Targeted Therapy for Breast Cancer
Jo Anne Zujewski, MD
Cancer Therapy Evaluation Program
Division of Cancer Diagnosis and Treatment
National Cancer Institute
May, 2011
Incremental Benefit
chemoTx + antiER + targeted
chemoTx + antiER
mastectomy
No surgery
Incremental benefit
chemoTx + antiER + targeted
Each incremental step assumed that no pt is
chemoTx + antiER
cured with the previous step
mastectomy
No surgery
• Significant overtreatment
• Necessity to conduct large trials
to demonstrate small benefit
Molecular profiling
PNAS 2005
Subtypes and Prognosis
Sorlie T et al, PNAS 2001
Oncotype DX 21 Gene
Recurrence Score (RS) Assay
16 Cancer and 5 Reference
Genes
From
3
Studies
RS = + 0.47 x HER2 Group Score
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
ESTROGEN
ER
PR
Bcl2
SCUBE2
GSTM1
INVASION
Stromolysin 3
Cathepsin L2
HER2
GRB7
HER2
- 0.34 x ER Group Score
+ 1.04 x Proliferation Group Score
+ 0.10 x Invasion Group Score
+ 0.05 x CD68
- 0.08 x GSTM1
- 0.07 x BAG1
BAG1
CD68
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
Category
RS (0 – 100)
Low risk
RS < 18
Int risk
RS ≥ 18 and < 31
High risk
RS ≥ 31
B-20 Summary
RS ≥ 31
RS 18-30
1.0
1.0
0.9
0.9
0.9
0.8
0.8
0.8
0.7
0.7
0.7
0.6
0.6
0.6
0.5
DRFS
1.0
DRFS
DRFS
RS < 18
0.5
0.5
0.4
0.4
0.4
0.3
0.3
0.3
0.2
0.2
Low Risk Patients (RS < 18)
Tam + Chemo
Tam
0.1
0.1
0.0
0
2
4
0.2
Int Risk (RS 18 - 30)
Tam + Chemo
Tam
6
Years
8
10
12
High Risk Patients (RS  31)
Tam + Chemo
Tam
0.1
0.0
0.0
0
2
4
6
Years
8
10
12
0
2
4
6
8
Years
• Patients with tumors that have high Recurrence
Scores have a large absolute benefit of
chemotherapy (similar results with CMF and MF)
• Patients with tumors that have low Recurrence
Scores derive minimal, if any, benefit from
chemotherapy
10
12
Recurrence Score as a Continuous Predictor
40%
Intermediate
Risk Group
Distant Recurrence at 10 Years
Low Risk Group
35%
High Risk Group
My RS is 30, What is the
chance of recurrence within
10 yrs?
30%
25%
20%
15%
10%
5%
95% CI
0%
0
5
10
15
20
25
30
Recurrence Score
35
40
45
50
Schema: TAILORx
Node Neg, ER (+), Breast Cancer
Register
Specimen
banking
RS < 10
Hormone
Therapy
Registry
N=1625
21-gene RS
n=11,233
RS 11 – 25
Randomize
Hormone Rx
vs.
Chemotherapy
+ Hormone Rx
N=6908
Accrual complete as of 10/06/2010
RS > 25
Chemotherapy
+
Hormone Rx
N=1731
17
Breast Cancer:
Stable from Preneoplasia to Metastasis
245 DCIS in
population-based study:
Subtype
Molecular subtype persists before and after
therapy and in metastases:
N (%)
Basal-like
19 (8%)
Luminal A
149 (61%)
Luminal B
23 (9%)
HER2+/ER-
38 (16%)
Unclass.
16 (6%)
*
*
Livasy, Human Pathol 2007
4 studies find basal-like
present but uncommon in
DCIS (5-10%)
*
Weigelt et al., Cancer Res, 2005
Basal-like Breast Cancer
• Comprise 15-20% of tumors
• Low ER (and related genes)
expression
HER2 cluster
Basal gene cluster
• Low HER2 cluster expression
 usually “triple negative”
• High basal cluster
Luminal (hormone
receptor-related)
cluster
–
–
–
–
basal cytokeratins
EGFR
c-kit
others…
• Very proliferative
• Often p53 mutant
Proliferation cluster
• Evidence of genomic
instability
Surrogates: Clinical Phenotypes versus
Molecular Subtypes
Triple negative
but not basal
10-30%
Can also include
“claudin-low”, a
subtype notable
for high expression
of stem cell
markers
Basal but not triple
negative
15-40% are ER+,
PR+, or HER2+
Triple negative
and
Basal-like
“Triple negative” (ER negative, PR negative, and HER-2
negative) breast cancer is mostly the basal-like subtype
Defining the biology of ER- breast cancer
• Aberrant expression of transcription factors and growth
factor receptors has been correlated with basal-like
(triple negative) subtype of breast cancer
• Mechanisms of ER loss can vary:
– ER promoter methylation in ER- breast cancer (25%)
– Src activated ER degradation
• ER- tumors share similarities with BRCA-1 associated
breast cancer
– Clinical & pathological features
– Gene profiling data
BRCA1-Associated and
Sporadic Basal-like Breast Cancer
Hereditary Basal-like
Sporadic Basal-like
BRCA1
BRCA1
?
?
Xiso XIST
Loss
Triple Neg
Cancer
Genomic
Instability
Xiso XIST
Loss
Triple Neg
Cancer
Genomic
Instability
Courtesy J. Garber
TNBC Shares Clinical and Pathologic Features with BRCA-1-Related Breast
Cancers
Characteristics
ER/PR/HER2 status
TP53 status
BRCA1 status
Gene-expression pattern
Tumor histology
Chemosensitivity to DNAdamaging agents
Hereditary BRCA1
Triple Negative/Basal-Like1,2,3
Negative
Negative
Mutant
Mutant
Mutational inactivation*
Diminished expression*
Basal-like
Basal-like
Poorly differentiated
(high grade)
Poorly differentiated
(high grade)
Highly sensitive
Highly sensitive
*BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID44
1Perou
et al. Nature. 2000; 406:747-752
et al.Lancet Oncol 2007;8:235-44
2Cleator
3Sorlie
4
et al. Proc Natl Acad Sci U S A 2001;98:10869-74
Miyoshi et al. Int J Clin Oncol 2008;13:395-400
1
PARP Inhibitor Treatment Strategies
1. Sensitization to DNA damaging therapy
2. ‘Chemical synthetic lethality’ in
genetically susceptible tumors
•
BRCA1, BRCA2, others?
DNA Damage Repair Pathways
Type of
damage:
Repair
pathway:
Doublestrand
breaks
(DSBs)
ATM
BRCA
O6alkylguanine
Insertions
& deletions
Mismatch
repair
Recombination
repair
HR
Repair
enzymes:
Bulky
adducts
NHEJ
DNA-PK
Nucleotideexcision
repair
XP,
polymerases
Direct
reversal
MSH2,
MLH1
AGT
PARP-1 Inhibition Increases DNA DS Damage
DNA SSB
PNK 1
XRCC1
pol β
LigIII
PARP
Inhibition of
PARP-1
prevents
recruitment of
repair factors
to repair SSB
Replication
(S-phase)
DNA DSB
Synthetic Lethality:
Selective effect of PARP-1 inhibition on cancer
cells with BRCA1 or BRCA2 mutation
DNA Damage
Base Excision Repair
PARP
Inhibitor
Cell
survival
Homologous Recombination
BRCA
Mutation
Cancer cell
death
HER-2 as a Target for Therapy: NeoALTTO
•Growth factor receptor: Overexpressed in 20-25% of breast
cancers
•Neo-ALTTO: pre-operative study of trastuzumab; lapatinib; or the
combination
HER-2
cancer cell
Trastuzumab (Herceptin)
Anti-HER-2 Antibody
pCR: COMBINATION 51.3%
Trastuzumab 29.5%
Lapatinib 24.7%
nucleus
Lapatinib (Tykerb)
Dual HER-1/HER-2
Tyrosine Kinase Inhibitor
cell division
Another HER-2 Targeted Therapy in Development
Trastuzumab-DM1 (T-DM1)
Trastuzumab
Mertansine: anti-tubulin
The Truth About Targeted Therapy
EGFR
Citri and Yarden, Nat Rev Mol Cell Biol 2006
Clean preclinical model
Multiple ligands
Heterodimerization
Mutated receptors
Cleaved receptors
Horizontal activation
Kinase alterations
Epigenetic alterations
Alternate signaling
pathways….
Messy clinical situation
• Cancers have redundant, modular pathways
• Answers will not come from purely clinical trials in unselected
populations.
• Real understanding of how to target will require more tissue-based
studies and global collaborations
Courtesy of Lisa Carey
Fig. 2
Predicting response to Endocrine
therapy
Tan, S.-H. et al. Clin Cancer Res 2008;14:8027-8041
Copyright ©2008 American Association for Cancer Research
The Host: Metabolic factors
Body Size in Operable Breast Cancer
Obesity – Breast Cancer
Interaction of Estrogen and Insulin / IGF Mechanisms
inflammatory
markers
+
+
Adipose
Tissue
+
adipocytokines
(e.g. leptin, TNF)
+
 estrogens

 insulin

 SHBG
(free)
+
+
 IGFBP-1
+
 IGF-I

+
+
+
*
+
Proliferation
Anchorage Independent Growth
Reduced Apoptosis
* PI3K, ras-raf-MAP Kinase signalling pathways
*
+
Molecular Action of Insulin
Adapted from Vigneri P et al., Endocr Relat Cancer 2009 Jul 20 (epub ahead of print)
Potential Treatment Targets
Lifestyle
• Weight Loss – LISA
• Physical Activity
• Diet – fat (WHI / WINS / WHEL)
– calories
Physiologic
Mediators
• Insulin
• Glucose
• Adipocytokines (e.g. leptin)
Cellular
Mediators
•
•
•
•
AMPK
PI3K / AKT/ mTOR pathway
ras / raf / MEK pathway
Insulin / IGF receptors
Mechanism of Metformin Action
Goodwin P J et al. J Clin Oncol 2009; 27:3271-3273
Copyright © American Society of Clinical Oncology
Pathologic Complete Response Between Study Groups
(Metformin, No Metformin, Non-Diabetic)
Jiralersprong S et al. J Clin Oncol
2009; 20:3297-3302
NCIC CTG MA.32
Multicentre Phase III Randomized Double-Blind Placebo
Controlled Trial in Early Stage Breast Cancer
R
A
N
D
O
M
I
Z
E
Metformin
850 mg po bid X 5 years
()
Identical Placebo
One caplet po bid X 5 years
FUNDED BY: NCI (US), CCS, BCRF, Apotex Canada
Biological Information Flow
Epigenetics
Genetics
Gene Expression
MICROENVIRONMENT