline taxane
resistant breast cancer
R
Niraparib – BRAVO Trial
BMN 673 – EMBRACA - NCT01945775
OLYMPIAD – Olaparib - NCT02000622
Physician Choice
within SOC options
Capecitabine
or
Vinorelbine
or
Eribulin
or
Gemcitabine
Primary
endpoint
PFS
Combinando QT target con inhibición PARP
Selective tumor cell killing
Increased
normal tissue
toxicity
predicted
Degree of PARP
trapping of
inhibitor may be
relevant
BRCA status and HRD Score examined in
PrECOG 0105
Newly
Diagnosed
Stage I-IIIA
Carboplatin AUC 2 D 1, 8
(T  1cm by MRI)
Triple-negative
Gemcitabine 1000 mg/m2 D 1, 8
(ER/PR ≤ 5%)
or
BRCA1/2
mutation
Iniparib 5.6 mg/kg D 1, 4, 8, 11
Definitive
Surgery
Assess
Pathologic
Response
Every 21 days x 6 cycles
n = 80
Primary Endpoint:
Pathologic complete response (pCR) [no invasive disease in breast + axilla]
Secondary Endpoints: Radiographic response by MRI
Breast conservation eligibility
Safety
Correlation of gene expression profiles & gene copy number with response
Telli et al ASCO 2013
Alta Respuesta Patológica asociada con
mutación BRCA1/2
Pathologic Response (n=80)
pCR [RCB 0]; n (%)
90% CI
RCB 0/1; n (%)
90% CI
All patients
*******
BRCA 1/2
wild-type
BRCA 1/2
mutant
TN & BRCA
1/2 mutant
n = 80
n = 61
n = 19
n = 16
29 (36%)
20 (33%)
9* (47%)
9* (56%)
27–46
23–44
27-68
33-77
45 (56%)
31 (51%)
14 (74%)
12 (75%)
46-66
40-62
52-89
52-91
* One BRCA1 carrier had bilateral TNBC & achieved pCR in both breasts
Can veliparib sensitized chemotherapy improve on a
platinum directed chemotherapy approach?
NCT01506609
Cisplatin with or without rucaparib after preoperative chemotherapy
in patients with triple-negative breast cancer (TNBC): Hoosier Cancer
Research Network BRE09-146 Abstract 1019
Sujaata Dwadasi, Yan Tong, Tom Walsh, Michael A. Danso, Cynthia X. Ma, Paula Silverman, MaryClaire King, Susan M. Perkins, Sunil S. Badve, Kathy Miller
Median RCB 2.6 v 2.7
•
Eligibility
– TNBC (or BRCA+)
– Residual disease (RCB
2/3, M-P 0-2, node +)
– No prior cisplatin (carbo
allowed)
– 128 patients
– 65 cisplatin
– 63 cis/rucaparib
Presented by: Steven Isakoff
- Discussant
1 Year DFS
C 83% v C/R 83%
R
a
n
d
o
m
i
z
e
Cisplatin
X 4 cycle
22/128 patients BRCA
mutation
DFS C 85% v C/R 100%
Cisplatin +
Rucaparib
30mg IVx3d
X 4 cycle
Rucaparib
100mg PO q wk
X 24 weeks
Post neoadjuvant gBRCA
TNBC,
Non-PathCR pts
Placebo
12 month
duration
Distant DFS; OS
Post adjuvant gBRCA
TNBC
T2 or N+
Randomise 1:1
Double blind
N=1320
IDFS
Restricted to Germline
Mutation carriers
Olaparib
300 mg bd
12 month
duration
Mejorando la selección de Pacientes
A Post Neo-adjuvant Umbrella Trial Platform? PHOENIX
Post-Rx
residual
disease
New Diagnosis
Relapse
Vs
Neoadjuvant Rx
No Relapse
Balko et al Cancer Discovery 2014
Definitive Surgery
Second Adjuvant Rx
Allocated by
Genomic Triage
Conclusiones
• Cáncer de mama TN tiene subpoblaciones con defectos en la
reparación del ADN: 10-15% BRCA1 mutados
• Defectos en la reparación HR puede generar sensibilidad a platinos
o inhibidores PARP
• No data randomizada publicada sobre comparación de platinos vs
standard of care en este grupo – TNT?
• Inhibidores PARP promisorios, pero…faltan resultados de estudios
fase III
Conclusiones Triple Negativo
Antes de San Antonio 2014
=
Después de San Antonio 2014
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Cáncer de mama Triple Negativo