cancer de mama 3n
TRANSCRIPT
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Dr. Adrián Agustín Nervo
Cancer de Mama Triple NegativoHeterogeneidad TumoralRol de Platinos e Inhibidores PARP
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Cancer de Mama Triple Negativo
5
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Triple Negativo
PertuzumabTDM1
HerceptinLapatinibPertuzumabTDM1
TamoxifenoIAFulvestrantInhibidores mTorInhibidores cDK
No target disponible
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90% DE LOS BRCA 1 MUTADOS
80-90% SON SIMIL – BASALES
10-15% DE LOS TN SON BRCA1 MUTADOS
Triple Negativo
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Triple Negativo
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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
0.25
0.15
0.10
0.05
0
HR 0.20
Other (290 of 1421)Triple negative (61 of 180)
n Bone, %
Soft Tissue, % Viscera, %
TNBC 79 13 13 74
ER+ 123 39 7 54
HER2+ 78 7 12 81
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Respuesta a la QT Neoadyuvante
• TNBC often responsive to conventional NAC with good outcome similar to other subtypes
• < pCR = poorer outcome1.0
0.9
0.8
0.7
0.6
0.5
0.41
Yrs After Surgery2 3 4 5 6 7
Prob
abili
ty o
f Bei
ng A
live
pCR/non-TNBCpCR/TNBCRD/non-TNBCRD/TNBC
98%94%
88%
68%
P = .24
P = .0001
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21 publically available gene expression data sets587 TNBC
San Antonio Breast Cancer Symposium, December 9-13, 2014
3N
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Basal-like 1 and 2
Mesenchymal-like
Luminal-AR
Immunomodulatory
Vanderbilt: subtipos de 3N- TNBCtype
Lehman et al JCI 2012
Mesenchymal Stem-like
San Antonio Breast Cancer Symposium, December 9-13, 2014
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Subtipos Moleculares de Cáncer de Mama
3N
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Posible origen de los subtipos 3N
Lim et al Nat Med 2009
Luminal AR
Mesenchymal stem-like
Basal-like+- mesencyhmal features
San Antonio Breast Cancer Symposium, December 9-13, 2014
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Dos subtipos mayores de 3N
Masuda et al CCR 2013
Subtypes split by intrinsic subtype by PAM50
San Antonio Breast Cancer Symposium, December 9-13, 2014
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Basal-like 1 and 2
Mesenchymal-like
Luminal-AR
Immunomodulatory
Vanderbilt: subtipos de 3N
Lehman et al JCI 2012
Mesenchymal Stem-like
San Antonio Breast Cancer Symposium, December 9-13, 2014
Basal-like
Luminal
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Significancia Clínica de los subtipos 3N
Basal-like TNBCLuminal AR
~80% TNBC10-15% TNBC
San Antonio Breast Cancer Symposium, December 9-13, 2014
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High expression hormonal driven pathways
Express androgen receptor
Sensitive in vitro to Bicalutamide
Líneas celulares Luminal AR
San Antonio Breast Cancer Symposium, December 9-13, 2014 Lehman et al JCI 2012
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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
Gucalp et al CCR 2013San Antonio Breast Cancer Symposium, December 9-13, 2014
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Masuda 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
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Significancia Clínica de los subtipos 3N
Basal-like TNBCLuminal AR Mesenchymal Stem-like
~80% TNBC10-15% TNBC5-10% TNBC
San Antonio Breast Cancer Symposium, December 9-13, 2014
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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
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Basal-like 1 and 2
Mesenchymal-like
Luminal AR
Immunomodulatory
Vanderbilt: subtipos de 3N
Lehman et al JCI 2012
Mesenchymal Stem-like
San Antonio Breast Cancer Symposium, December 9-13, 2014
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Tumour infiltrating lymphocyctes in breast cancer
Adams et al JCO 2014
3N Predminio Linfocitario
Stromal
Intra-tumoural
San Antonio Breast Cancer Symposium, December 9-13, 2014
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Tumour infiltrating lymphocyctes in breast cancer
Loi et al JCO 2013
ALL ER pos
TNBCHE
R23N Predominio Linfocitario
Analysis of BIG 02-98 AC-CMF +- docetaxel
pre-trastuzumabSan Antonio Breast Cancer Symposium, December 9-13, 2014
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Adams et al JCO 2014
Intra-tumoural TILs
Stromal TILs
Tumour infiltrating lymphocyctes in breast cancer
3N Predominio Linfocitario
San Antonio Breast Cancer Symposium, December 9-13, 2014
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Significancia clínica de los subtipos 3N
Basal-like TNBCLuminal AR Mesenchymal Stem-like
~80% TNBC10-15% TNBC5-10% TNBC
Lymphocyte predominant Lymphocyte depleted
San Antonio Breast Cancer Symposium, December 9-13, 2014
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Basal-like 1 DNA repair activated
Mesenchymal-like
Luminal AR
Immunomodulatory
Vanderbilt: subtypos de 3N
Lehman et al JCI 2012
Mesenchymal Stem-like
Basal-like 2 Growth factor receptor
San Antonio Breast Cancer Symposium, December 9-13, 2014
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Y saliendo de las tinieblas, vamos a algo más terrenal….o no
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Targeting the positives in TNBC Platinums, PARPS and novel approaches to
high risk disease
Andrew TuttDirector
Breakthrough Breast Cancer Research CentreLondon
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BRCA1 BRCA2 Mutation associated
Alexandrov et al Nature 2013
Stable genome- low instability
Unstable genome- high instability
TNBCs have highly variable Chromosome structural instability
Triple Negativo: Inestabilidad Genómicaalta heterogeneidad tumoral
pocas mutaciones pasibles de targets
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BRCA1 está mutado en ≈15% de pacientes 3N
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BRCA1/2 y mecanismos de reparación del ADN
Single strand breaks• Nucleotide excision repair
• Base excision repair• PARP1
Replication lesions• Base excision repair
– PARP1
DNA adducts/base damage • Alkyltransferases
• Nucleotide excision repair
• Base excision repair– PARP1
DNA DAMAGE
Cell death
Environmental factors(UV, radiation, chemicals)
Normal physiology(DNA replication, ROS)
MAJOR DNA REPAIRPATHWAYS
Chemotherapy(alkylating agents, antimetabolites)Radiotherapy
Helleday T, et al. Nat Rev Cancer. 2008;8:193-204. O’Shaughnessy J, et al. ASCO 2009. Abstract 3. Reproduced with permission.
Double strand breaks Nonhomologous end-joining Homologous recombination
– BRCA1/BRCA2
Fanconi anemia pathway Endonuclease-mediated repair
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PlatinoUna Larga historia en Cáncer de Mama……
1988 JCO
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Platino e Inhibidores de la PARP
BRCA-1BRCA-2
1. Platinum chemotherapyInflicts DNA damage via adducts and DNA crosslinking
2. PARP1upregulationsBase-excision repair of DNA damage
3. Inhibition of PARP1Disables DNA base-excision repair
Cell Survival Cell Death
PARP inhibitor
Pt
Pt
Pt
Pt
Pt
PARP1
PARP1
PARP1
Activo en TNBC BRCA 1 BRCA1 sensibles a agentes
que producen cross-link en el DNA
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Platino en 3N metastásicos
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TNT Trial-Abst S3-01
RECIST ORR
TTPPFS
ORR 2nd lineToxicity
OS
376 patients
First Line Advanced TNBC or BRCA1/BRCA2 Breast Cancer
Central ER / PR / HER2 Basal PhenotypesGermline BRCA1/2
genotype53BP loss
HR Genome ScarSomatic BRCA1/2
BRCA1 methylationWhole Exome NGS
RNA Seq
Recurrent Disease BXGenome Scars
Reversion MutationsWhole Exome NGS
RNA Seq
Correlative BiologyProgram
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TNT - Trial
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TNT-Trial Abst S3-01
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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 2línea de tratamientoenenfermedadmetastásica. TNT??
San Antonio Breast Cancer Symposium December 9-13, 2014
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BRCA1 Mutation
Carriers with Tumors >2cm
Clinical and Pathological Response
Platino en Neoadyuvancia en BRCA1 Mutatados
.
CISPLATIN 75mg/m2
q 3wks IV x 12 wks
•N = 25•median age: 46 •28% with clinically positive lymph nodes•22 pts completed 4 cycles of Cisplatin
Pathological Response 72%
Gronwald et al ASCO 2009
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Platino en Neoadyuvancia
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Platino en Neoadyuvancia
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Alta pCR con antraciclinas y taxanos en BRCA1/2 mutados
• 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
Platino no standard en neo/adyuvanciaSeguimos con nuestro combo
AC x4 – Paclitaxel w
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Lig3XRCC1
PolßPNK
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
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Inhibidores PARP
BRCA-1BRCA-21. Platinum chemotherapy
Inflicts DNA damage via adducts and DNA crosslinking
2. PARP1upregulationsBase-excision repair of DNA damage
3. Inhibition of PARP1Disables DNA base-excision repair
Cell Survival Cell Death
PARP inhibitor
Pt
Pt
Pt
Pt
Pt
PARP1
PARP1
PARP1
• 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
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Inhibidores PARP en gBRCA m
400 mg td 100 mg td
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Estudios en marcha……
R
Potent PARP inhibitor at MTD as
continuous exposure
Physician Choice within SOC options
Capecitabineor
Vinorelbineor
Eribulinor
Gemcitabine
gBRCA1 / BRCA2 Carriers
Advanced anthracycline taxane
resistant breast cancer
Primary endpoint
PFS
Niraparib – BRAVO Trial
BMN 673 – EMBRACA - NCT01945775
OLYMPIAD – Olaparib - NCT02000622
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Selective tumor cell killingIncreased
normal tissue toxicity
predicted
Degree of PARP trapping of
inhibitor may be relevant
Combinando QT target con inhibición PARP
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BRCA status and HRD Score examined in PrECOG 0105
Every 21 days x 6 cyclesn = 80
Definitive SurgeryAssess
Pathologic Response
Carboplatin AUC 2 D 1, 8
Gemcitabine 1000 mg/m2 D 1, 8
Iniparib 5.6 mg/kg D 1, 4, 8, 11
Newly Diagnosed
Stage I-IIIA (T 1cm by
MRI)
Triple-negative (ER/PR ≤ 5%)
or
BRCA1/2 mutation
Primary Endpoint: Pathologic complete response (pCR) [no invasive disease in breast + axilla]
Secondary Endpoints: Radiographic response by MRI Breast conservation eligibility
SafetyCorrelation of gene expression profiles & gene copy number
with responseTelli et al ASCO 2013
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Alta Respuesta Patológica asociada con mutación BRCA1/2
Pathologic Response (n=80)All patients
*******
n = 80
BRCA 1/2 wild-type
n = 61
BRCA 1/2 mutant
n = 19
TN & BRCA 1/2 mutant
n = 16
pCR [RCB 0]; n (%) 29 (36%) 20 (33%) 9* (47%) 9* (56%)
90% CI 27–46 23–44 27-68 33-77
RCB 0/1; n (%) 45 (56%) 31 (51%) 14 (74%) 12 (75%)
90% CI 46-66 40-62 52-89 52-91
* One BRCA1 carrier had bilateral TNBC & achieved pCR in both breasts
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Can veliparib sensitized chemotherapy improve on a platinum directed chemotherapy approach?
NCT01506609
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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, Mary-Claire King, Susan M. Perkins, Sunil S. Badve, Kathy Miller
Presented by: Steven Isakoff - Discussant
Randomize
CisplatinX 4 cycle
Cisplatin +Rucaparib30mg IVx3dX 4 cycle
Rucaparib100mg PO q wkX 24 weeks
• 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
Median RCB 2.6 v 2.7
1 Year DFSC 83% v C/R 83%
22/128 patients BRCA mutation
DFS C 85% v C/R 100%
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Randomise 1:1Double blindN=1320
IDFS
Distant D
FS; O
S
Post neoadjuvant gBRCA TNBC,
Non-PathCR pts
Post adjuvant gBRCA TNBCT2 or N+
Olaparib 300 mg bd 12 month duration
Placebo 12 month duration
Restricted to Germline Mutation carriers
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Mejorando la selección de PacientesA Post Neo-adjuvant Umbrella Trial Platform? PHOENIX
New DiagnosisPost-Rx residual disease
Neoadjuvant Rx
Relapse
Vs
No Relapse
Definitive Surgery
Second Adjuvant RxAllocated by
Genomic TriageBalko et al Cancer Discovery 2014
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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
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Conclusiones Triple Negativo
Antes de San Antonio 2014
= Después de San Antonio 2014