An overview on the targeted therapy options in breast cancer management

1. Targeted Therapy
in
Breast Cancer
Dr N Kannan

2. Turnaround:
decline in mortality rates
35
30
20
15
UK
Netherlands
Sweden
Italy
France
10
5
0
19
51
19
54
19
57
19
60
19
63
19
66
19
69
19
72
19
75
19
78
19
81
19
84
19
87
19
90
19
93
19
96
19
99
20
02
Mortality rate
25
Year
Veronesi et al 2005

4. Cancer is a multistep process
Cures need to attack many features of tumors
Creating own
instructions to grow
Ignoring body’s own
orders to stop growing

Avoiding
cell death
Growing new
blood supply
Tissue invasion
& metastasis
∞
Endless potential
to replicate
Adapted from Hanahan and Weinberg, Cell 2000

5. Six Essential Alterations
in Cell Physiology in Malignancy
Self-sufficiency in
growth signals
Evading
apoptosis
Hanahan & Weinberg,
Cell 100:57 (2000)
Insensitivity to
anti-growth signals
Targets for classical drugs?
Targets for novel drugs?
Sustained
angiogenesis
Tissue invasion
& metastasis
Limitless replicative
potential

6. Molecular alterations in breast cancer
progression
p53
BRCA1
BRCA2
Normal
Growth factor,
hormone, ER
deregulation?
Hyperplasia
Dysplasia
- p53
- BRCA 1, 2
+HER-2
+Cyclin-D
+myc
In Situ
Carcinoma
- p53
- BRCA 1, 2
+HER-2
+Cyclin-D
+myc
Invasive
Carcinoma

7. Targeted Therapy: A definition
• Drugs targeted at pathways, processes and
physiology which are uniquely disrupted in cancer
cells:
–
–
–
–
Receptors
Genes
Angiogenesis
Tumor pH
• these pathways etc. are not so distinct or unique
• Smart bombs can cause collateral damage

8. New cancer treatments present a complex picture…
Metastases
Inhibitors
AntiAngiogenesis
EGFR
inhibitors
mTOR
inhibitors
HIF
inhibitor
Proteasome
inhibitor
Tubulininteracting
agents
MUC-1
Directed
antibodies
Src
inhibitor
MEK
inhibitors
Raf
inhibitor
Death
Receptors
IGF-1R
inhibitors
HER2-R
inhibitors
Cell Cycle
inhibitors
HSP90
inhibitors
Mdm2
inhibitor
Pro-apoptotic
drugs
HDAC
Inhibitors
Farnesyl
Transferase
Inhibitors
Aurora Kinase
inhibitor
Kinesins

9. The Homing Pigeons
•
•
•
•
•
Hormonal receptor
HER2 inhibitors
Tyrosine Kinase Inhibitors
VEGF inhibitors
PARP inhibitors

10. Hormonal therapy

12. Rationale for Hormonal Treatment
of Breast Cancer
• Endocrine manipulation can:
– Decrease levels of estrogen that
stimulate tumor growth
– Block estrogen interaction with
estrogen receptors
• Less toxicity
• Response rates in metastatic disease:
– 30% of unselected patients
– ≥50% of ER-positive patients

13. Hormonal Therapies
(FDA indications)
• 1st line therapy:
– Tamoxifen, anastrozole (Arimidex), letrozole
(Femara)
• 2nd line therapy:
– Fulvestrant (Faslodex), toremifene (Fareston),
exemestane (Aromasin)
• “Palliative”
– Goserelin (LHRH analog, Zoladex)

14. Hormonal Therapies for Postmenopausal Metastatic
• Tamoxifen 20 mg po daily
• Aromatase inhibitors:
• anastrozole 1 mg po daily,
• letrozole 2.5 mg po daily
• exemestane 25 mg po daily
• Fulvestrant 250 mg IM q month
• Megace 40 mg po QID
• Aminoglutethimide 250 mg po QID with
hydrocortisone

15. Hormonal therapy for Premenopausal
Metastatic
• LHRH analog 7.5 mg depot every 28 days
• Tamoxifen 20 mg po daily
• May be considered with LHRH analog:
• anastrozole 1 mg po daily,
• letrozole 2.5 mg po daily
• exemestane 25 mg po daily
• Fulvestrant 250 mg IM q month ??
• Premenopausal dose may be higher?
• Megace 40 mg po QID

16. Treatment Sequence for Postmenopausal
Women With Metastatic Breast Cancer
First line
Second line
Antiestrogen or Nonsteroidal
Aromatase Inhibitor (AI)
Nonsteroidal AI or Antiestrogen
if response
Third line
Steroidal AI
if response
Fourth line
Progestin
if response
Fifth line
Androgen
No
Response
Chemotherapy

17. Proportion of patients
Breast cancer events in ER+/PgR+
subgroup (n=5704) (ATAC)
1.0
0.95
0.9
0.85
HR (95% CI)
0.8
A vs T
0
6
P-value
0.82 (0.65–1.03)
0.091
12
18
24
30
36
- Anastrozole
- Tamoxifen
- Combination
42
Time to event (months)
48
54

18. Proportion of patients
Breast cancer events in ER+/PgRsubgroup (ATAC)
1.0
0.95
0.9
0.85
0.8
0.75
HR (95% CI)
0.7
A vs T
0
6
0.48 (0.33–0.71)
- Anastrozole
- Tamoxifen
- Combination
P-value
<0.001
12
18
24
30
36
42
Time to event (months)
48
54

21. FIRST (Fulvestrant fIRst-line Study Comparing
Endocrine Treatments)
Phase II, randomized, open-labeled, multi-center
Advanced breast
cancer
ER positive
First line
Ellis et al SABCS 2008, Abst 6126
Fulvestrant HD
(500 mg/mos plus 500 mg D14)
Anastrozole 1 mg/d

22. Kaplain Meier Plot for Time to Progression (TTP)

23. TEAM Trial DFS: 5 Yrs (ITT)
no difference on OS, DFS
1.0
Probability
0.8
HR: 0.97
(95% CI: 0.88-1.08;
P = .604)
0.6
0.4
0.2
0
T→E
E
1
0
Patients at Risk, n
T → E: 4868
E: 4898
5 yrs T → E = 85.4%
5 yrs E = 85.7%
4
3
2
Yrs Since Randomization
111/4660
109/4716
Rea D, et al. SABCS 2009. Abstract 11.
160/4436
117/4533
5
155/4140 108/3377 100/2529
166/4272 133/3575 107/2564

24. IES Trial ER+/Unknown
DFS
100
Exemestane
Tamoxifen
E = 530/2294
80
70
Absolute difference
at 5 yrs = 3.0%
(95% CI: 1.3-4.6)
60
50
T = 622/2305
40
30
20
10
0
0
1
Events/Patients at Risk, n
E 0/2294
55/2193
81/2193
T 0/2305
2
t ne maert f o dn E
t
Women Surviving ,
Alive and Disease Free (%)
90
59/2124
101/2077
Bliss JM, et al. SABCS 2009. Abstract 12.
Absolute difference
at 8 yrs = 4.4%
(95% CI: 1.8-7.2)
HR: 0.82 (95% CI: 0.73-0.92; P = .0009)
3
80/2017
98/1948
4
5
Yr From Randomization
70/1915
69/1847
67/1810
65/1745
6
7
8
9
61/1662
70/1596
51/1333
65/1244
53/758
44/676
27+7*/267
22+7*/255

27. Estrogen signaling interacts with
EGFR/HER pathways
EGFR/HER
estrogen
shc
ER Src
MNAR
ER
ARO
cytoplasm
ER
ER
MAPK/AKT
Ligand-independent
Ligand-dependent
SRC-3
ER
nucleus
ER
ER P
TF
Growth
Survival
Angiogenesis

28. The importance of EGFR as a target
EGFR activation
Survival/protection
from apoptosis
Dedifferentiation
Signalling cascade
Angiogenesis
•
•
•
•
•
•
•
•
Gene
activation
M
G2
G1
S
Cell proliferation
Metastasis: cell
migration and
invasion

29. EGFR Expression associated with poorer
prognosis
Colon
Head and Neck
Pancreatic
NSCLC
Renal cell carcinoma
Breast
Ovarian
Glioma
Bladder
25-77%
95-100%
30-89%
40-80%
50-90%
14-91% (45%)
35-70%
40-63%
31-48%

30. The erB Family
• 4 tyrosine kinase receptors
• act as signal transductors for cell proliferation
and differentiation via the MAPK path
– erB-1: aka EGFR and HER1
– erB-2: aka HER2 (no ligands; potent signal)
– erB-3: aka HER3 (no TK; uses PI3K/AKT)
– erb-4: aka HER4

31. Multiple Activation Mechanisms for EGFRTK1-4
1. Overexpression of EGFR protein
2. Increased ligand expression/autocrine loop
3. Heterodimerization
4. Lateral signal propagation, cross talk (G-protein
coupled receptors, cytokine receptors, cell stress)
5. Mutant EGFR – constitutive activation
6. Decreased phosphatase
7. Altered downstream signal function
1. Raymond E et al. Drugs. 2000;60(suppl 1):15-23. 2. Velu TJ. Mol Cell Endocrinol. 1990;70:205-216. 3. Wells A. Int J
Drugs.
Endocrinol.
Biochem Cell Biol. 1999;31:637-643. 4. Moghal N et al. Curr Opin Cell Biol. 1999;11:190-196.
Biol.
Biol.

32. HER2
• HER2 gene (neu, c-erb-2) ecodes a
transmembrane gycoprotein receptor
• HER 2 is over expressed by 1/4 human
breast cancer and correlates with poorer
outcome
• MoAb against the receptor inhibits the
growth of overexpressing cells
• 15% chance of PR and 4% Cr as single
therapy

34. Trastuzumab Trials in EBC

36. Unanswered ?
•
•
•
•
Duration of trastuzumab
Ideal chemotherapy combination
Role in equivocal HER2 by FISH
Can Anthracyclines be omitted to reduce
cardiotoxicity

38. Trastuzumab Resistance
Virtually all HER2+ metastatic breast cancers
develop resistance
Adjuvant trastuzumab reduces the annual
hazard rate by 1/2, ie, 1/2 of recurrences are
not prevented
Sledge GW. 42nd ASCO; June 2-6, 2006. Education Session.

40. Possible Causes of Trastuzumab
Resistance
 Suboptimal drug delivery
 Altered target expression persistant
signaling by full length or trunkated C
terminal end
 Activation of other receptors EGFR and IGFR
 Modified target-regulating proteins PTEN
mutation leading to uncoupling of PI 3
kinase pathaway
 Alternative pathway signaling
Sledge GW. 42nd ASCO; June 2-6, 2006. Education Session.

41. Phase I/II trial of trastuzumab +
bevacizumab in relapsed/MBC
Phase I
COHORT 1 (N=3)
Trastuzumab qw +
bevacizumab 3 mg/kg day 7 then q2w
HER2+
(FISH+)
N=9
COHORT 2 (N=3)
Trastuzumab qw +
bevacizumab 5 mg/kg day 7 then q2w
COHORT 3 (N=3)
Trastuzumab qw +
bevacizumab 10 mg/kg day 7 then q2w
•
•
•
Investigator-initiated, investigator held IND
First report of 2 humanized MAbs in human subjects
Primary endpoints:
PK – no evidence for a PK interaction between these humanized MAbs
Safety – generally well tolerated, one pt with ↓LVEF
Pegram et al. Breast Cancer Res Treat. 2004;88(suppl 1):S124. Abstract 3039.

42. Phase I trastuzumab + bevacizumab clinical efficacy:
2CR, 3PR, 2SD (>6months)
Day 0
9 months
Pre-treatment
Post-treatment
Pegram, et al., SABCS (2004) #3039

43. Updated Analysis: Phase III Trial of
Lapatinib ± Trastuzumab in HER2+
MBC
EGF104900
Lapatinib 1500 mg PO QD
(n = 148)
Heavily pretreated patients
with HER2-positive
metastatic breast cancer
and progression on
trastuzumab
(N = 296)
Optional crossover to
trastuzumab arm if
PD after 4 wks (n = 77)
Lapatinib 1000 mg PO QD +
Trastuzumab 4 mg/kg loading dose, then
2 mg/kg IV wkly
(n = 148)
Stratified by visceral disease
and hormone receptor status
Blackwell K, et al. SABCS 2009. Abstract 61.
Primary endpoint:
PFS
Secondary endpoints:
OS
ORR
CBR

44. Updated Analysis: Phase III Trial of
Lapatinib ± Trastuzumab in HER2+
MBC
• Lapatinib + trastuzumab associated with 26%
improvement in OS vs lapatinib alone
– Significant survival benefit despite 52% crossover to
combination therapy at disease progression
• Lapatinib + trastuzumab well tolerated
– AEs comparable to lapatinib alone
– Higher incidence of serious cardiac AEs with
combination vs lapatinib alone
• Findings support continued use of trastuzumab
• Offers possible options for heavily pretreated
patients who progress on trastuzumab

45. A Phase II Study of Trastuzumab-DM1
(T-DM1), a HER2 Antibody-Drug Conjugate, in Patients with HER2Positive Metastatic Breast Cancer (MBC): Interim Results
• DM1 Mertansine is conjugated to trastuzumab via a nonreducible thioether bond to a linker molecule (MCC).1
Average number DM1 molecules/monoclonal antibody=3.5
1. Beeram M., et al. J Clin Oncol. 2008; 26 (May 20 suppl; abstr 1028).

46. Trastuzumab-DM1 in Heavily
Pretreated HER2+ MBC
• T-DM1 demonstrated significant clinical benefit
in heavily pretreated HER2+ metastatic breast
cancer patients
– ORR (by independent review): 32.7%
– CR + PR + SD ≥ 6 mos (by independent review): 44.5%
– Median PFS: 7.3 mos
• T-DM1 well tolerated with manageable adverse
effects
• Offers therapeutic option for heavily pretreated
HER2+ patients
– Possible utility in earlier therapeutic strategies

47. Trastuzumab + Heat Shock Protein (HSP)
Inhibitor: Tanespimycin
 Inhibition of HSP90 chaperone function induces degradation
of client protein like HER2
 Phase I trial of KOS-953, an HSP90 inhibitor, plus
trastuzumab:
17 HER2+ patients with trastuzumab-resistant metastatic
breast cancer
– 1 partial response, 3 minimal response, 5 prolonged (>4
mo) stable disease
 Phase II trial under way
Modi S, et al. 42nd ASCO; June 2-6, 2006. Abstract 501.

48. Change in Serum HER2 and
Outcome
Change in HER2
Serum Levels
DR
(median/d)
TTP
(median/d)
OS
from Baseline
ORR
(median/d)
<20% decrease
28.4%
230
182
593
>20% decrease
56.5%
369
320
898
P value
<.001
.008
<.001
.018
Patients with <20% decrease in serum HER2 have decreased benefit from
trastuzumab and should be considered for additional HER2-targeted
therapies
ORR = objective response rate; DR = duration of response; TTP = time to tumor progression;
OS = overall survival.
Ali SM, et al. 42nd ASCO Abstracts. J Clin Oncol. 2006;24:Abstract 500. Reprinted with
permission from the American Society of Clinical Oncology.

49. ER+/PR- Status
Compared with ER+/PR+ disease, ER+/PRbreast cancer has
– Lower response rate to estrogen deprivation
– Worse prognosis
– May be dependent on other signaling pathways
ER = estrogen receptor; PR = progesterone receptor.
Finn RS, et al. 42nd ASCO; June 2-6, 2006. Abstract 514.

50. ER+/PR- Breast Cancer and EGFR Inhibition
 Presurgical exposure to short-term gefitinib, an EGFR inhibitor,
in 43 patients with operable breast cancer
 Tissue obtained at surgery
– ER+/PR- tumors more likely to show molecular growth
inhibition
– ER+/PR+ tumors more likely to show molecular growth
proliferation
 Conclusions
– ER+/PR- breast cancer is growth factor dependent
– ER+/PR- patients may be more likely to benefit from EGFR
inhibition
ER = estrogen receptor; PR = progesterone receptor; EGFR = epidermal growth factor receptor.
Finn RS, et al. 42nd ASCO; June 2-6, 2006. Abstract 514.

51. VEGF inhibition

52. Vascularization is required to convert an in-situ
carcinoma into a rapidly growing malignancy
Premalignant
stage
Malignant
tumor
(Avascular
tumor)
(Angiogenic
switch)
Tumor
growth
(Vascularized
tumor)
Vascular
invasion
Dormant
micrometastasis
Overt
metastasis
(Tumor cell
intravasation)
(Seeding in
distant organs)
(Secondary
angiogenesis)
Stages at which angiogenesis plays a role in tumor progression
Adapted from Poon RT, et al. J Clin Oncol. 2001;19:1207–25

53. Tumor characteristics and environment promote
VEGF expression
Hypoxia
EGF
PDGF
IGF-1
IL-8
bFGF
Binding and activation
of VEGFR
VEGF release
COX-2
NO
Oncogenes
Increased expression
(MMP, tPA, uPA, uPAr,
eNOS, etc.)
P–
P–
–P
–P
Survival Proliferation Migration
ANGIOGENESIS
PDGF = platelet-derived growth factor; IGF-1 = insulin-like growth factor 1
IL-8 = insulin-like growth factor 8
Permeability

54. Bevacizumab (Avastin)- first
effective anti-VEGF targeted
agent
• Bevacizumab (Avastin) - a
major breakthrough in
cancer treatment
– Monoclonal antibody
– Mode of action that
differs fundamentally
from chemotherapy
– Novel target – antiVEGF/angiogenesis
– First agent to specifically
target VEGF and show
improved survival

55. Progression-free survival proportion
E2100 MBC: progression-free
survival
1.0
0.9
0.8
Paclitaxel + Avastin: 10.97 months
0.7
Paclitaxel: 6.11 months
0.6
0.5
0.4
HR=0.49
p=<0.001
0.3
0.2
0.1
0
6.11
0
10.97
10
20
Months
30

56. AVADO: Bevacizumab + Docetaxel in First-line
Treatment of Advanced Breast Cancer
• Adding bevacizumab to docetaxel in first-line
treatment of advanced breast cancer improves PFS but
not OS[1]
– Previous analysis: addition of bevacizumab to docetaxel
significantly improved PFS in locally recurrent or
metastatic breast cancer with both 7.5-mg/kg and 15.0mg/kg doses[2]
• Updated results confirmed preliminary findings:
addition of bevacizumab 15 mg/kg to docetaxel
– Significantly increased ORR
– Prolonged PFS
– Toxicity profile similar among treatment arms
1. Miles DW, et al. SABCS 2009. Abstract 41. 2. Miles D, et al. ASCO 2008. Abstract LBA1011.

59. RIBBON-2: Phase III Trial of SecondLine Bevacizumab + Chemotherapy:
PFS
Primary Endpoint of PFS, ITT Population
Proportion of Progression Free
1.0
Chemo/placebo (n = 225)
Chemo/bevacizumab (n = 459)
0.8
0.6
Median PFS: 7.2 vs. 5.1 mos
HR: 0.78 (P = .0072)
0.4
0.2
0
0
2
4
6
8
10
12
Patients at Risk, n
Chemo/placebo 225 165 129 93 77 44
Chemo/bev
459 381 334 254 190 130
33
87
Brufsky A, et al. SABCS 2009. Abstract 42.
14 16 18 20 22
Duration of PFS (Mos)
19
47
12
27
8
18
5
9
4
5
24
26
28
30
32
34
3
2
1
1
1
1
0
0
0
0
0
0

60. RIBBON-2: Phase III Trial of SecondLine Bevacizumab + Chemotherapy:
ORR*
45
40
Response (%)
35
CR
PR
30
ORR = 29.6%
1.1%
25
P = .0193†
ORR = 39.5%
2.2%
28.5%
37.3%
20
15
10
5
0
Chemo/Placebo
Chemo/Bevacizumab
*Includes only patients with measurable disease at baseline.
†
Not significant at pre-specified α = 0.01
Duration of response: 7.3 mos in chemo/bevacizumab vs 7.5 mos in chemo/placebo
Brufsky A, et al. SABCS 2009. Abstract 42.

61. RIBBON-2: Phase III Trial of SecondLine Bevacizumab + Chemotherapy in
MBC
• Study met primary endpoint
– Improved PFS with combination bevacizumab + standard
chemotherapy vs chemotherapy alone for second-line
treatment of HER2-negative MBC
• Observed improvement in PFS supported by secondary
endpoint of ORR
– OS data immature
• Bevacizumab combination chemotherapy regimens
well tolerated with no unexpected adverse events
• Feasible to consider bevacizumab in second-line
setting
Brufsky A, et al. SABCS 2009. Abstract 42.

62. RIBBON-2: Phase III Trial of SecondLine Bevacizumab + Chemotherapy in
MBC
• Study met primary endpoint
– Improved PFS with combination bevacizumab + standard
chemotherapy vs chemotherapy alone for second-line
treatment of HER2-negative MBC
• Observed improvement in PFS supported by secondary
endpoint of ORR
– OS data immature
• Bevacizumab combination chemotherapy regimens
well tolerated with no unexpected adverse events
• Feasible to consider bevacizumab in second-line
setting
Brufsky A, et al. SABCS 2009. Abstract 42.

63. Tyrosine Kinase Inhibitors

64. Turning Off the EGFR-TK Signal
At the Source1-3
 Inhibition of the EGFR-TK
itself—inside the cell—
completely inhibits EGFRTK signaling regardless of
the triggering event
Inhibition
of apoptosis
Proliferation
Invasion
Metastasis
Angiogenesis
1. Leserer M et al. IUBMB Life. 2000;49:405-409. 2. Raymond E et al. Drugs. 2000;60(suppl 1):15-23.
3. Prenzel N et al. Endocr Relat Cancer. 2001;8:11-31.

65. Drugs
•
•
•
•
Lapatinib
Sorafenib
Sunitinib
Motesanib (pan VEGF inhibitor)

66. Tykerb (lapatinib)—A Dual Receptor
Tyrosine Kinase Inhibitor
• Potent, oral, reversible
dual tyrosine kinase
inhibitor
• Binds to ATP site of
erbB-1 and erbB-2
receptor kinases,
blocking kinase activity
and downstream
signaling

67. Lapatinib
• Phase 3 RCT 392 pts HER2+ve, progressed following
herceptin N Engl J Med. 2006 355(26): 2733-43
– Capecitabine vs Capecitabine + Lapatinib 1250mg
daily continuously
– PFS 4.4 vs 8.4 months
• Lapatinib is effective in patients who have
been previously treated with Anthracyclines ,
Taxanes and Herceptin.

69. Lapatinib Monotherapy
in Inflammatory Breast Cancer
Cohort A:
erbB2+
(n = 24)
Partial response
Cohort B:
erbB1+/erbB2(n = 12)
62%
8.3%
erbB2 overexpression, but not erbB1 expression alone,
predicts for sensitivity to lapatinib in inflammatory breast
cancer
Spector NL, et al. 42nd ASCO; June 2-6, 2006. Abstract 502

70. Lapatinib in ER positive disease
• Cross talk between EGFR and ER responsible
for endocrine Rx resistance,
• Lapatinib upregulates ER
• EGF 30008 RCT Phase III
• Lapatinib + Letrozole vs Letrozole
– PFS 11.9 vs 10.9
– PFS 8.2 vs 3.0 for HER2 positive

71. Sorafenib
(in advanced metastatic Her 2 negative breast cancer)
• SOLTI 0701
– Capeciabine vs Capecitabine + Sorafenib
– PFS 4.1 vs 6.4 months
– Response better when patients who had recd prior
chemo were excluded
• TIES
–
–
–
–
company funded trials
Paclitaxel vs Paclitaxel +Sorafenib
PFS 5.6 vs 6.9 months
Deaths in indian arm skewed results
TTP 5.6 vs 8.1 months (p 0.017)

72. Motesanib
• CIRG/TORI 010 trial
PFS
Response rate
Paclitaxel
9
41.49
Pacli + Motesanib
9.49
49.45
Pacli + Bevacizumab
11.5*
51.55
• High GI and Hepatobiliary toxicity
* Better response than ECOG 2100

73. PARP Inhibitors

74. Poly ADP ribose Polymerase
• Enzyme central to DNA repair (base excision
repair pathway) of single stand breaks
• 17 iso enzymes detected so far of which
PARP1 and 2 are located in the nucleus
• Enhances the effect of cytotoxic drugs and RT
• PARP 1 levels are elevated in TNBC
• It is a valuable approach to BRCA 1 and 2
associated breast cancers and ‘Basal type’
TNBC

75. Mechanism of action

79. Caspase Cascade

80. mTOR
• It acts as a central regulator of cell proliferation, angiogenesis,
and cell metabolism
• It is a key intracellular point of convergence for a number
of signaling pathways that are abnormally activated in many
types of cancer
• It appears to be a stable target that does not mutate
• Inhibiting mTOR:
– May inhibit abnormal cell proliferation, tumor angiogenesis, and
abnormal cell metabolism
– May potentially enhance the efficacy of other cancer treatments

82. Temsolimus, Everolimus
• The efficacy of the drug in combination with
AI depends on cell proliferation dependance
on the PI3K/Akt/mTOR pathway
• High levels of a downstream molecule
(pS6240 kinase) suggests response to the
combination

83. Denosumab—Mechanism of Action
RANKL
– A key mediator of osteoclast formation,
function, and survival, thus, a pivotal factor in
much of the pathologic bone destruction
associated with bone metastases
Denosumab
– Binds to and inhibits RANKL, potentially
reducing bone destruction in patients with
breast cancer
RANKL = receptor activator of NFKappa B ligand.
Lipton A. 42nd ASCO; June 2-6, 2006. Abstract 512.

85. New drugs

86. NCI Phase II Clinical Trials for Breast
Cancer
• BMS-247550
– Epothilone B analog
– Microtubule stabilizer
– Active in taxane
resistant tumors
• Phase II trial
– Measurable disease
– Metastatic or locally
advanced patients for
whom you would
consider taxane
therapy
• Tamoxifen/
Zarnestra
– Oral farnesyl
transferase
inhibitor, (inhibits
ras oncogene
pathway)
– May reverse
tamoxifen
resistance
• Phase II trial
– Measurable
disease
– Hormone receptor
positive
• T cell depleted
allogeneic stem cell
transplant
– Immunotherapy
to induce a graft
vs tumor effect
• Phase II trial
– Measurable
disease
– HLA matched
sibling donor
– Prior
chemotherapy

87. Each breast cancer has unique features
New Breast Cancer Taxonomy
Basal-like
HER-2
“Normal”
Luminal B
Luminal A
Sorlie T et al, PNAS 2001

88. Conclusions
• Targeted therapies which improve
the therapeutic index are the future
of anti-cancer therapy
• Advances in molecular pathology will provide
the means to identify the targets and will be
used to subtype tumours and will provide
predict response to therapy and provide
prognostic information

89. Future therapy
Breast
Ca
Target
Identifying
and
Matching
Integrated
Device
(TIMID)
Customized
prescription
Rx:
……mab
…….cin
…….erb
……ib
……ane
……..rib