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CANCER DE MAMATRIPLE NEGATIVO
Dr. LUIS MIGUEL ZETINA-TOACHEONCOLOGIA MEDICA
CANCER CONSULTANTS GTONCOMEDICA S.A
Objetivos………………………………..
Clasificacion Genomica Diferentes Tipos de TNBC Importancia de la Clasificacion Caracteristicas Clinicas del TNBC Opciones de Tratamiento Opciones a Futuro
Cancer Growth and Metastases
Tumor
Crece, in
vade y metastasiza
Histologia del cancer de mama
Tipo HistológicoFrecuencia
(%)Supervivencia a
5 años (%)
Carcinoma Ductal Infiltrante 63.6 79
Carcinoma Lobulillar infiltrante 5.9 84
Carcinoma Ductal & Lobular Infiltrante 1.6 85
Carcinoma Medular 2.8 82
Carcinoma Mucinoso 2.1 95
Comedocarcinoma 1.4 87
Enfermedad de Paget 1.0 79
Adenocarcinoma No Esp. 7.5 65
Sin un claro patron
De comportamiento biologico
No establece SVG o SLE
TRATAMIENTO SISTÉMICO DEL CÁNCER DE MAMA METASTÁSICO CON HER2 NORMAL
OPCIONES C
LARAS
DE TRATAMIENTO
. Adapted from Hanahan and Weinberg. Cell. 2000;100:57.
Evadingapoptosis
Self-sufficiency in growth signals
Tissue invasionand metastasis
Limitless replicative potential
Sustainedangiogenesis
Insensitivity to antigrowth
signals
Cancercells
Fundamental Hallmarks of Cancer
ANALISIS GENOMICO DE TUMOR
CLASIFICACIONMOLECULAR
Smalley M. Ashworth A. Nat. Cancer Reviews 2003;3,832-844
Luminal Epithelial CellsLow molecular wt CK 7, 8, 18 and 19Mucin, BCL2, Hormone Receptors
Basal Cells (Myoepithelial cells)High molecular wt CK 5, 6, 14 and 17SMA, Calponina, p63, P-caderin
Perou C, et al. Nature 460:747-752, 2000
Terminal Duct Lobular Unit (TDLU)
Overall and relapse-free survival analysis of the 49 breast cancer patients, uniformly treated in a prospective study, based on different gene expression classification.
Therese Sørlie et al. PNAS 2001;98:10869-10874
©2001 by National Academy of Sciences
ESTABLECE CLARO
PATRON BIO
LOGICO Y TERAPEUTIC
O
Clasificación molecular del Cancer de Mama
6 biomarcadores:
1. RE2. RP3. HER2
4. EGFR5. CK5/66. Ki67
SJ Schnitt et al - 2010
St. Gallen 2011:
1. RE2. RP
3. HER24. Ki67
Why is subtype important?
• Different outcomes• Prognostic significance• Selection of
therapeutic options• Response to treatment
Orígenes del Cancer Mama
Hipótesis I: cada subtipo tiene SU célula de origen
Polyak K - 2007
Orígenes del Cancer De Mama
Hipótesis II: una sola célula de origen para todos los subtipos,y el fenotipo, determinado por eventos genéticos y epigenéticos.
Polyak K - 2007
New Developments in Metastatic Breast Cancer
Metzger-Filho O, et al. J Clin Oncol. 2012;30:1879-1887. Reprinted with permission. © (2012) American Society of Clinical Oncology. All rights reserved.
Heterogeneities in the Nomenclature and Classification of TNBC
EGFR andcytokeratins
Claudin-lowsubtype
Basal-liketumors
TNBCER-negative
PgR-negativeHER2-
negative
BRCA1 mutantand BRCAness Immune system
Different histologicsubtypes
Clasificación molecular del CMTN:Subtipo “basal - like”
Perou CM, 2010
Perou CM, 2010
Clasificación molecular del CMTN:Subtipo “claudin – low”
Aclarando conceptos…
Chacon R - 2010
Triple Negative
Basal
~75% of TNBC have Basal gene expression
1. Pal & Mortimer. Maturitas 2009; 2. Gluz et al. Ann Oncol 2009; 3. Anders & Carey. Oncology 2008.4. Young et al. BMC Cancer 20095. Schneider, B. P. et al. Clin Cancer Res 2008;14:8010-8018
Triple-Negative vs. Basal-Like: DefinitionsER- / PR- / HER2-
~15% of all breast carcinomas
Poorly differentiated
Express CK 5/6, 17, EGFR (+)
• BRCA1-2 mutated tumors• ~5% of Breast Cancer• 50% BRCA-1 carriers are basal-like
• Basal but not triple negative
• Definition by gene expression
• Includes most BRCA1 mutated tumors
• 15-40% are ER+, PR+ or HER2+
• Triple negative but not basal
• Definition by IHC• Includes other
histologies (medullar, adenoid cystic)
• 10-30% can also include “claudin-low,” a subtype notable for high expression of stem cell markers
• 90% of TNBC do not have BRCA mutations
BRCA 1-2
“BRCAness”: Characteristics shared between BRCA-associated and sporadic breast cancers.
Lisa A. Carey The Oncologist 2011;16:71-78
©2011 by AlphaMed Press
Lehmann B, et al. JCI, 121:2750, 2011
Prat A, Perou CM, 2009
En resumen….(con respecto a la clasificación)
CÁNCER DE MAMA:
Conjunto de neoplasias distintas que asientan en la mama
CÁNCER DE MAMA TRIPLE NEGATIVO:
Grupo heterogéneo de un subtipo de cáncer de mama
New Developments in Metastatic Breast Cancer
What Is a Triple-Negative Breast Cancer (TNBC)? “Triple negative”: ER negative, PgR negative, HER2
negative
– Depending on thresholds used to define ER and PgR positivity and methods for HER2 testing
TNBC accounts for 10% to 17% of all breast carcinomas
Significantly more aggressive than other molecular subtype tumors
Majority grade 3 tumors
Most frequently high grade invasive ductal carcinomas of no special type
Reis-Filho JS, et al. Histopathology. 2008;52:108-118.
Who gets triple negative breast cancer?
15 % of breast cancer in US Young women African American women BRCA1 positive
Any woman can get any type of breast cancer
Epidemiology
Carey LA et al - 2006Carolina Breast Cancer Study
n = 1.424
New Developments in Metastatic Breast Cancer
Characteristics and Features of TNBC Phenotype Weak relationship between tumor size and nodal status
Rapid rise in risk of recurrence following diagnosis
Peak risk of recurrence at 1-3 yrs
Distant recurrence rarely preceded by local recurrence
Local recurrence not predictive of distant recurrence
Increased mortality rate first 5 yrs
Majority of deaths occurs within first 5 yrs
Rapid progression from distant recurrence to death
Dent R, et al. Clin Cancer Res. 2007;13:4429-4434.
New Developments in Metastatic Breast Cancer
Clinical Characteristic of Metastatic TNBC
No consistent association with nodal status or stage
Relapse pattern
– Higher risk
– Early timing
– Sites differ from luminal:
– CNS 46% of time n Bone, % Soft Tissue, % Viscera, %
TNBC 79 13 13 74
ER+ 123 39 7 54
HER2+ 78 7 12 81
Liedtke C, et al. J Clin Oncol. 2008;26:1275-1281. Lin NU, et al. Cancer. 2008;113:2638-2645.
0.35
0.30
0.25
0.15
0.10
0.05
0
HR 0.20
0 1 2 3 4 5 6 7 8 9 10Yrs After First Surgery
Other (290 of 1421)Triple negative (61 of 180)
Rates of distant recurrences in triple-negative and other breast cancers.
Dent R et al. Clin Cancer Res 2007;13:4429-4434
©2007 by American Association for Cancer Research
Opciones de manejo
QuimioterapiaRadioterapia
Terapia endócrinaTerapia dirigida
Opciones de manejo
Ca de mama RE/P (+) Ca de mama HER2 (3+)
Cirugía Neoadyuvancia
/adyuvancia (antraciclinas – taxanos)
Radioterapia +/- Terapia endócrina
(5 años) Recaída: hormonoterapia
2da y 3era linea
Cirugía Neo Ady (antraciclinas –
taxanos Trastuzuma/Pertuzumab)
Radioterapia +/- Recaída: ( Kadcyla,
capecitabina, lapatinib, gemcitabina,vinorelbine, eribulina, ixabepilona, etc)
Myths about triple negative breast cancer
• There are no effective treatments.• Patients are doomed to relapse.• Women with triple negative cancers are
doomed to die of their disease.• You have to have a mastectomy for triple
negative breast cancer.
Opciones de manejo
Ca de mama Triple (-)
• Cirugía• Neoadyuvancia /adyuvancia
(antraciclinas – taxanos)• Radioterapia +/-• Recaída
( capecitabina, platinos,• gemcitabina, inhib. de PARP• Bevacizumab, PIK3, PDL1.• Terapia endócrina NO• Terapia dirigida NO
Johnston S R Clin Cancer Res 2010;16:1979-1987
©2010 by American Association for Cancer Research
Targeted Therapies
Nu
mb
er o
f sa
mp
les
wit
h a
ber
rati
on
s
PI3K/mTOR DNA Repair Ras/MAPK Cell Cycle GFRs0
10
20
30
40TSC1
PIK3CA
PTEN
PIK3R1
RICTORRAPTORAKT1AKT2
AKT3
BRCA1
BRCA2ATM
RB1
AURKA
CDNK2A
CCNE1
CCND3
CCND2
CCND1
CDK6CDK4
NF1CRAFBRAFKRAS EGFR
MET
IGF1RKITFGFR1
FGFR2
FGFR4
PI3K/mTOR inhibitors
Targeted RTK inhibitors
DNA-repair targeting
agents
Cell cycle/mitotic
spindle inhibitors
RAF/MEK inhibitors
Arteaga C, et al. Vanderbilt
Clinically targetable pathways in TNBC
~90% of all patients had an aberration in at least one of these
pathways
Triple Negative Breast Cancer Treatment
• Chemotherapy
• Parp inhibitors • EGFR inhibitors
• Angiogenesis inhibitors
• Tyrosine Kinase inhibitors
Effectiveness of Chemotherapy
Triple Negative / Basal Disease
Chemosensitivity: Pathologic complete response (complete tumor eradication) to preoperative chemotherapy [9, 10].
Lisa A. Carey The Oncologist 2011;16:71-78
©2011 by AlphaMed Press
Basal-like BC Responds to Conventional Chemotherapy
T-FAC
(N=82)*AC-T
(n=107)*
Luminal A/B 7% 7%
Normal-like 0 NA
HER2+/ER- 45% 36%
Basal-like/triple negative 45% 26%
Rouzier, et al. Clin Cancer Res, 2005 Carey LA, et al. Clin Cancer Res 2007
• Basal-like / triple negative breast cancer responds to primary chemotherapy.
Explanation of higher response but worse outcome?
Pathologic Complete Response:
Responsiveness to conventional chemotherapy.
Lisa A. Carey The Oncologist 2011;16:71-78
©2011 by AlphaMed Press
Opciones de manejo:Platinos
Silver, DP et al - 2010
The Role of Carboplatin in TNBC (Neo)
Trial N StandardChemotherapy
Chemo +Carboplatin P-value
CALGB 40603 443 41% 54% 0.003
I-SPY 2 NA 26% 52% 90% prob. for superiority
GeparSixto(TNBC pts) 315 38% 59% <0.05
Sikov W, et al. SABCS 2013.Rugo H, et al. SABCS 2013.
Von Minckwitz G, et al, The Lancet Oncology 15:747, 2014.
Opciones de manejo:Platinos
Silver, DP et al - 2010
Utilidad enBRCA (+)
Adjuvant therapy for early breast cancer (90% are early at diagnosis).
Lisa A. Carey The Oncologist 2011;16:71-78
©2011 by AlphaMed Press
Rates of breast-specific survival in triple-negative and other breast cancers.
Dent R et al. Clin Cancer Res 2007;13:4429-4434
©2007 by American Association for Cancer Research
Rates of distant recurrences following surgery in triple-negative and other breast cancers.
Dent R et al. Clin Cancer Res 2007;13:4429-4434
©2007 by American Association for Cancer Research
Angiogenesis
Taxol + Avastin in metastatic patients
Benefit in triple negative patients
ECOG 2100: Randomized phase III trial of bevacizumab added to paclitaxel in stage IV breast cancer.
Lisa A. Carey The Oncologist 2011;16:71-78
©2011 by AlphaMed Press
Opciones de manejo:Bevacizumab
Hudis CA, Gianni L - 2011
Beneficio en pacientes Triple Negativo
TNBC PatientsER 1-10% (6%)
Age <60 83%T2-T3 86%LN+ 55%Grade III 86%
CALGB/Alliance 40603pCR in Breast and Axilla
Sikov W, et al. SABCS 2013
Opciones de manejo:Ixabepilona
Pacientes MTTSresistentes o progresadasa antraciclinas y taxanos.
Hudis CA, Gianni L - 2011
Study Schema
CarboplatinAUC5
q3wks x 4
Paclitaxel 80 mg/m2 qwk x 12
CP-CEF
P-CEF
HER2 (-) BCStage II/IIIA18-70 years
PS 0/1Good Organ
functionWritten IC
S U
R G
E R
Y
CEF 500/100/500 mg/m2
q3wks x 4
R
CEF 500/100/500 mg/m2
q3wks x 4
Paclitaxel 80 mg/m2 qwk x 12
Enrolled 181 ptsN= 75 for TNBC56% Node positive
pCR rates
CP-CEF P-CEF0
20
40
60
80
100
32%17%
All patients
pC
R r
ate
(%)
CP-CEF P-CEF0
20
40
60
80
100
62%
26%
TNBC patients
pC
R r
ate
(%)
Primary Endpoint
P =0.04
pCR rates by EGFR
expression
EGFR- EGFR+
p=0.010
(%)
0All AllCP CPP P
11.518.2
6.7
45.0
63.6
22.220
40
60
80
p=0.040
p= N.S.
pC
R r
ate
Results
PARP Inhibitors in Development
• Olaparib (Astra Zeneca) PO• Veliparib (ABT888 - Abbvie) PO• BMN-673 (Biomarin) PO• Niraparib (MK-4827) PO• CEP 9722 (Cephalon) PO• GPI 21016 (MGI Pharma) PO• Iniparib (BSI 201 – Sanofi-Aventis) IV• Rucaparib aka AGO 14699 (Pfizer) IV• INO 1001 (Inotek – Genentech/Roche) IV
• Others?
Opciones de manejo:Inhibidores del PARP
PARP 1:Prot. nuclear que va al sitio donde se hallael DNA dañado y cataliza la transferenciade ADP-ribosas del NAD+ para modularla reparación del DNA.
Paciente con BRCA mutado:No tienen mecanismo de reparación del DNApor este medio.
Opciones de manejo:Inhibidores de PARP
DNADNA
dañadoREPARACIÓN
BRCA
Reposiciónde
nucleótidos
EVENTO MUTADO
PARP
Mechanisms of Synthetic Lethality-PARP-1
60Image from: Iglehart JD, Silver DP. Synthetic Lethality-A new direction in cancer-drug development. NEJM 2009; 361 (2) ; 189-191. 2009 Massachusetts Medical Society.
All rights reserved. Permission requested.
Rugo H, et al. SABCS 2013
I-Spy 2 Trial Neoadjuvant Veliparib/Carboplatin followed by wPac/AC
Parp Inhibitors
One trial in metastatic TNBC patients.
Gemcitabine/carboplatin
Improvement in tumor response and survival with Parp inhibitors
Opciones de manejo:Inhibidores de PARP
DNADNA
dañadoREPARACIÓN
BRCA
Reposiciónde
nucleótidos
EVENTO MUTADO
PARP
Inhibidordel
PARP
Paclitaxel + Trastuzumab* +
New Agent A
Paclitaxel + New Agent C
Patient is on Study
Paclitaxel+ Trastuzumab
Paclitaxel + Trastuzumab* +
New Agent B
Paclitaxel
Paclitaxel + New Agent E
AC
ACHER 2 (+)
HER 2(–)
Randomize
Randomize
Surgery
Surgery
Learn and adapt from each patient as
we go along
Paclitaxel + New Agent F
Paclitaxel + Trastuzumab* +
New Agent C
Paclitaxel + New Agent DPaclitaxel +
New Agent GH
Paclitaxel + Trastuzumab* +
New Agent F
MRI
ResidualDisease(Pathology)
Key
64
I-SPY 2 TRIAL:
Learn, Drop, Graduate, and Replace Agents Over Time
Veliparib/Carboplatin GRADUATES in the Triple Negative Signature
SIGNATURE
Estimated pCR Rate(95% probability interval) Probability
Veliparib +Carbo is
Superior to Control
Predictive Probability of Success in
Phase 3Veliparib/
CarboConcurrent
Control
All HER2- 33% (22-43%)
22% (10-35%)
92% 55%
HR+/HER2- 14% (4-27%)
19% (6-35%)
28% 9%
HR-/HER2- 52% (35-69%)
26% (11-40%) 99% 90%
Rugo et. al. SABCS 2013
EGFR inhibitors
Two trials in metastatic breast cancer
Irinotecan/carboplatin + cetuximab
Cetuximab alone or with carboplatin
EGFR Inhibition for TNBC
• TNBC is strongly associated with EGFR expression• EGFR inhibitors combined with platinum • Current data are conflicting
TBCRC 001(n=102)
O’Shaugnessy et al(n=78)
Cetuximab Carboplatin + Cetuximab
Irinotecan + Carboplatin
Irinotecan + Carboplatin + Cetuximab
ORR,% 6 18 49 30
Clinical benefit, % 10 27 NR NR
PFS, mo 2 5.1 4.7
Efficacy data from phase II trials
NR=not reported; PFS=progression-free survival; RR=response rate; TBCRC=Translational Breast Cancer Research Consortium
Carey et al. ASCO 2008; abstr 1009; O’Shaughnessy et al. SABCS 2007; abstr 308.
TNBC recent perspectivesLooking for a target...
• Other Chemotherapy?• Androgen Receptor• PI3K pathway alterations• EGFR inhibitors• Anti-angiogenics• Src inhibitors• C-Kit alteration• Clinical Trail• Likely will need combos
Opciones de manejo:Otras “potenciales” opciones
1. Anti – EGFR:cetuximab
2. Inhibidores de Tirosin-kinasa: sunitinib
3. Anti – mTOR:everolimus
4. Antiandrógenos: bicalutamida
Santana-Davila R, Pérez EA - 2010
TNBC: potential therapeutic targets
Mayer I A et al. Clin Cancer Res 2014;20:782-790
©2014 by American Association for Cancer Research
SWOG Proposed Study
R
TNBC Post NAC PT1C or N+
N=400
Placebo x 1 year
MK3475 x 1 yearAnti-PD1 antibody
Primary endpoint:
DFS
A randomized, phase III trial to evaluate the efficacy and safety of MK-3475 as adjuvant therapy for triple receptor-negative breast cancer with >1 cm residual invasive cancer or any positive lymph nodes
(>pN1mic) after neoadjuvant chemotherapy
SAFIR 01 Study
Outcomes
Andre F, et al. Lancet Oncol 2014
Targets addressed:
• PI3KCA mutation
• EGFR amplification
• AKT mutation
• FGFR amplification
• IGF-1R amplificationOverall Benefit Rate:12/407 (3%)Response Rate: 4/407 (1%)
17 Targeted Regimens
Novel Agents in Development for TNBC• Met inhibitor: ARQ197, onartuzumab
(Metmab), foretinib• PI3K and/or inhibitor: BKM 120,
temsirolimus (+ neratinib)• HDAC inhibitors: entinostat, vorinosat• Demethylating agents: azacitidine
(+ entinostat)• PARP inhibitors: ABT-888, E7449,
Biomarin-BMN673, AZD2281, rucaparib• Olaparib+ BKM120; • Angiogenesis inhibitor: cediranib
(+ olaparib), ramicurumab, IMC18F1, foretenib, sorafenib
• Hsp90 inhibitors: ganetespib • Aurora kinase inhibitors: ENMD 2076• Androgen Receptor Blockers:
enzalutamide
• EGF inhibitors: erlotinib (+ metformin), apatanib
• Lucitanib (FGFR+VEGF inhibitor)• Masitinib (C-Kit inhibitor)• MEK inhibitors: GSK1120212• Wnt inhibitor: LGK974• CDK inhibitor: dinaciclib, P276-00• FMS-Kit inhibitor: PLX3397 • Apoptosis inducer: LCL161 (deactivating
inhibitor of apoptosis proteins) • Immunotherapy: MUC1 vaccine,
adoptive cellular therapy (DC-CIK)• Cytotoxics: SN38 -NK012, AEZS-108
(LHRH-dox); • Checkpoint inhibitors (anti PD-1, anti
PDL-1)
TNBC: Conclusions
• TNBC is a recognized distinct subtype of BC– ER, PR, HER2-negative by IHC
• Surrogate of basal-like BC– More aggressive biology (morphology, clinical, molecular)
• TNBC responds to a variety of CT agents although no specific standard regimen or agent can be singled out
• TNBC has no identified specific therapeutic target• Represents an heterogeneous group of tumors probably
with different response patterns to different treatments– Introduction of novel agents (PARPi, others) ?– Biomarkers: RAD-51, Neuropilin ?
En conclusión…
• Presente como cáncer de intervalo• Poca asociación entre tamaño de tumor y estado axilar.
• Metástasis tempranas y agresivas.• Recurrencia pico entre 1º y 3º años del diagnóstico.
• La recurrencia local no predice recaída a distancia.
En conclusión…
• Más prevalente en jóvenes.• Fuerte asociación con obesidad.• Alta prevalencia de mets cerebrales.• La mayoría de las muertes son a 5 años.• Altamente quimiosensible.• Todos los tratamientos en estudios.
Triple Negative Breast Cancer
• Represents a subtype of breast cancer with unique molecular and clinical characteristics .
• Characterized by more aggressive clinicopathologic features including younger age, higher mean tumor size, and higher-grade tumors .
• More likely to occur among premenopausal women of African-American descent .
• Association with BRCA1 mutation status. • More likely to develop a recurrence during the
first 3 years following therapy • More aggressive visceral and soft-tissue relapse
and less common bone recurrence.• High response to systemic chemotherapy.
103
Future Directions
• Increase participation in clinical trials.• Design and implement cancer prevention trials
applicable to at risk populations.• Increase understanding of risk factors and
biology underlying triple-negative breast cancer.• Improving treatment strategies. • Continuous review of current methods.
104
POR FAVORENCUENTREN
UNA CURA ANTES QUE
DESARROLLE
Gracias!
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