1. Expert Review of Breast Cancer Treatment
Clinical Application of Evolving Treatment Paradigms in Advanced Breast Cancer
Clifford A. Hudis, MD
Chief, Breast Cancer Medicine Service
Memorial Sloan Kettering Cancer Center
Professor of Medicine
Weill Cornell Medical College
New York, NY

2. Case 1
47 year-old woman, BRCA1 (+) with h/o stage IIa breast cancer (3-years ago) at age 44
ER weakly positive
PR negative
HER2 negative
Treatment: dose-dense AC→T and on tamoxifen for 2+ years
Presents now with RUQ pain, 4kg weight loss, and fatigue
LFTs normal
CT with multiple hepatic metastases confirmed by biopsy c/w original tumor

3. Case 1 Which treatment option would you recommend: Hormone therapy
Chemotherapy
Bevacizumab

4. Case 1 Which treatment option would you recommend:
Hormone therapy
Chemotherapy
Bevacizumab
Recommended Approach:
Clinical considerations for selection of appropriate treatment will be discussed

5. Management of Metastatic Breast Cancer
Diagnosis of Metastatic Breast Cancer No
Response
Determination of sites and extent of disease. Assessment of HER2,
hormonal receptor status, disease-free interval, age, and menopausal status
No life-threatening disease
Hormone-responsive
Hormone-unresponsive, or
Life-threatening disease
1st-line hormonal therapy
1st-line chemotherapy
2nd-line hormonal therapy
2nd-line chemotherapy
Progression
3rd-line hormonal therapy
3rd-line chemotherapy
Supportive care

6. Many Chemotherapy Options
Spindle toxins
paclitaxel (Pac)
docetaxel (Doc)
vinorelbine (Vin)
nab-Pac* (ABI-007)
Ixabepilone (Ixa)
Nucleoside analogues
gemcitabine (Gem)
capecitabine (Cap)
5-fluorouracil (5-FU_
Topoisomerase inhibitors
CPT-11 (Topo)
– doxorubicin (Dox)
Platinums
Antifolates
methotrexate (MTX)
pemetrexed (PTX)
Unique delivery
liposomal doxorubicin (LD)
Targeted therapy
HER2: trastuzumab (Trastuzumab) and lapatinib (Lap)
VEGF: BVM and small-molecule TKIs (investigational)
farnesyltransferase inhibitors
EGFR inhibitors (investigational)
*Albumin-bound paclitaxel.
CPT = camptothecin; VEGF = vascular endothelial growth factor; BVM = bevacizumab;
mAb = monoclonal antibody; TKI = tyrosine kinase inhibitor; EGFR = epidermal growth factor receptor.

7. Approval is Different from Common Usage
Adjuvant
Metastatic1
Anthracyclines (A)
1st Line
2nd Line
3rd Line
Taxanes (after A)
Cap (after A+T)
Cap (after A + T)
Ixa (after A+T+Cap)
Ixa (after A + T +Cap)
Combination
Cap+taxane
(after A)
Gem + taxane
Cap + Ixa
(after A + T)
Taxanes (T)
Despite treatment, most advanced tumors become resistant and progress2
Chemoresistance is the major cause of treatment failure3
1. Adapted from National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer V Accessed April 30, 2007;
2. Bernard-Marty C et al. Oncologist. 2004;9(6): ;
3. Longley DB, Johnson PG. J Pathol. 2005;205(2):

8. Rationale for Combination Therapy
in the Treatment of MBC

9. Principles of Treatment With Multiple Agents
MBC-inherent drug resistance = barrier to response (cure)
There are many subpopulations of cancer cells with different types of resistance
Combination CT should reduce the different sensitive subpopulations of cancer cells, leading to an improved disease response
Improved disease response will translate into an improvement in outcome
Meta-analysis (2005): standard CT vs intensified CT (10 trials, 2126 patients)
Intensified CT associated with OR=0.60 for response
Tumor response was predictive of survival (P<0.001)
Median OS: CR=29 mon; PR=21 mon; NR=15 mon
OR = odds ratio; OS = overall survival; CR = complete response;
PR = partial response; NR = no response.
Bruzzi P et al. J Clin Oncol. 2005;23(22):

10. Single-agent vs Combination Front-line CT in MBC
Response rate  favors combination
TTP  favors combination
Survival  ?
Toxicity  favors single agent
Quality of life  ?
Very few combination trials using investigational drugs truly tested
the hypothesis of combination vs sequential single-agent therapy
TTP = time to progression.

11. Single-agent vs Combination Trials
Clinical Trial*
Median TTP (mon)
Overall Survival (mon)
Grade IV Neutropenia (%)
Albain et al (N=529)
Pac Pac + Gem
2.9
5.2
15.8
18.5 7 17
O’Shaughnessy et al (N=511) Docetaxel (Doc) Doc + Cap
11 12
Albain KS et al. J Clin Oncol. 2004;22(14) Abstract 810.
O'Shaughnessy J et al. J Clin Oncol. 2002;20(12):

12. E1193 Phase III Trial Dox vs Pac vs Dox + Pac Combination in MBC
Results: Efficacy and Tolerability
Outcome
Dox
Pac
Dox + Pac
P Value
Response rate (%) 36 34 47
0.007* †
Median survival (mon)
18.9
22.2
22.0 NS
TTP (mo)
6.0
6.3
8.2
0.0022* †
Gr III/IV leukopenia (%) 60 55 —
Gr III/IV infection (%)
4.1
8.3
12.7
Gr III/IV neurologic complications (%)
1.6
3.7
10.7
*Dox vs Dox + Pac; †Pac vs Dox + Pac.
*Sledge GW et al. J Clin Oncol. 2003;21(4):

13. CALGB 9840: Design 1998–2000 (N=171) (HER2 status unknown)
Pac q wk + Trastuzumab
         
Pac q 3 wks + Trastuzumab
   
Pac q wk
Pac q 3 wks
2000–2003 (N=406) (HER2 status known)
1998–2000 (N=171) (HER2 status unknown)
Pac 80 mg/m2 q wk –or– 175 mg/m2 q 3 wks
Tras 4-mg/kg load, then 2 mg/kg/wk
Seidman AD et al. J Clin Oncol. 2004;22(14 suppl): Abstract 512.

14. CALGB 9840 Results (All Patients)
Pac Weekly (N=344)
Pac q 3 Wks (N=373)
Response Rate (%)
Tumor Response
HR=1.61; P=0.017
Time to Progression
Time (mon)
Adjusted HR=1.45; P=0.0008
Events/patients: / /385
Seidman AD et al. J Clin Oncol. 2004;22(14 suppl): Abstract 512.

15. CALGB 9840
Conclusions
Pac once weekly is superior to Pac q 3 wks for the treatment of MBC (with respect to response rate and TTP)
Pac once weekly is associated with slightly less frequent myelosuppression but more frequent neurotoxicity than Pac q 3 wks
Trastuzumab does not improve outcome when added to Pac in HER2-neutral MBC
Seidman AD et al. J Clin Oncol. 2004;22(14 suppl): Abstract 512.

16. TAX-31: Docetaxel vs Paclitaxel s/p anthracycline / 0-1 prior chemo for MBC
Docetaxel 100q3w
(N=225)
Paclitaxel 175q3w
(N=224)
ORR (ITT)
TTP OS
32%
5.7*
15.4*
25%
3.6
12.7
Severe AE (>5%)
Neutropenia*
Feb Neutropenia*
Infection
Anemia*
Neurosensory
Neuromotor
Asthenia*
Peripheral oedema*
Stomatitis
Diarrhea*
(3 deaths)
93%
15%
10% 7% 5%
21%
11%
(0 deaths)
55% 2% 4% 1% 0%
*P ≤ 0.05
Jones et al. JCO 2005.

17. New Formulations

18. Lumen of tumor microvessel
Nab-Pac Transport & Tumor Targeting
Tapping Into Biology of Albumin and Rapid Cell Growth
Tumor cell
Lumen of tumor microvessel
Caveolae (vesicles)
Leaky junction
Tumor interstitium
Albumin-receptor (gp60, albondin)
SPARC
(A) Albumin,
the body’s natural
transporter
of water-insoluble nutrients
(B) Receptor-mediated transcytosis of albumin complexes (gp60/caveolin-1 pathway)
(C) High tumor uptake
(SPARC binding of
albumin complexes)
SPARC = secreted protein and rich in cysteine.

19. Phase III Trial Albumin-Bound (Nab) Pac vs Pac in MBC
Albumin-bound Pac: 260 mg/m2 q3w; Pac: 175 mg/m2 q3w
Albumin-Bound (Nab) Pac
(N=229)
Pac
(N=225)
P Value
ORR (%) 33 19
0.001
TTP (wk)
23.0
16.9
0.006
Gr IV neutropenia (%) 9 22
<0.001
Gr III sensory neuropathy (%)
10* 2
*Median time to improvement: 22 days.
Gradishar WJ et al. J Clin Oncol. 2005;23(31):

20. Phase II Study of Weekly or q3wk Nab-Pac vs q3wk Doc as First-line Therapy in MBC
R A N D O M I Z E
Arm A: nab-Pac 300 mg/m2 q3wk
Eligibility criteria:
Stage IV adenocarcinoma
No prior CT for metastatic disease
Arm B: nab-Pac 100 mg/m2 weekly, 3 out of 4
Arm C: nab-Pac 150 mg/m2 weekly, 3 out of 4
Arm D: Doc 100 mg/m2 q3wk
Primary endpoint
Antitumor response (q 8 wks) and toxicity
Comparisons
nab-Pac vs Doc (A, B, C vs D) weekly vs q3wk nab-Pac (B, C vs A) low- vs high-dose weekly nab-Pac (B vs C)
Gradishar W et al. SABCS Abstract 46.

21. Where Exactly Are We?
Hudis JCO 2005.

22. Novel Microtubule Inhibitors
Need for change in
Novel microtubule inhibitors
Toxicity profile
Albumin-bound Pac (nab-Pac)
Therapeutic Efficacy
Halicrobdrin analogue (E7389)
Improve effect at target site
Epothilones (Ixa, patupilone)
Overcome resistance
Polyglutamic acid conjugated Pac (CT 2103)
Cross blood-brain barrier
Vinflunine (novel vinca alkaloid)
Lee JJ, Swain SM. Semin Oncol. 2005;23(2 suppl 7):S22-26.
Cortes J, Baselga J. Oncologist. 2007;12(3):

23. Epothilones in Clinical Development for Breast Cancer
Agent (Manufacturer)
Epothilone Analog
Phase in Development
Clinical Toxicities
EPO-906/patupilone
Epothilone B (natural product)
III
Diarrhea
ZK-EPO
Epothilone B (fully synthetic) II
Neuropathy, nausea, ataxia
KOS-1584
Epothilone D (desoxyepothilone B)
Myelosuppression, neuropathy
BMS
Epothilone B (semi-synthetic)
I / II
Hypersensitivity reactions, pancytopenia, neuropathy, arthralgia/myalgia
Goodin S et al. J Clin Oncol. 2004;22(10):
Kolman A. Curr Opin Investig Drugs. 2005;6(6):
Schmid P et al. J Clin Oncol. 2005;23(16 suppl): Abstract 2051.

24. Ixabepilone (Ixa) First in the New Class of Epothilones
Naturally occurring epothilone B chemically modified to improve metabolic activity, protein binding, and antitumor activity1
Tubulin-binding mode distinct from other microtubule- stabilizing agents1
Active against multiple tumor xeno grafts, including drug- resistant types that overexpress P-gP, MRP-1, and b-III tubulin isoforms1
Active in taxane-resistant disease2,3 S N HN O OH
Ixabepilone Semi-synthetic analog of epothilone B
1. Ixempra (ixabepilone) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2007.
2. Perez E et al. J Clin Oncol. 2007;25(23):
3. Thomas E et al. J Clin Oncol. 2007;25(23):

25. Ixa: Mechanism of Action
ß-tubulin
MRP-1
P-gP
Tubulin
ßIII-tubulin
Extracellular
Intracellular
Poor substrate for efflux pumps, eg, P-gP and MRP-11
P-gP and MRP-1 are involved in drug resistance2
Binds multiple ß-tubulin isoforms, including ßIII-tubulin to inhibit microtubule dynamics1
Overexpression of ßIII is associated with in vivo and clinical resistance to taxanes3,4
1. Ixempra (ixabepilone) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2007.
2. Lee JJ, Swain SM. Semin Oncol. 2005;32(6 suppl 7):S22-S26.
3. Kamath K et al. J Biol Chem. 2005;280(13):
4. Mozzetti S et al. Clin Cancer Res. 2005;11:

26. Phase II Trial Ixa in Anthracycline-, Taxane-, and Capecitabine-Resistant MBC Efficacy
Efficacy (N=113 Evaluable Patients)
ORR
11.5% SD
50.0%
Median PFS
3.1 mo
Grade III/IV Toxicities %
Neutropenia 54
Peripheral neuropathy 14
Fatigue 10
Myalgia 7
Stomatitis
Single-agent Ixa 40 mg/m2 IV over 3 hrs q3w until disease progression
Perez E et al. J Clin Oncol. 2007;25(23):

27. Demonstrated resistance to anthracycline and taxane N=752
Ixa Study 046 Design
Ixa in Combination With Cap in Patients Resistant to an Anthracycline and a Taxane
MBC
Demonstrated resistance to anthracycline and taxane N=752
Combination therapy:
Ixa 40 mg/m2 IV over 3 h q 21 days + Cap 2000 mg/m2/d PO Days 1–14
Monotherapy:
Cap 2500 mg/m2/d PO Days 1–14
Primary Endpoint
PFS (IRR)
Strict resistance criteria prospectively defined as
Disease progression = 3 mon of the last anthracycline dose in the metastatic setting –OR– recurrence = 6 mon in the adjuvant or neoadjuvant setting
–AND–
Disease progression = 4 mon of the last taxane dose in the metastatic setting –OR– recurrence = 12 mon in the adjuvant or neoadjuvant setting
*Pts who received a minimum cumulative dose of 240 mg/m2 of Dox or 360 mg/m2 of epirubicin were also eligible.
RR = independent radiologic review.
Imprexa (ixabepilone) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2007.
Thomas ES et al. J Clin Oncol. 2007; 25(33):

28. Ixabepilone Study 046 Significant Improvement in Median PFS*
Months
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Ixa + Cap
Cap
P=0.0003†
Proportion not Progressed
Median PFS
5.8 mos vs 4.2 mos (95% CI, 3.8–4.5)
HR = 0.75 (95% CI, 0.64–0.88)
*Based on IRR of ITT population; †Stratified by visceral metastasis in liver/lung, prior CT in metastatic setting, and anthracycline resistance..
Thomas ES et al. J Clin Oncol. 2007; Early online release; 0: JCO v1.

29. Grade 3/4 Non-hematologic Toxicities
Peripheral neuropathy 23
Myalgia 8
0.3
Hand-foot syndrome 18 17
Diarrhea 6 9
Mucositis 3 2
Vomiting 4
Fatigue
Nausea
Arthralgia
% of Patients
Ixabepilone + Capecitabine (N=369)
Capecitabine (N=368) 20 40 60 80

30. What About Anti-angiogenics?

31. E2100 Study Design RANDOMI ZE Pac + Bev Pac Stratify:
28-day cycle
Pac 90 mg/m2
D1, 8, and 15
BVM 10 mg/kg
D1 and 15
Stratify:
DFI ≤24 mon vs >24 mon
<3 vs ≥3 metastatic sites
Adjuvant CT: yes vs no
ER(+) vs ER(–) vs ER unknown
Pac + Bev
DFI = disease-free interval.
Miller KD et a. SABCS Abstract 3.

32. First-line Therapy of Metastatic Breast Cancer with Bevacizumab Added to Paclitaxel Improved PFS
0.0
0.2
0.4
0.6
0.8
1.0
Months
PFS Probability 6 12 18 24 30
HR = 0.51 ( )
Log Rank Test P <
Pac. + Bev mos
Paclitaxel mos
484 events reported
Miller K, NEJM 2007.

33. AVADO Double-blind, Placebo-controlled Trial
Docetaxel* 100mg/m2 + placebo q3w
Docetaxel* + bevacizumab 7.5mg/kg q3w
Docetaxel* + bevacizumab 15mg/kg q3w
All patients given option to receive bevacizumab with 2nd line chemotherapy
1st line locally recurrent or mBC (N=705)
Stratification factors:
region
prior taxoid/time to relapse since adjuvant chemo
measurable disease
hormone receptor status
Treat with placebo/ bevacizumab to disease progression
*Docetaxel was administered for a maximum of 9 cycles, but earlier discontinuation was permitted
Primary endpoint: Progression-free survival
Secondary endpoints: Overall response rate, duration of response, time to treatment failure, overall survival, safety, quality of life

34. Progression-free Survival (ITT population)
Months
PFS estimate
*Data censored for non-protocol therapy prior to PD
†mg/kg q3w
HR + 95% CI (unstratified)
Bev 7.5† + docetaxel (n=248)
1.0
0.8
0.6
0.4
0.2
0.0
HR + 95% CI (stratified*)
0.69 (0.54–0.89) P =
0.79 (0.63–0.98) P =
Placebo + docetaxel (n=241)
Median
8.7
8.0
0.61 (0.48–0.78) P <
8.8
0.72 (0.57–0.90) P =
Bev 15† + docetaxel (n=247)

35. Sorafenib Targets Both Tumor-cell Proliferation and Angiogenesis
RAS
Endothelial cell or pericyte
Proliferation
Angiogenesis:
PDGF-b
VEGF
VEGFR-2
PDGFR-b
Paracrine stimulation
Differentiation
Mitochondria
Apoptosis
Tumour cell
PDGF
EGF/TGF-a
Survival
EGF/IGF
HIF-2
Nucleus
Autocrine loop
ERK
MEK
RAF
Sorafenib
Migration
Tubule formation
Mcl-1
PDGF = platelet-derived growth factor
EGF = epidermal growth factor VEGF = vascular endothelial growth factor
TGF-a = transforming growth factor-alpha
Mcl-1 = myeloid cell leukemia-1
Wilhelm SM, et al. Cancer Res 2004;64:7099–109.

36. OF SORAFENIB IN BREAST CANCER
Sorafenib in Breast Cancer Six Randomized, Double-blind, Placebo-controlled Phase 2b Trials
Paclitaxel
Dr. GRADISHAR
(Northwestern,
ACORN)
Started Jun 07
Capecitabine*
Dr. BASELGA
(SOLTI)
Started Aug 07
Aromatase
Inhibitors*1
Dr. PEREZ
(MCCRC)
Planned
Docetaxel or
Letrozole
Dr. GIANNI
(Michelangelo)
Gemcitabine*3
Drs. HUDIS &
SCHWARTZBERG
(MSKCC/
Triplet2
Dr. SLEDGE
(HOG)
TRIALS INVESTIGATING THE EFFECTS
OF SORAFENIB IN BREAST CANCER
*includes 2nd line patients
1. Letrozole, anastrozole, or exemestane
2. Paclitaxel/bevacizumab +/- sorafenib
3. Bevacizumab-progressors

37. Conclusions
Newly approved and other novel agents for the treatment of patients with MBC continue to improve outcomes
The addition of biologics may make a substantial impact
There is a clear and immediate need for larger, better designed clinical trials to assess the role of these new agents
As monotherapy
As combination therapy
As additions to therapies employing a growing number of biologics