Current Approaches in Metastatic
Breast Cancer
Edgardo Rivera, MD
Chief, Breast Medical Oncology Section
The Methodist Hospital/Weill Cornell University
Houston, TX
1 in 4 Deaths
CANCER
-Leading cause of death among
women aged 40 to 79 years
-Leading cause of death among
men aged 60 to 79 years
Abnormal
GROWTH
Normal
Premalignant
Cancer
Normal
DCIS/ADH
Breast Ca
Estimated New Cases*
----------------------------------------------------------------------------------------------------------------------------- -Males Females
Prostate
218,890
29%
Breast
178,480
26%
Lung & bronchus
114,760
15%
Lung & bronchus
98,620
15%
Colon & rectum
79,130
10%
Colon & rectum
74,630
11%
Urinary bladder
50,040
7%
Uterine corpus
39,080
6%
Non-Hodgkin lymphoma
34,200
4%
Non-Hodgkin lymphoma
28,990
4%
Melanoma of the skin
33,910
4%
Melanoma of the skin
26,030
4%
Kidney & renal pelvis
31,590
4%
Thyroid
25,480
4%
Leukemia
24,800
3%
Ovary
22,430
3%
Oral cavity & pharynx
24,180
3%
Kidney & renal pelvis
19,600
3%
Pancreas
18,830
2%
Leukemia
19,440
3%
All Sites
678,060
100%
All Sites
766,860 100%
Ten Leading Cancer Types for the Estimated New Cancer Cases, by Sex, US, 2007
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder. Estimates are rounded to the
nearest 10.
1,444,920
Estimated New Cancer Cases
Estimated Deaths
----------------------------------------------------------------------------------------------------------------------------- -Males Females
Lung & bronchus
89,510
31%
Lung & bronchus
70,880
26%
Prostate
27,050
9%
Breast
40,460
15%
Colon & rectum
26,000
9%
Colon & rectum
26,180
10%
Pancreas
16,840
6%
Pancreas
16,530
6%
Leukemia
12,320
4%
Ovary
15,280
6%
Liver & intrahepatic bile duct
11,280
4%
Leukemia
9,470
4%
Esophagus
10,900
4%
Non-Hodgkin lymphoma
9,060
3%
Urinary bladder
9,630
3%
Uterine corpus
7,400
3%
Non-Hodgkin lymphoma
9,600
3%
Brain & other nervous system
5,590
2%
Kidney & renal pelvis
8,080
3%
Liver & intrahepatic bile duct
5,500
2%
All Sites
289,550 100%
All Sites
Ten Leading Cancer Types for Estimated Deaths, by Sex, US, 2007
270,100 100%
Annual cancer mortality / 100,000 women, ages 35 - 69*
U.S.A.
1950-2001
70
60
50
40
Lung
Breast
Uterus
Breast
30
20
Stomach
10
Lung
Colon &
rectum
Uterus
Stomach
0
1950 1960 1970 1980 1990 2000 2010
EBCTCG Lancet 2005
Declining U.S. Mortality
• Behavior Modification
• Early detection
• Improvements in treatment
Impact of Chemotherapy
Ross et al., Cancer 55:341-346, 1985
Survival after Recurrence
Giordano et al, Cancer 100:44-52, 2004
Impact of New
Therapies
Giordano et al, Cancer 100:44-52, 2004
Historical Changes in Overall Survival (OS)
_______________________________________
Median OS (days)
GONO
(NCI, Genoa, Italy)
N =790
British Columbia Cancer Agency
N = 2152
Cohort 1 (1983–86)
546
Cohort 1 (1991–92)
438
Cohort 2 (1987–89)
522
*Cohort 2 (1994–95)
450
Cohort 3 (1992–94)
584
▼Cohort 3 (1997– 98) 564
*Cohort 4 (1995–97)
793
■ Cohort 4 (1999–01) 667
Cohort 5 (1998–2001) 713
_______________________________________________________________
* Inclusion of paclitaxel in MCB regimen
▼Release of docetaxel and AI’s
■ Release of capecitabine and trastuzumab
Chia, SKL. Proc ASCO, #22, 2003
Gennari, A. Proc ASCO, #634, 2004
Recently FDA-Approved Drugs for
Metastatic Breast Cancer
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Paclitaxel
Goserelin
Anastrozole
Toremifene
Docetaxel
Pamidronate
Letrozole
Capecitabine
Trastuzumab
Exemestane
Fulvestrant
Gemcitabine
Abraxane
Lapatinib
1994
1995
1995
1996
1996
1996
1997
1998
1998
1999
2002
2004
2005
2007
Staging
The process of finding out how
widespread the cancer is and whether it
has spread to other parts of the body
AJCC
Stages I – IV
T-N-M
Metastatic Breast Cancer
• 3 – 5% of women present with metastases at
time of diagnosis
• 5 yr survival 5 – 15%
• Therapy targeted at metastatic disease
• Local therapy historically reserved for
palliation for those with local progression of
tumor
Goals of therapy in MBC
• Palliate or delay onset of symptoms
• Improve quality of life
• Prolong life
• ?? Cure
Advanced Breast Cancer Is Treated
Based on the Biology of the Tumor
_______________________________________
Advanced Breast Cancer
Requiring Therapy
ER and/or PR Positive
Hormonal Treatments
Refractory to
Hormonal Therapy
ER and/or PR Negative
Chemotherapy
HER2 Positive
Chemotherapy
+Trastuzumab
HER2 Negative
Chemotherapy
Characteristics of the Long-Term
Disease-Free Survivors
• Limited metastatic disease (one
organ site involved)
• Young age
• Excellent performance status
• Normal organ function
• Absence of significant co-morbidity
Hortobagyi GN, et al, 1996
Selection of Chemotherapy
for MBC
•
•
•
•
Activity
Prior therapy
Performance status
Co-morbidities
• CHF, peripheral vascular disease, diabetes
•
Patient Considerations
 Convenience vs compliance vs control
 Toxicities affecting normal functioning
• Peripheral neuropathy• Mucositis
• Diarrhea
 Patient appearance
• Alopecia
• IV Port
Chemotherapy for MBC:
Simultaneous or Sequential?
The Issue
• Patients with metastatic breast cancer receive
multiple cytotoxic agents during their clinical
course
• Do combinations of two or more drugs given
simultaneously give better results than each
single agent given until progression and then the
others given sequentially?
Simultaneous vs Sequential Combinations:
Advantages and Disadvantages
•
•
•
•
•
•
Simultaneous
Higher response rate
Higher complete
response rate
Longer time to
progression
Covers multiple
mechanisms of
resistance
Exploits synergistic
interactions
Generates more adverse
events
•
•
•
•
•
Sequential
Avoids additive or
overlapping toxic effects
Simpler scheduling
Lower response rate
Shorter time to
progression
Equivalent median
survival
E1193 Schema
Randomize
Arm A
DOX
mg/m2
60
q3wx8
Arm B
Arm C
TAX
mg/m2
175
q3w
DOX
50
mg/m2
x8
TAX
150 mg/m2
PD
PD
TAX
DOX
G
C
S
F
PD
5 mg/kg d 3-12
E1193: Results
Treatments ORR (CR)
TTP
Survival
Doxorubicin
36 (6)
6
19.1
Paclitaxel
34 (3)
6.3
22.5
Doxorubicin
+ paclitaxel
47* (9)
8.2*
22.4
Sledge G, et al, JCO 21:588-592, 2003
Chemotherapy for MBC:
Simultaneous or Sequential?
Conclusions
• Both simultaneous and sequential administration of
combinations of drugs represent a standard of care for
different clinical situations.
• Research should continue to develop more effective,
potentially curative approaches for MBC
• Simultaneous combinations based on potential synergy
should be explored as new agents are developed
Novel Agents
Ixabepilone: A Novel Antineoplastic Agent
• New antineoplastic class
• Semisynthetic analog of epothilone B
• Specifically designed to overcome
tumor resistance mechanisms
– MRP-1 and P-gp efflux pumps
– b (III) tubulin overexpression
– b tubulin mutations
Ixabepilone: Preclinical Antitumor Activity
• In vitro and in vivo activity in
taxane-resistant tumors1,2
Tumor response (log cell kill)
1
2
Ixabepilone
Paclitaxel
Doxorubicin
• Synergy with capecitabine in
preclinical and phase I/II settings2
Median tumor weight (mg)
0
Control
Capecitabine
2500
Ixabepilone
Combination
250 mg/kg (MTD)
2000
10 mg/kg (MTD)
1500
1000
500
(P=0.0001)
0
10
30
50
Days post-tumor implant
1. Jordan MA, et al. Proc Amer Assoc Cancer Res. 2006;47:abstr LB280. 2. Lee FY, et al. J Clin Oncol. 2006;24(18s):abstr 12017.
Ixabepilone Single-Agent Activity
in Metastatic Breast Cancer
45
42
40
35
ORR (%)
30
25
22
19
20
15
18
12
10
5
0
Roché1
After adjuvant
anthra
Low2
Taxane-pretreated
MBC
Conte3
Taxane-resistant
MBC
Thomas4
Multiresistant
(anthra / tax / cape)
MBC
Baselga5
Neoadjuvant
T2-4, N0-3, M0
1. Roché H et al. International Union Against Cancer World Cancer Congress, 8-12 July 2006; abstr 96-3. 2. Low et al. J Clin Oncol.
2005;23:2726–2734. 3. Conte P et al. J Clin Oncol. 2006;24(18S):abstr 10505. 4. Thomas E et al. J Clin Oncol. 2006;24(18S):abstr
660. 5. Baselga J et al. Breast Cancer Res Treat. 2005;94(Suppl 1):S31:abstr 305.
Phase III Study Design
N=375
Ixabepilone
40 mg/m2 IV over 3h
d1 q3wk
+
N=752
Stratification
• Visceral liver/lung metastases
• Anthracycline resistance
• Prior chemo for MBC
• Study site
Capecitabine 2000 mg/m2/day PO
BID
d1-d14 q3wk
N=377
Capecitabine 2500 mg/m2/day PO
BID
d1-d14 q3wk
Vadhat et al ASCO 2007 abstract #1006
Patient Eligibility
Inclusion Criteria
Exclusion Criteria
• Women ≥18 years
• >3 prior chemo regimens
(metastatic)
• Locally advanced or MBC
• Anthracycline-resistant or
minimum cumulative dose
• Taxane-resistant
• KPS 70–100
• Life expectancy ≥12 wk
• ≥G2 motor/sensory neuropathy
• Reduced hematologic/
renal function
• ≥G2 liver function tests*
• No CNS metastases
*Protocol amendment excluded patients with ≥G2 liver function tests regardless of liver metastases; 377 patients (33 with ≥G2 liver
function tests) had been enrolled before amendment.
Vadhat et al ASCO 2007 abstract #1006
37
Results: Progression Free Survival
1.0
Proportion Not Progressed
0.9
Ixabepilone + Capecitabine 5.8 mo (95% CI 5.5-7.0)
0.8
Capecitabine 4.2 mo (95% CI 3.8-4.5)
0.7
0.6
HR: 0.75 (95% CI 0.64-0.88)*
0.5
P=0.0003
0.4
0.3
0.2
0.1
0.0
0
4
8
12
16
20
24
28
32
36
40
Months
Vadhat et al ASCO 2007 abstr 1006
*Adjusted for interim analysis.
Results: Response Rate
ORR – %
(95% CI)
Ixabepilone +
Capecitabine
N=375
Capecitabine
N=377
35
(30–40)
14
(11–18)
P<0.0001
CR – %
PR
SD
PD
Not evaluable
Vadhat et al ASCO 2007 abstr 1006
0.3
34
41
15
9
0
14
46
27
12
Enhanced Anti-tumor Activity of ABI-007 vs
Taxol in Mice
Tumor Volume (mm3)
Human MX-1 Mammary Carcinoma (n = 5/group); Dose: 5  Daily
2000
1750
Control
1500
1250
1000
750
30 mg/kg/dose
nab-Paclitaxel
Cremophor®-EL Paclitaxel
30 mg/kg/dose*
500
250
0
0
10
20
30
40
50
60
70
80
90
100 110
Days Post-implant
*30 mg/kg/day of Cremophor®-EL paclitaxel causes 20% mortality; no death with nab paclitaxel.
Hawkins, et al., AACR. 2003; Abstract Poster # A3
ABI-007 Q3W regimen in MBC
PHASE I
DOSE- FINDING STUDY
N=19
PHASE II
175 MG/M2 DOSE STUDY
N=41
• Overall Response Rate 40%
• 1st Line Response 45%
• Well Tolerated Without Steroids
• 0% Grade ¾ Neuropathy
• No routine premedication
required
• DLTs at 375 mg/m2: keratitis,
neuropathy-sensory, stomatitis
• MTD: 300 mg/m2
• Bi-exponential distribution,
linear PK
PHASE II
300 MG/M2 DOSE STUDY
N=63
• Overall Response Rate
48%
• 1st Line Response 64%
• Well Tolerated Without Steroids
• 11% Grade ¾ Neuropathy
PIVOTAL PHASE III STUDY
260 MG/M2 ABI-007 DOSE VS 175MG/M2 TAXOL
DOSE N=460 (3,4)
Ibrahim,et al.,Clin Cancer Res. 2002;8:1038-1044.
O’Shaughnessy, et al., SABCS. 2003; Abstract #44
Phase III Trial Design ABI-007 versus Taxol
ABI-007 260 mg/m2 paclitaxel
IV over 30 min q 3 wk
No Premedication
Randomization (1:1)
N = 460
Taxol® 175 mg/m2 paclitaxel
IV over 3 hrs q 3 wk
Standard Premedication with
Dexamethasone and Anti-histamines
O'Shaughnessy, et al., SABCS 2003. Abstract #44
Phase III Trial ABI-007 versus Taxol
Study Objectives
PRIMARY ENDPOINTS:
• Objective response rates (RR)
– All treated patients and first line (planned analysis)
– RECIST criteria
• Safety and tolerability
SECONDARY ENDPOINTS:
• Time to tumor progression (TTP)
• Overall survival (OS)
O’Shaughnessy, et al., SABCS. 2003; Abstract #44.
Phase III Overall Response Rates (ORR):
ABI-007 vs Taxol
All treated
patients
First-line
patients
ABI-007
n=229
Taxol
n=225
ABI-007
n=97
Taxol
n=89
CR+PR
33%
19%
42%
27%
95% CI
27-39%
14-24%
32-52%
18-36%
p-Value*
p<0.001
*Cochran-Mantel-Haenszel test.
O’Shaughnessy, et al., SABCS. 2003; Abstract #44.
p=0.029
Phase III:
Time to Disease Progression (All Patients)
Proportion not progressed
1.00
ABRAXANETM (n=229)
TAXOL® (n=225)
0.75
0.50
Median = 23.0 weeks
(95% CI = 19.4 -26.1)
0.25
Median = 16.6 weeks
(95% CI = 15.1 – 20.1)
P=value=0.002
HR = 0.726 (95% CI 0.589 – 0.895)
0
0
8
16 24 32 40 48 56 64 72 80 88 96 104 112 120
Week
O’Shaughnessy, et al., SABCS. 2003; Abstract #44.
Phase III Randomized Trial:
Survival (All Patients)
1.00
Probability of survival
ABRAXANETM (n=229)
TAXOL® (n=225)
0.75
P = 0.322
HR = 0.899 (95% CI 0.728 – 1.110)
Median = 65.0 weeks
(53.4 – 76.9)
0.50
Median = 55.3 weeks
(48.0 – 66.4)
0.25
0
0
8 16 24 32 40 48 56 64 72 80 88 96 104 112 120128136 144
Week
Note: P-value from log-rank test.
American BioScience, Inc., Data on file, 2005.
Lapatinib:
Targeting EGFR and HER-2
• Lapatinib oral tyrosine
kinase inhibitor of
ErbB1 and ErbB2
– Blocks signaling
through EGFR and
HER-2 homodimers
and heterodimers
– May also prevent
signaling between
ErbB1/ErbB2 and other
ErbB family members
Phospholipid cell
membrane
PTEN
P13K
Lapatinib
Shc
Grb2
Ras
Raf
So8
pAkt
pErk
Rusnak DW, et al. Mol Cancer Ther. 2001;1:85-94; Xia W, et al. Oncogene. 2002;21:6255-6263.
EGF100151: Lapatinib + Capecitabine in
Advanced Breast Cancer
Refractory, progressive
metastatic or locally
advanced HER-2+ breast
cancer previously treated
with anthracycline,
taxane, or trastuzumab
(N=528 planned*)
Lapatinib 1250 mg daily +
Capecitabine 2000 mg/m2 daily
for days 1-14, 3-week cycles
(n=160)
Capecitabine 2500 mg/m2 daily
for days 1-14, 3-week cycles
(n=161)
Follow-up:
until progression
or unacceptable
toxicity
*Study enrollment terminated early by IDMC due to superiority of combination arm in primary
endpoint; Geyer CE, et al. ASCO 2006. Clinical Science Symposium.
Lapatinib + Capecitabine Vs Capecitabine
Alone in HER2+ MBC
Capecitabine Capecitabine
+ Lapatinib
N=201
N=198
HR
P-Value
Time to Progression
4.3 mo
6.2 mo
0.57
.00013
Overall Survival
15.3 mo
15.6 mo
0.78
.177
14%
24%
-
.017
13 (6%)
4 (2%)
-
.045
Overall Response
Rate
Brain Mets as Site of
First Progression*
N (%)
* Exploratory Analysis
Cameron et al. ASCO 2007 Abstract 1035
Agents Targeting VEGF
Class
Examples
Stage of
Development
Targets
Agents targeting the VEGF ligand
Antibodies
Bevacizumab VEGF
Soluble
receptors
VEGF-TRAP
VEGF and PlGF
Company
Phase III
Genentech
Phase II
Regeneron/Sanofi
Aventis
Agents targeting the VEGF Receptors
Small
molecule
inhibitors
Sunitinib
VEGFR-2, PDGFR, c-Kit
Phase II/III*
Pfizer
Axitinib
VEGFR-2, PDGFR
Phase II
Pfizer
SU014813
VEGFR1,2; c-Kit
Phase I/II
Pfizer
Pazopanib
VEGFR1,2;PDGFR, c-Kit
Phase I/II
GSK
Sorafenib
PTK-787
Raf, VEGFR1,2; c-Kit
VEGFR-1/2 PDGFR, c-Kit
Phase II**
Phase II/III
Bayer/Onyx
Novartis
AEE788
VEGFR1,2; ErbB1,2
Phase II
Novartis
Vandetinib
VEGFR-2/EGFR
Phase II
Astra Zeneca
AZD2171
VEGFR, c-Kit
Phase II
Astra Zeneca
AMG706
VEGFR1,2; PDGFR, c-Kit
Phase I/II
Amgen
*Approved in RCC and GIST. **Approved in RCC
Bevacizumab and Paclitaxel in Metastatic
Breast Cancer
Paclitaxel
(n=339)
Paclitaxel +
bevacizumab
(n=341)
P-value
HR (95% CI)
All patients
13.9
29.9
<0.0001
–
Measurable
disease
16
37.7
<0.0001
–
PFS, months
6.11
11.4
<0.0001
0.51 (0.43-0.62)
OS, months
25.2
28.4
0.12
0.84 (0.64-1.05)
Outcome
Response, %
Miller KD, et al. SABCS 2005. Abstract 3.
Sunitinib
• SU11248 is an oral TKI of:
–VEGFR
–PDGFR
–Kit
–Flt-3
• Phase II study in heavily
pretreated MBC
• 50 mg: 4 weeks on, 2
weeks off
N=64
Partial Response
7 (11%)
Stable disease > 6
months
3 (5%)
Overall clinical benefit
10 (16%)
• Toxicity
–34% grade 3 NTP
–16% grade 2
thrombocytopenia
–Fatigue, diarrhea, anorexia,
mouth pain
–38% dose reduction, 53%
dose interruption
Miller et al, SABCS 2005
Conclusions
• Understanding of breast cancer as a molecular
disease is leading to novel therapies
– Improved survival and response rate in early
stage and metastatic breast cancer
• However, newer therapies have led to newer
toxicity issues that require further evaluation as
well as longer follow up
The Balancing Act
Control
of
Disease
Quality
of
Life