breast cancer

2.  Clasificacion Genomica
 Diferentes Tipos de TNBC
 Importancia de la Clasificacion
 Caracteristicas Clinicas del TNBC
 Opciones de Tratamiento
 Opciones a Futuro

3. Cancer Growth and Metastases

4. Histologia del cancer de mama
Tipo Histológico
Frecuencia
(%)
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

6. TRATAMIENTO SISTÉMICO DEL CÁNCER DE
MAMA METASTÁSICO CON HER2 NORMAL

7. . Adapted from Hanahan and Weinberg. Cell. 2000;100:57.
Evading
apoptosis
Self-sufficiency in
growth signals
Tissue invasion
and metastasis
Limitless replicative
potential
Sustained
angiogenesis
Insensitivity to
antigrowth signals
Cancer
cells
Fundamental Hallmarks of Cancer

8. CLASIFICACION
MOLECULAR

10. Smalley M. Ashworth A. Nat. Cancer Reviews 2003;3,832-844
Luminal Epithelial Cells
Low molecular wt CK 7, 8, 18 and 19
Mucin, BCL2, Hormone Receptors
Basal Cells (Myoepithelial cells)
High molecular wt CK 5, 6, 14 and 17
SMA, Calponina, p63, P-caderin
Perou C, et al. Nature 460:747-752, 2000
Terminal Duct Lobular Unit (TDLU)

11. 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

13. Clasificación molecular del
Cancer de Mama
6 biomarcadores:
1. RE
2. RP
3. HER2
4. EGFR
5. CK5/6
6. Ki67
SJ Schnitt et al - 2010
St. Gallen 2011:
1. RE
2. RP
3. HER2
4. Ki67

14. Why is subtype important?
• Different outcomes
• Prognostic significance
• Selection of therapeutic
options
• Response to treatment

16. Hipótesis I: cada subtipo tiene SU célula de origen
Polyak K - 2007

17. Hipótesis II: una sola célula de origen para todos los subtipos,
y el fenotipo, determinado por eventos genéticos y epigenéticos.
Polyak K - 2007

18. 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 and
cytokeratins
Claudin-low
subtype
Basal-like
tumors
TNBC
ER-negative
PgR-negative
HER2-
negative
BRCA1 mutant
and BRCAness
Immune system
Different histologic
subtypes

19. Clasificación molecular del CMTN:
Subtipo “basal - like”
Perou CM, 2010

20. Perou CM, 2010
Clasificación molecular del CMTN:
Subtipo “claudin – low”

21. Aclarando conceptos…
Chacon R - 2010

22. 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 2009
5. Schneider, B. P. et al. Clin Cancer Res 2008;14:8010-8018
Triple-Negative vs. Basal-Like: Definitions
ER- / 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

23. “BRCAness”: Characteristics shared between BRCA-associated and sporadic breast
cancers.
Lisa A. Carey The Oncologist 2011;16:71-78
©2011 by AlphaMed Press

24. Lehmann B, et al. JCI, 121:2750, 2011

25. Prat A, Perou CM, 2009
En resumen….
(con respecto a la clasificación)

26. 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.

27. Any woman can get any type of breast cancer

28. Epidemiology
Carey LA et al - 2006
Carolina Breast Cancer Study
n = 1.424

29. 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.

30. 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 10
Yrs After First Surgery
Other (290 of 1421)
Triple negative (61 of 180)

31. 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

32. Opciones de manejo

33. 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)

34. 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.

35. 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

36. Johnston S R Clin Cancer Res 2010;16:1979-1987
©2010 by American Association for Cancer Research
Targeted Therapies

37. Numberofsampleswithaberrations
PI3K/mTOR DNA Repair Ras/MAPK Cell Cycle GFRs
0
10
20
30
40
TSC1
PIK3CA
PTEN
PIK3R1
RICTOR
RAPTOR
AKT1
AKT2
AKT3
BRCA1
BRCA2
ATM
RB1
AURKA
CDNK2A
CCNE1
CCND3
CCND2
CCND1
CDK6
CDK4
NF1
CRAF
BRAF
KRAS
EGFR
MET
IGF1R
KIT
FGFR1
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

38. Triple Negative Breast Cancer
Treatment
• Chemotherapy
• Parp inhibitors
• EGFR inhibitors
• Angiogenesis inhibitors
• Tyrosine Kinase inhibitors

39. Effectiveness of Chemotherapy
Triple Negative / Basal Disease

40. 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

42. 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:

43. Responsiveness to conventional chemotherapy.
Lisa A. Carey The Oncologist 2011;16:71-78
©2011 by AlphaMed Press

44. Opciones de manejo:
Platinos
Silver, DP et al - 2010

45. The Role of Carboplatin in TNBC (Neo)
Trial N
Standard
Chemotherapy
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.

46. Opciones de manejo:
Platinos
Silver, DP et al - 2010
Utilidad en
BRCA (+)

47. Adjuvant therapy for early breast cancer (90% are early at diagnosis).
Lisa A. Carey The Oncologist 2011;16:71-78
©2011 by AlphaMed Press

48. 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

49. 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

50. Angiogenesis
 Taxol + Avastin
in metastatic
patients
 Benefit in triple
negative patients

51. 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

52. Opciones de manejo:
Bevacizumab
Hudis CA, Gianni L - 2011
Beneficio en pacientes Triple Negativo

53. TNBC Patients
ER 1-10% (6%)
Age <60 83%
T2-T3 86%
LN+ 55%
Grade III 86%
CALGB/Alliance 40603
pCR in Breast and Axilla
Sikov W, et al. SABCS 2013

54. Opciones de manejo:
Ixabepilona
Pacientes MTTS
resistentes o progresadas
a antraciclinas y taxanos.
Hudis CA, Gianni L - 2011

55. Study Schema
Carboplatin
AUC5
q3wks x 4
Paclitaxel
80 mg/m2 qwk x 12
CP-CEF
P-CEF
HER2 (-) BC
Stage II/IIIA
18-70 years
PS 0/1
Good Organ
function
Written IC
SURGERY
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 pts
N= 75 for TNBC
56% Node positive

56. pCR rates 32%
17%
0
20
40
60
80
100
CP-CEF P-CEFpCRrate(%)
All patients
62%
26%
0
20
40
60
80
100
CP-CEF P-CEF
pCRrate(%)
TNBC patients
Primary
Endpoint
P =0.04
pCR rates by
EGFR
expression
EGFR- EGFR+
p=0.010
(%)
0
All AllCP CPP P
11.5
18.2
6.7
45.0
63.6
22.2
20
40
60
80
p=0.040
p= N.S.
pCRrate
Results

57. 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?

58. Opciones de manejo:
Inhibidores del PARP
PARP 1:
Prot. nuclear que va al sitio donde se halla
el DNA dañado y cataliza la transferencia
de ADP-ribosas del NAD+ para modular
la reparación del DNA.
Paciente con BRCA mutado:
No tienen mecanismo de reparación del DNA
por este medio.

59. Opciones de manejo:
Inhibidores de PARP
DNA
DNA
dañado
REPARACIÓN
BRCA
Reposición
de
nucleótidos
EVENTO MUTADO
PARP

60. Mechanisms of Synthetic
Lethality-PARP-1
60
Image 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.

61. Rugo H, et al. SABCS 2013
I-Spy 2 Trial
Neoadjuvant Veliparib/Carboplatin followed by wPac/AC

62. Parp Inhibitors
 One trial in metastatic
TNBC patients.

Gemcitabine/carboplatin
 Improvement in tumor
response and survival
with Parp inhibitors

63. Opciones de manejo:
Inhibidores de PARP
DNA
DNA
dañado
REPARACIÓN
BRCA
Reposición
de
nucleótidos
EVENTO MUTADO
PARP
Inhibidor
del
PARP

64. 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 D
Paclitaxel +
New Agent GH
Paclitaxel +
Trastuzumab* +
New Agent F
MRI
Residual
Disease
(Pathology)
Key
64
I-SPY 2 TRIAL:
Learn, Drop, Graduate, and Replace Agents Over Time

65. 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 3
Veliparib/
Carbo
Concurrent
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

66. EGFR inhibitors
Two trials in metastatic
breast cancer
 Irinotecan/carboplatin +
cetuximab
Cetuximab alone or with
carboplatin

67. 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.

68. TNBC recent perspectives
Looking 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

69. 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

70. TNBC: potential therapeutic targets
Mayer I A et al. Clin Cancer Res 2014;20:782-790
©2014 by American Association for Cancer Research

71. SWOG Proposed Study
R
TNBC
Post NAC
PT1C or N+
N=400
Placebo x 1 year
MK3475 x 1 year
Anti-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

72. SAFIR 01
Study
Outcomes
Andre F, et al. Lancet Oncol 2014
Targets addressed:
• PI3KCA mutation
• EGFR amplification
• AKT mutation
• FGFR amplification
• IGF-1R amplification
Overall Benefit Rate:12/407
(3%)Response Rate: 4/407 (1%)
17 Targeted Regimens

73. 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)

74. 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 ?

75. 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.

76. 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.

77. 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

78. 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