Medical Update for Women Living with Advanced Breast Cancer

1
Medical Update for Women Living with Advanced
Breast Cancer
Julie R. Gralow, M.D. Associate Professor,
Medical Oncology University of Washington School
of Medicine Fred Hutchinson Cancer Research
Center Seattle Cancer Care Alliance Co-Chair,
Southwest Oncology Group Breast Committee
2
Goals in the Treatment of Advanced Breast Cancer

• Control and regression of disease
• Prolongation of life
• Improvement in quality of life
• ??Cure

3
A Balancing ActBalancing treatment efficacy and
toxicity is a major objective
Quantity of Life
Quality of Life
4
Choices in the Treatment of Advanced Breast Cancer

• Choice of treatment is based on many factors
• patient age, menopausal status, general health
  and functional status
• tumor ER status, HER-2 status
• previous treatments
• time since diagnosis or previous treatment
• response to previous treatment
• extent and sites of disease
• presence of life-threatening disease

5
Personalizing Treatment to the Specific Tumor
6
Breast Cancer Up Until NowTesting for 1 or 2
Specific Molecules
Estrogen Receptor 75 of breast cancers are ER
HER-2 20-25 of breast cancers are HER-2
7
Cancers Are the Result of Multiple Changes in the
DNAMultiple Genes and Pathways Likely Need to
Be Targeted to Completely Eradicate Every Last
Cancer Cell
8
Multiple DNA Changes Must Occur to Allow Cancer
to Develop, Survive and Spread
?
?
normal breast cell
atypical cell
breast cancer cell

• A better understanding of the genes and proteins
  associated with cancer development and
  progression will lead to better treatment
  strategies

9
Molecular Classification of Breast CancerSorlie
et al, Proc Natl Acad Sci 1008418, 2003
Luminal Subtype A
Luminal Subtype B
Basal Subtype
Normal Breastlike
HER-2
Red dots Genes are turned up in cancer cells
compared to normal cells
Individual genes
Individual patients
10
The Era of Genomic/Molecular Profiling
Genomic Health Oncotype Dx 21-Gene Recurrence
Score Assay
11
21 Gene Recurrence Score Assay 16 Cancer Genes
and 5 Reference Genes
PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2
ESTROGEN ER PR Bcl2 SCUBE2
HER2 GRB7 HER2
REFERENCE Beta-actin GAPDH RPLPO GUS TFRC
INVASION Stromolysin 3 Cathepsin L2
GSTM1
CD68
BAG1
12
Gene Expression Profiles as Predictors of
Response Docetaxel (Taxotere)Chang JC et al,
Lancet 362362-369, 2003
Residual Tumor Size

• Identified 92-gene expression pattern to predict
  response to docetaxel
• Separated into sensitive and resistant groups

sensitive
resistant
13
Endocrine Therapy
14
Drugs Targeting Estrogen and Its Receptor in
Breast Cancer
Aromatase inhibitors, ovarian suppression
SERMS (tamoxifen, raloxifene), SERDS (fulvstrant)
Cell Growth and Division
Estrogen
Estrogen Receptor
15
Aromatase Inhibitors
Adrenal Hormones

Cortisol
Androstenedione
Aldosterone
Testosterone
Estrone
Aromatase inhibitors block post-menopausal
estrogen production
Anastrozole (Arimidex) Letrozole
(Femara) Exemestane (Aromasin)
Estradiol
16
Personalizing Endocrine Treatment to the
Specific Patient
17
Personalizing Drugs to the Patient CYP2D6 and
Tamoxifen Metabolism
Jin Y et al, J Natl Cancer Inst 20059730-39
CYP2D64 an inherited genetic variant
associated with a CYP2D6 poor metabolizer state

• 4-OH-Tamoxifen and Endoxifen are important active
  metabolites of tamoxifen
• CYP2D6 enzyme involved in their metabolism

Plasma Endoxifen level (nM)
18
Tamoxifen Treated Patients, CYP2D6, and Breast
Cancer Relapse
CYP2D6 4/4 patients have higher recurrence
rates when treated only with tamoxifen, and also
no hot flashes!
Wt/Wt (67)
Wt/4 (23)
4/4 (10)
Knox et al ASCO 2006
19
CYP2D6 is a Key Metabolizer of Some
Anti-Depressants
Should not give paroxitine (paxil) with tamoxifen
Plasma Endoxifen (nM)
Wt/Wt, noinhibitor
Venlafaxine (Effexor)
Sertraline (Zoloft)
Paroxetine (Paxil)
4/4, noinhibitor
Jin Y et al J Natl Cancer Inst 9730, 2005
CP1229323-8
20
New Hormonal Agents Fulvestrant (Faslodex) A
Selective Estrogen Receptor Downregulator

• Binds to Estrogen Receptor
• Pure anti-estrogen
• Given as an IM shot monthly
• Approved for treatment of advanced breast cancer
• Equal effectiveness compared to anastrozole
  (Arimidex)
• Equal effectiveness compared to tamoxifen

21
Can We Combine Hormonal Therapies? S0226
Anastrozole (Arimidex) /- Fulvestrant (Faslodex)
in Advanced Breast CancerPI R. Mehta

• Advanced Breast Cancer
• Anastrozole Anastrozole
• Fulvestrant
• Fulvestrant

22
A Promising New Class of Endocrine AgentsPhase I
Trial of Steroid Sulfatase Inhibitor
STX64Stanway S et al, ASCO 2006, abstract 580

• Steroid sulfatase (STS) inhibitors
• Block sulfatase path of estrogen formation in
  postmenopausal women (block estrone sulfate to
  estrone)
• Inhibit synthesis of androstenediol (steroid
  with estrogenic properties) from DHEAS
• Patients 14 postmenopausal, ER, metastatic
  breast cancer pts (2 previous lines endocrine
  therapy)
• Treatment
• 2-weekly cycles (5 days of oral STX64 5 mg, 9
  days off)
• Results
• 98-99 inhibition of serum and tumor STS up to
  90 decrease in serum estrone, androstenediol and
  androstenedione
• 4/14 patients with stable disease 6 months
  (all progressed on AI)

23
Chemotherapy
24
How a Drug is Given Matters.CALGB 9840 Weekly
vs. q3 Weekly Paclitaxel Seidman A et al, ASCO
2004, abstract 512

• Patients 576 stage IV breast cancer patients
• Treatment Randomized to weekly paclitaxel 80
  mg/m2 vs q3 weekly paclitaxel 175 mg/m2
• Results Weekly Q3 Weekly
• RR 40 28 p0.017
• TTP 9 mo 5 mo p0.0008
• OS 24 mo 16 mo p0.17
• Toxicities (grade 3,4)
• Neutropenia 5 15
• Motor Neuropathy 8 4
• Sens Neuropathy 23 12
• Myalgia/Arthralgia 1 5

25
How a Drug is Packaged Matters.Albumin
Bound-Paclitaxel (Abraxane)

• AB albumin bound
• Nonsoluble drug becomes water-soluble
• No cremophor or other solvents
• Rapidly bioavailability
• Potential for more selective tumor uptake via
  gp60 albumin receptor on tumor cell

26
AB-paclitaxel (Abraxane) vs. Paclitaxel (Taxol)
in Advanced Breast Cancer Gradishar W et al, J
Clin Oncol 23, 2005
AB-paclitaxel (Abraxane) 260 mg/m2 IV over 30
min every 3 weeks No Standard Premedication
Randomization
Paclitaxel (Taxol) 175 mg/m2 IV over 3 hrs
every 3 weeks Standard Premedication with
Steroids and Anti-histamines
27
Albumin-Bound Paclitaxel (Abraxane) vs.
Paclitaxel (Taxol) in Metastatic Breast Cancer

• Paclitaxel AB-Paclitaxel
• (175 mg/m2) (260 mg/m2)
• Results
• RR 11.1 21.5 p0.003
• TTP 17 weeks 23 weeks p0.006
• Toxicities (grade 3,4)
• Neutropenia 53 34 p
• Feb neutropenia
• Sens Neuropathy 2 10 p

28
Comparison of Ab-Paclitaxel (Abraxane) vs
Docetaxel (Taxotere)Gradishar W et al, ASCO
2007, abstract 1032
Response Rate ()
300 mg/m2 100 mg/m2 150 mg/m2 docetaxel
q3w qw 3/4 qw 3/4 100 mg/m2 q3w (A n
76) (B n 76) (C n 74) (D n 74)
Ab-paclitaxel (Abraxane)
29
New Chemotherapy AgentsPegylated Liposomal
Doxorubicin (Doxil)
PEG
Evades immune system Significantly prolongs
time in body Remains encapsulated until it
reaches tumor Concentrates in tumor
Doxorubicin
Liposome
30
Cardiac Events vs. Cumulative Chemotherapy Dose
100
Liposomal doxorubicin
80
Doxorubicin
60
Cardiac events ()
40
450 mg/m2
20
0
0
0
100
100
200
200
300
300
400
400
500
500
600
600
700
700
800
800
900
900
1000
1000
Cumulative anthracycline dose (mg/m2)
31
A New Anti-Tubulin Class (Epothilones)Phase III
Trial of Capecitabine (Xeloda) /- Ixabepilone in
Patients with Metastatic Breast CancerVahdat L
et al, ASCO 2007, abstract 1006

• Patients 752 metastatic breast cancer patients
  s/p anthracycline and resistant to taxanes
• Treatment
• Capecitabine 1250 mg BID (14/21)
• vs
• Capecitabine 1000 mg BID (14/21) Ixabepilone 40
  mg/m2 q3 weeks

32
Classes of Cancer Chemotherapy Drugs
Anti-Tubulins

• Anti-Tubulins (plant alkaloids) block cell
  division during mitosis (mitotic spindle
  interference)
• Vinca alkaloids vinorelbine (Navelbine)
• Taxanes paclitaxel (Taxol), docetaxel (Taxotere)
• Epothilones

33
Phase III Trial of Capecitabine (Xeloda) /-
Ixabepilone in Patients with Metastatic Breast
CancerVahdat L et al, ASCO 2007, abstract 1006

• Results C C I
• OR 14 35 p
• PFS 4.2 mo 5.8 mo p
• 12-week PFS 55 71 p
• Toxicity (grade 3, 4)
• Neuropathy 0 23
• Hand/foot 17 18
• Fatigue 3 9
• Neutropenia 11 68
• FDA has granted ixabepilone priority review status

34
Biological Therapy Targeting Factors That Allow
a Cancer Cell to Develop, Survive and Spread
35
The HER Family of Receptors

• Lapatinib

HER3
HER1 EGFR
HER2
HER4
Tumor Cell

• Erlotinib (Tarceva)
• Gefitinib (Iressa)
• Cetuximab (Erbitux)

• Trastuzumab (Herceptin)
• Pertuzumab (Omnitarg)

36
Drugs Targeting HER-2 in Breast Cancer
HER-2 Oncogene overexpressed in 20-25 of breast
cancers
HER-2
Trastuzumab (Herceptin) Anti-HER-2 Antibody (IV)
cancer cell
nucleus
Lapatinib (Tykerb) Dual HER-1/HER-2 (oral)
Tyrosine Kinase Inhibitor
cell division
37
Chemotherapy /- Trastuzumab (Herceptin) in
Metastatic Breast CancerSlamon D et al, N Eng J
Med 2001
Trastuzumab chemotherapy (n235)
Chemotherapy (n234)
Months (TTP, survival)
ORR ()
MedianTTPPMediansurvivalP0.046
ORR P65 of Chemo-alone group crossed over to
trastuzumab at progression
38
A Promising New HER-2 Targeted DrugLapatinib
(Tykerb)

• Specificity for both HER-1 (EGFR) and HER-2
  receptors
• Binds inside the cancer cell, to the enzyme
  portion of HER-2/HER-1
• Oral
• Crosses blood-brain barrier

Trastuzumab (Herceptin) binds here
HER-1 (EGFR)
HER-2
kinase
kinase
Cell division/tumor growth
Tumor Cell
39
Phase III Capecitabine (Xeloda) /- Lapatinib
(Tykerb) Geyer C et al, ASCO 2006, special
education session
Capecitabine
Capecitabine Lapatinib
Weeks (TTP)
ORR, Progressing ()
MedianTTP
progressing P0.00016
Response
40
Phase III Capecitabine (Xeloda) /- Lapatinib
(Tykerb) Geyer C et al, ASCO 2006, special
education session

• Additional Results capecitabine
  capecitabine lapatinib
• Brain relapse 11 4
• Toxicity (grade 3,4)
• capecitabine capecitabine lapatinib
• Diarrhea 12 11
• Hand/foot synd 6 5
• Rash 2.5 7
• LVEF drop 1 4 (asymptomatic,
• resolved)

41
Lapatinib as 1st-Line Treatment in HER-2
Advanced Breast CancerGomez HL et al, ASCO 2005,
abstract 3046 Patient D Brain Lesion Baseline
and 12 Weeks
42
CALGB 40302 Fulvestrant (Faslodex) /- Lapatinib
(Ongoing) PI H. Burstein

• Postmenopausal, advanced breast cancer
• ER or PR
• Tumor expression of HER-1 (EGFR) or HER-2
• Treatment
• Fulvestrant
• Lapatinib (orally daily) placebo

43
Pertuzumab (Omnitarg) Anti-HER-2 Monoclonal
Antibody
Pertuzumab (2C4) antibody binding
EGF
HER-2

• Binds to HER-2
• Blocks communication with other HER family
  members
• Inhibits signaling in both HER-2 low- and
  high-expressing tumors

44
EGFR (HER-1) Targeted Therapy in Breast Cancer

• Gefitinib (Iressa) and erlotinib (Tarceva) have
  been tested as single agents in unselected,
  advanced breast cancer
• Minimal clinical activity seen to date
• Triple Negative (ER-, PR-, HER-2-) phenotype
• Higher incidence of EGFR?
• More sensitivity to platinum chemo agents?
• Ongoing triple negative trials
• J OShaughnessey (US Oncology)
• irinotecan carboplatin cetuximab (Erbitux)
• L Carey (UNC)
• cetuximab (Erbitux) vs cetuximab
  (Erbitux)/carboplatin

45
Conjugated AntibodiesTrastuzumab Conjugated to
an Anti-tubulin Drug (T-DM1)Beeram M et al, ASCO
2007, abstract 1042
toxin
toxin
toxin
toxin
toxins, radioactivity, chemotherapy Can be
attached to the antibody
46
In Addition to Targeting the Cancer Cell, We Can
Also Target the Cancer Environment to Make it
Less Friendly

• The blood vessels
• The bone

47
Targeting the Cancer Environment Angiogenesis
Inhibition
Bevacizumab (Avastin) Anti-VEGF Antibody binds
to VEGF and blocks tumor blood vessel growth
BLOOD VESSEL CELL
VEGF Receptor
VEGF
Other VEGF/VEGFR inhibitors sunitinib sorafenib
CANCER CELL
48
E2100 Paclitaxel (Taxol) /- Bevacizumab
(Avastin) in Advanced Breast CancerPI K. Miller
RANDOMI ZE

• Eligibility
• No prior treatment for mets
• HER-2 negative

weekly paclitaxel bevacizumab
weekly paclitaxel
49
Paclitaxel (Taxol) /- Bevacizumab (Avastin) in
Metastatic Breast Cancer(E2100 Study)
28
months
25
38

16
11
6
Chemo alone Chemo Bevacizumab
50
Addition of Bevacizumab (Avastin) and Trastuzumab
(Herceptin) to Paclitaxel (Taxol) Slamon D et al,
NEJM 2001 Miller KD et al, San Antonio 2005,
abstract 3
HER-2 Negative
HER-2 Positive
Paclitaxel /- Trastuzumab
Paclitaxel /- Bevacizumab (E2100)
Paclitaxel trastuzumab Paclitaxel
Paclitaxel bevacizumab
Paclitaxel
PFS
11.4 months
6.9 months
6.11 months
3.0 months
0
10
20
30
Months
Months
Progression-free survival
51
Capecitabine (Xeloda ) /- Bevacizumab (Avastin)
in Advanced Breast Cancer KD Miller et al, San
Antonio 2002, abstract 36
RANDOMI ZE
Capecitabine Bevacizumab
Eligibility - One or two prior therapies OR -
Relapse within 12 months of adjuvant chemo
Capecitabine
Increase in response rate from adding
bevacizumab, but no change in time to tumor
progression or survival
52
Randomized Phase II Trial of Metronomic
Chemotherapy Bevacizumab (Avastin)Burstein H
et al, SABCS 2005, abstract 4
CM alone (N 21) Cyclophosphamide 50 mg PO QD
Methotrexate 2.5 PO BID days 1,2 each week
R
CM bevacizumab (N 34) Same chemo
Bevacizumab 10 mg/kg IV q 14 days
53
Breast Cancer and the Bone Microenvironment

• The skeleton is the initial site of recurrence in
  35-40 of breast cancer patients
• Incidence of bone metastases in advanced breast
  cancer is 65-75

54
Breast Cancer and Bisphosphonates (Inhibitors of
Bone Breakdown)
Growth factors
osteoblasts, macrophages
breast cancer cells
osteoclasts
Growth factors
55
Bisphosphonates in Treating Bone Metastases

• Several bisphosphonates approved throughout the
  world for treatment of reducing in
  skeletal-related complications or symptoms in
  patients with bone metastases
• clodronate (Bonefos) oral
• pamidronate (Aredia) IV - US
• zoledronic acid (Zometa) IV - US
• Ibandronate (Bondronat) IV, oral

56
Zoledronic Acid vs. Placebo in Stage IV Breast
Cancer with Bone MetastasesKohno N et al, J Clin
Oncol 23, 2005
49.6
38.9
40
35
29.8
30
25.4
25
17.7
Patients,
20
15
11.5
8.8
8.8
10
3.5
2.6
5
0
All SREs
Radiation to bone
Fractures
Spinal cord compression
HCM
Zoledronic acid 4 mg (n 114)
Placebo (n113)
Events at 12 Months
57
Zoledronic Acid (Zometa) vs. Placebo in Stage IV
Breast CancerPain Scores (Brief Pain
Inventory) Kohno N et al, J Clin Oncol 23, 2005
58
Osteoclast Inhibition and Bone Metastases New
Agents Under Study

• RANK-ligand pathway inhibitors
• Denosumab (AMG 162) humanized monoclonal
  antibody to RANK ligand, given SQ
• Bone targeted src tyrosine kinase (STK)
  inhibitors implicated in osteoclast-dependent
  bone resorption
• SWOG S0622 Phase II trial of dasatinib
  (Sprycell) in patients with bone-predominant
  metastatic breast cancer

59
Novel Cancer Targets for Treatment
HER-2 Inhibitors
Metastasis Inhibitors
IGF-R Inhibitors
MUC-1 Antibodies
EGFR Inhibitors
Anti-Angiogenesis
Src Inhibitors
mTOR Inhibitors
Farnesyl Transferase Inhibitors
MEK Inhibitors
HIF Inhibitors
Cell Cycle Inhibitors
Aurora Kinase Inhibitors
HSP90 Inhibitors
Pro-apoptotic Drugs
Raf Inhibitosr
Proteosome Inhibitors
Mdm2 Inhibitors
Kinesins
HDAC Inhibitors
Tubulin-interacting Agents
Death Receptors
Courtesy of D. Budman
60
Wellness
61
Ginseng May Help Combat Fatigue in Cancer
PatientsBarton D et al, ASCO 2007, abstract
9001

• Patients 282 patients with cancer, 6 month
  life expectancy, and fatigue
• Treatment Randomized to
• Placebo 2x per day
• 750 mg American Ginseng 2x per day
• 1,000 mg American Ginseng 2x per day
• 2,000 mg American Ginseng 2x per day
• Results
• 1,000 and 2,000 mg twice a day doses showed an
  effect in alleviating cancer-related fatigue

62
Ginseng May Help Combat Fatigue in Cancer
PatientsBarton D et al, ASCO 2007, abstract
9001

• Endpoints Placebo 750 1,000 2,000
• Change in vitality scale 7.3 8.8 14.6 10.5
• Change in overall 5.6 5.3 12 6.5
• physical well-being
• with mod-very much 10 10 25 27
• improved fatigue
• satisfied with 13 24 33 34
• treatment

Source of drug Wisconsin Ginseng Cooperative
63
Team Survivor Northwest An Exercise and Fitness
Program for All Women Affected by Cancer