targeted therapy for breast cancer

1. Jo Anne Zujewski, MD
Cancer Therapy Evaluation Program
Division of Cancer Diagnosis and Treatment
National Cancer Institute
May, 2011
Targeted Therapy for Breast Cancer

2. No surgery
mastectomy
chemoTx + antiER
chemoTx + antiER + targeted
Incremental Benefit

3. No surgery
mastectomy
chemoTx + antiER
chemoTx + antiER + targeted
Incremental benefit
Each incremental step assumed that no pt is
cured with the previous step
• Significant overtreatment
• Necessity to conduct large trials
to demonstrate small benefit

4. PNAS 2005
Molecular profiling

5. Subtypes and Prognosis
Sorlie T et al, PNAS 2001

6. RS = + 0.47 x HER2 Group Score
- 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
Oncotype DX 21 Gene
Recurrence Score (RS) Assay
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
ESTROGEN
ER
PR
Bcl2
SCUBE2
INVASION
Stromolysin 3
Cathepsin L2
HER2
GRB7
HER2
BAG1
GSTM1
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
CD68
16 Cancer and 5 Reference Genes From 3 Studies
Category RS (0 – 100)
Low risk RS < 18
Int risk RS ≥ 18 and < 31
High risk RS ≥ 31

7. B-20 Summary
• 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
RS < 18 RS 18-30 RS ≥ 31
0 2 4 6 8 10 12
Years
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
DRFS
Low Risk Patients (RS < 18)
Tam + Chemo
Tam
0 2 4 6 8 10 12
Years
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
DRFS
Int Risk (RS 18 - 30)
Tam + Chemo
Tam
0 2 4 6 8 10 12
Years
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
DRFS
High Risk Patients (RS  31)
Tam + Chemo
Tam

8. Recurrence Score as a Continuous Predictor
0%
5%
10%
15%
20%
25%
30%
35%
40%
0 5 10 15 20 25 30 35 40 45 50
Recurrence Score
Distant
Recurrence
at
10
Years
Low Risk Group High Risk Group
Intermediate
Risk Group
My RS is 30, What is the
chance of recurrence within
10 yrs?
95% CI

9. Schema: TAILORx
17
Node Neg, ER (+), Breast Cancer
RS < 10
Hormone
Therapy
Registry
N=1625
RS 11 – 25
Randomize
Hormone Rx
vs.
Chemotherapy
+ Hormone Rx
N=6908
RS > 25
Chemotherapy
+
Hormone Rx
N=1731
21-gene RS
n=11,233
Register
Specimen
banking
Accrual complete as of 10/06/2010

10. Breast Cancer:
Stable from Preneoplasia to Metastasis
245 DCIS in
population-based study:
Livasy, Human Pathol 2007
Subtype N (%)
Basal-like 19 (8%)
Luminal A 149 (61%)
Luminal B 23 (9%)
HER2+/ER- 38 (16%)
Unclass. 16 (6%)
Molecular subtype persists before and after
therapy and in metastases:
*
*
*
Weigelt et al., Cancer Res, 2005
4 studies find basal-like
present but uncommon in
DCIS (5-10%)

11. HER2 cluster
Basal gene cluster
Luminal (hormone
receptor-related)
cluster
Proliferation cluster
Basal-like Breast Cancer
• Comprise 15-20% of tumors
• Low ER (and related genes)
expression
• Low HER2 cluster expression
 usually “triple negative”
• High basal cluster
– basal cytokeratins
– EGFR
– c-kit
– others…
• Very proliferative
• Often p53 mutant
• Evidence of genomic
instability

12. Surrogates: Clinical Phenotypes versus
Molecular Subtypes
Triple negative
and
Basal-like
Basal but not triple
negative
15-40% are ER+,
PR+, or HER2+
Triple negative
but not basal
10-30%
Can also include
“claudin-low”, a
subtype notable
for high expression
of stem cell
markers
“Triple negative” (ER negative, PR negative, and HER-2
negative) breast cancer is mostly the basal-like subtype

13. 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

14. Hereditary Basal-like Sporadic Basal-like
BRCA1
Xiso XIST
Loss
Triple Neg
Cancer
Genomic
Instability
?
?
BRCA1
Xiso XIST
Loss
Triple Neg
Cancer
Genomic
Instability
Courtesy J. Garber
BRCA1-Associated and
Sporadic Basal-like Breast Cancer

15. Characteristics Hereditary BRCA1 Triple Negative/Basal-Like1,2,3
ER/PR/HER2 status Negative Negative
TP53 status Mutant Mutant
BRCA1 status Mutational inactivation* Diminished expression*
Gene-expression pattern Basal-like Basal-like
Tumor histology
Poorly differentiated
(high grade)
Poorly differentiated
(high grade)
Chemosensitivity to DNA-
damaging agents
Highly sensitive Highly sensitive
TNBC Shares Clinical and Pathologic Features with BRCA-1-Related Breast
Cancers
3Sorlie et al. Proc Natl Acad Sci U S A 2001;98:10869-74
4 Miyoshi et al. Int J Clin Oncol 2008;13:395-400
*BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID44
1Perou et al. Nature. 2000; 406:747-752
2Cleator et al.Lancet Oncol 2007;8:235-44
1

16. PARP Inhibitor Treatment Strategies
1. Sensitization to DNA damaging therapy
2. ‘Chemical synthetic lethality’ in
genetically susceptible tumors
• BRCA1, BRCA2, others?

17. DNA Damage Repair Pathways
Double-
strand
breaks
(DSBs)
Recombination
repair
ATM
BRCA
DNA-PK
HR NHEJ
Type of
damage:
Repair
pathway:
Repair
enzymes:
Bulky
adducts
Insertions
& deletions
O6-
alkylguanine
Nucleotide-
excision
repair
Mismatch
repair
Direct
reversal
XP,
polymerases
MSH2,
MLH1
AGT

18. PARP-1 Inhibition Increases DNA DS Damage
PARP
Inhibition of
PARP-1
prevents
recruitment of
repair factors
to repair SSB
XRCC1
LigIII
PNK 1
pol β
Replication
(S-phase)
DNA DSB
DNA SSB

19. Cell
survival
Base Excision Repair
Synthetic Lethality:
Selective effect of PARP-1 inhibition on cancer
cells with BRCA1 or BRCA2 mutation
Homologous Recombination
DNA Damage
PARP
Inhibitor
BRCA
Mutation
Cancer cell
death

20. HER-2 as a Target for Therapy: NeoALTTO
HER-2
nucleus
cancer cell
cell division
Trastuzumab (Herceptin)
Anti-HER-2 Antibody
Lapatinib (Tykerb)
Dual HER-1/HER-2
Tyrosine Kinase Inhibitor
•Growth factor receptor: Overexpressed in 20-25% of breast
cancers
•Neo-ALTTO: pre-operative study of trastuzumab; lapatinib; or the
combination
pCR: COMBINATION 51.3%
Trastuzumab 29.5%
Lapatinib 24.7%

21. Another HER-2 Targeted Therapy in Development
Trastuzumab-DM1 (T-DM1)
Trastuzumab
Mertansine: anti-tubulin

22. The Truth About Targeted Therapy
• 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
Citri and Yarden, Nat Rev Mol Cell Biol 2006
EGFR
Clean preclinical model Messy clinical situation
Multiple ligands
Heterodimerization
Mutated receptors
Cleaved receptors
Horizontal activation
Kinase alterations
Epigenetic alterations
Alternate signaling
pathways….
Courtesy of Lisa Carey

23. Copyright ©2008 American Association for Cancer Research
Tan, S.-H. et al. Clin Cancer Res 2008;14:8027-8041
Fig. 2
Predicting response to Endocrine therapy

24. The Host: Metabolic factors
Body Size in Operable Breast Cancer

25. Obesity – Breast Cancer
Interaction of Estrogen and Insulin / IGF Mechanisms
Adipose
Tissue
 estrogens  insulin  IGFBP-1
 IGF-I
 SHBG
(free)
+
+ +
+
+
+
+
+
+



*
*
Proliferation
Anchorage Independent Growth
Reduced Apoptosis
* PI3K, ras-raf-MAP Kinase signalling pathways
+
inflammatory
markers
adipocytokines
(e.g. leptin, TNF)
+
+

26. Molecular Action of Insulin
Adapted from Vigneri P et al., Endocr Relat Cancer 2009 Jul 20 (epub ahead of print)

27. 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

28. Copyright © American Society of Clinical Oncology
Goodwin P J et al. J Clin Oncol 2009; 27:3271-3273
Mechanism of Metformin Action

29. Pathologic Complete Response Between Study Groups
(Metformin, No Metformin, Non-Diabetic)
Jiralersprong S et al. J Clin Oncol 2009; 20:3297-3302

30. NCIC CTG MA.32
Multicentre Phase III Randomized Double-Blind Placebo
Controlled Trial in Early Stage Breast Cancer
Metformin
850 mg po bid X 5 years
()
Identical Placebo
One caplet po bid X 5 years
R
A
N
D
O
M
I
Z
E
FUNDED BY: NCI (US), CCS, BCRF, Apotex Canada

31. Biological Information Flow
Epigenetics
Gene Expression
Genetics
MICROENVIRONMENT