São Paulo, August 2014
Triple Negative Breast Cancer
Do we have a “better” chemotherapy regimen?
Carlos H. Barrios, M.D. | PUCRS School of Medicine| Porto Alegre, Brazil
Potential Conflicts of Interest
• No financial conflicts to declare
• Consulting and research support
– Roche, Astra Zeneca, Sanofi, Merck.
Terminal Duct Lobular Unit (TDLU)
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
Smalley M. Ashworth A. Nat. Cancer Reviews 2003;3,832-844
Gene Expression of Breast Cancer
Basal- like Group
• Low HER2 cluster
expression
HER2 cluster
Basal gene
cluster
Luminal (hormone
receptor-related)
cluster
• Low ER (and related
genes) expression
Usually “triple negative”
• High basal cluster
– basal CK (5, 6, 14, 17)
– EGFR, c-kit
– others…
• Very proliferative
• Often p53 mutant
Proliferation
cluster
• Evidence of genomic
instability
Basal-like Breast Cancer and
Genomic Instability
Array CGH
in 89 LABC:
% DNA copy
number
alterations
Red=gain
Green=loss
Genome-wide
aberrations
Chromosome
Bergamaschi et al, Genes Chromosomes Cancer, 2006.
Triple-Negative vs. Basal-Like: Definitions
ER- / PR- / HER2~15% of all breast carcinomas
Poorly differentiated
Express CK 5/6, 17, EGFR (+)
1.
2.
3.
4.
5.
• Triple negative
but not basal
• Definition by IHC
• Includes other
histologies
(medullar,
adenoid cystic)
• 10-30% can also
include “claudinlow,” a subtype
notable for high
expression of
stem cell
markers
• 90% of TNBC do
not have BRCA
mutations
~75% of TNBC have
Basal gene expression
Triple
Negative
Pal & Mortimer. Maturitas 2009;
Gluz et al. Ann Oncol 2009;
Anders & Carey. Oncology 2008.
Young et al. BMC Cancer 2009
Schneider, B. P. et al. Clin Cancer Res 2008;14:8010-8018
Basal
BRCA 1-2
• 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+
Deconstructing the Molecular Portraits of Breast Cancer:
TNBC gene expression profiles
Prat A, Perou C. Molecular Oncology, Nov 24, 2010 (PMID: 21147047)
Genomic Analyses of Six Cancer Types Identify
Basal-like Breast Cancer as a Unique Molecular Entity
55% of Basal-like breast
tumors were found more
similar to SQCLC than to
non-basal breast cancers.
Luminal A (76%), Luminal B (72%)
and HER2-enriched (17%) breast
tumors.
Prat A, et al. Sci Rep 2013
Lehmann B, et al. JCI, 121:2750, 2011
Number of samples with aberrations
Clinically targetable pathways in TNBC
40
TSC1
AKT3
AKT2
AKT1
RAPTOR
RICTOR
30
~90% of all patients
had an aberration in
at least one of these
pathways
RB1
AURKA
CDNK2A
20
CCNE1
PTEN
CCND3
PIK3R1 BRCA2
10
PI3K/mTOR
PI3K/mTOR
inhibitors
NF1
BRCA1
PIK3CA
0
ATM
DNA Repair
DNA-repair
targeting
agents
MET
CCND2
CRAF
BRAF
KRAS
Ras/MAPK
RAF/MEK
inhibitors
FGFR4
CCND1
CDK6
IGF1R
CDK4
Cell Cycle
Cell cycle/mitotic
spindle inhibitors
FGFR1
KIT
FGFR2
EGFR
GFRs
Targeted RTK
inhibitors
Arteaga C, et al. Vanderbilt
Take Home
• TN Breast cancers represent an heterogeneous
group of diseases
• Highly complex and genetically unstable
• Should consider the challenge of a molecular
vs. a histological classification
Basal-like BC Responds to Conventional Chemotherapy
Pathologic Complete Response:
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%
• Basal-like / triple negative breast cancer responds
to primary chemotherapy.
Explanation of higher response but worse outcome?
Rouzier, et al. Clin Cancer Res, 2005
Carey LA, et al. Clin Cancer Res 2007
TNBC: Responsiveness to Neoadjuvant
Conventional Chemotherapy
TNBC is 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
pCR/non-TNBC
pCR/TNBC
RD/non-TNBC
RD/TNBC
0.4
1
2
3
4
5
Yrs After Surgery
6
7
Liedtke C, et al. J Clin Oncol. 2008;26:1275-1281.
TIL are prognostic in TNBC treated with
adjuvant chemotherapy (BIG 02-98)
RCT 2009 patients (256 TNBC)
A-CMF vs. AC-CMF
Highest TIL in HER2 and TNBC
Prognostic correlation in TNBC
(not in the other subtypes)
Continuous: better with each 10%
Binary: LPBC (>50% better)
Loi S et al. JCO 2013
Take Home
• TN Breast cancers respond to conventional
chemotherapy
• Strong prognostic value of Response to
Neoadjuvant Chemotherapy
• Strong prognostic value of TIL
Bevacizumab for TNBC
Trial / Arm
Median PFS (m) in TNBC
Subset
E2100
Paclitaxel (n=110)
5.3
Paclitaxel + bevacizumab (n=122)
10.6
AVADO
Docetaxel + placebo (n=52)
5.4
Docetaxel + bevacizumab 15 mg/kg (n=58)
8.2
RIBBON-1
Taxane/anthracycline + placebo (n=46)
6.2
Taxane/anthracycline + bevacizumab (n=96)
6.5
Capecitabine + placebo (n=50)
4.2
Capecitabine + bevacizumab (n=87)
6.1
ATHENA
Taxane-based regimen + bevacizumab (n=577)
*Median PFS vs non-TNBC subgroup.
No Survival data available in the TNBC subset
7.2*
EGFR Inhibition for TNBC
Efficacy data from phase II trials
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
5.1
4.7
PFS, mo
2
• TNBC is strongly associated with EGFR expression
• EGFR inhibitors combined with platinum
• Current data are conflicting
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.
I-Spy 2 Trial
Neoadjuvant Veliparib/Carboplatin followed by wPac/AC
Rugo H, et al. SABCS 2013
CALGB/Alliance 40603
pCR in Breast and Axilla
TNBC Patients
ER 1-10% (6%)
Age <60
T2-T3
LN+
Grade III
83%
86%
55%
86%
Sikov W, et al. SABCS 2013
The Role of Carboplatin in TNBC (Neo)
Trial
N
CALGB 40603 443
Standard
Chemotherapy
Chemo +
Carboplatin
P-value
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.
Platinum-sensitivity of BRCA1mut TNBCs
Trial
Byrski
Silver
Ryan
•
•
Characteristics
Regimen
n°
pRC
BRCA1+mut carriers
Not-platinum-based
90
14 (16%)
BRCA1+mut carriers
CDDP 75mg/m2 x4
12
10 (83%)
Sporadic TNBCs
(not BRCA1+mut
carriers)
CDDP 75mg/m2 x4
26
4 (15%)
BRCA1mut carriers
CDDP 75mg/m2 x4
2
2 (100%)
Sporadic TNBCs (not
BRCA1+mut
carriers)
CDDP 75mg/m2 x4 +
bevacizumab 15 mg/kg
q3wk x3
51
8 (16%)
Neo-adjuvant setting:
– Retrospective trials suggest platinum-based regimens activity;
– Data from prospective trials on TNBCs are controversial;
Metastatic TNBCs:
– control arm in BALI-1 study with DDP alone – 10% RR
Byrski, JCO 2009; Silver JCO 2009: Baselga ESMO 2010; Isakoff SABCS 2010
Phase II Trial of Olaparib in BRCA Deficient MBC
•Multicenter POC phase II, single-arm sequential cohort
•Confirmed BRCA1 or BRCA2 mutation
•Advanced refractory breast cancer
(stage IIIB/IIIC/IV after failure of ≥1 prior CT for advanced disease)
ITT cohort
Overall Response Rate, n (%)
Complete Response, n (%)
Partial Response, n (%)
Olaparib
400 mg bid
(n=27)
Olaparib
100 mg bid
(n=27)
11 (41)
6 (22)
1 (4)
0
10 (37)
6 (22)
MTD, maximum tolerated dose (determined during Phase I evaluation)
Audeh et al. ASCO 2009. Abstract #5500
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
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 ?