Download Breast Cancer: The Basics

Breast Cancer for PathoBiology
Students
Lisa A. Carey, M.D.
Medical Oncology
UNC
Goals:
Understand issues in translating bench to
bedside cancer care and direction in
cancer therapeutics
Incidence/Mortality
 Over 200,000 cases yearly (USA), 1,500
male. Likelihood (birth to 80) 12% (1 in
8).
 Under 40,000 deaths/year in the USA,
mortality decreasing over past decade.
Annual Age-adjusted Cancer Incidence
Annual Age-adjusted Cancer Death Rates
Case
RB is a 37 year old woman whose mother
and two of three aunts died of breast or
ovarian cancer. Realizing that her risk
was elevated, she has had aggressive
screening with breast self examinations,
examinations by a physician, and yearly
mammograms.
She came to the UNC Breast Center
October 2, 2002 with widely metastatic
breast cancer.
Familial Breast Cancer: 5-10%
One Defective Gene Copy Carried in a Germ Cell
High Level of Cancer Susceptibility
50-90% Lifetime Risk
Familial breast cancer
• Genes:
– 80% BRCA1/2 (5-10% overall)
– 5% Li-Fraumeni (p53)
– Rare: Cowden synd (PTEN), Peutz Jeghers, AT
heterozygotes (?).
• Mostly autosomal dominant (men are carriers!)
• More likely to have:
– Bilateral and/or premenopausal disease
– Ovarian cancer (esp BRCA1, 25% lifetime risk)
– Male breast cancer (BRCA2)
• Other inherited syndromes, e.g. Lynch II, can
include breast.
Dark = disease
• = carry mutation
/ = dead
BRCA 1 and 2
• Where are these genes?
– BRCA1 chromosome 17q
– BRCA2 chromosome 13q
• What do they do?
– DNA repair pathways
– ? transcription factors
• How do we find mutations (there are lots)?
– 80% frameshift or nonsense – abnormal protein
– Founder mutations e.g. Ashkenazi Jews – 2 on
BRCA1, 1 on BRCA2
– Gene sequences are proprietary
Prevention
Strategy
Effect on Breast
Cancer
Drug: Tamoxifen
50% decrease
Prophylactic
mastectomy
90% decrease
Prophylactic
removal of ovaries
(premenopausal)
50% decrease
Hormonal Stimulation
PgR mitosis
Cytoplasm
E2
E2
+
RNA
Chromatin
ER
E2
ER
E2•ER
PgR
=
=
=
=
Estradiol
Estrogen receptor
Estradiol-receptor complex
Progesterone receptor
E2•ER
E2•ER
Nucleus
Inhibition of
Estrogen-Dependent Growth
Antiestrogens
Estrogen
biosynthesis
Nucleus
Estrogen
biosynthesis
Aromatase
inhibitors
Tumor cell
Inhibition of
cell
proliferation
Tamoxifen
• Selective estrogen receptor modulator
• Competitively inhibits ER, which affects
transcription of certain genes.
• Tissue-specific effects may be from
variations in coactivator proteins.
• Raloxifene (another SERM) also  breast
cancer incidence, extent unknown.
Tamoxifen and Prevention
Events
40
Placebo
175
Tamoxifen
89
Rate per 1000
43.4
22.0
Placebo
Rate/1000
30
P < 0.00001
20
10
Tamoxifen
0
0
1
2
3
Years
Adapted from Fisher et al. J Natl Cancer Inst 1998;90:1371-1388.
4
5
Inherited Breast Cancer and Hormone
Sensitivity
• BRCA1 common marker phenotype
– ER-, PgR-, HER-2– 2/3 of inherited breast cancer
• BRCA2 common marker phenotype:
– ER+, PgR+, HER-2– 1/3 of inherited breast cancer
Prophylactic Mastectomy
Group
Breast
Cancers (%)
High-risk women
with mastectomy
Observed 3 (1.4)
Their sisters with
no mastectomy
Observed 156 (38.7)
Expected 83 (38.7)
From: Hartmann L et al. N Engl J Med 1999
>90% reduction in
risk and death!
Ovarian Removal and Breast Cancer Risk in
BRCA1/2 Carriers
18
HR =
0.25
% with Cancers at 2 years
16
14
12
“Self-Randomization”
10
Surveillance: 72
Oophorectomy: 98
8
6
*
4
2
*
0
Breast Ca
Ovarian Ca
Pertnl Ca
From Kauff ND, et al NEJM 2002.
All Ca's
* includes 3 ovarian
cancers present at
oophorectomy.
Breast Conservation = Mastectomy
(conservation is lumpectomy/radiation (L/RT))
% Disease-free
% Without Mets
% Alive
Squares = mast., triangles=L/no RT, dark triangles = L/RT
Lumpectomy and BRCA1/2 Carriers
% Breast Events
at 12 yr
P=
0.007
50
40
30
20
10
0
P=
0.001
IPS BreastCL Breast
(same breast)
From Haffty BG, et Al. Lancet 2002
(other breast)
Sporadic:
105
BRCA 1, 2:
22
Case
55 year old woman has surgery for a breast
mass. It ends up being a 3 cm, nodenegative, ER-positive tumor.
What is the risk of this tumor recurring
systemically? When? What can we do
about it?
95% of breast cancer patients
have local disease at the time of
diagnosis, but can relapse later.
Prognostic Factor = Something
measurable at the time of diagnosis
that predicts whether the patient will
relapse.
Prognostic relevance of LN
Prognostic Factors in Clinical Use
 Tumor size
 Lymph node involvement
 ER (PR)
 (Histopathology if unusual)
 HER-2, grade
 ?bone marrow involvement
Estimates of Recurrence Risk:
TNM Stage
•
•
•
•
•
•
•
•
0:
I:
IIA:
IIB:
IIIA:
IIIB:
IIIC:
IV:
Tis
T1N0
T0-1N1; T2N0
T2N1; T3N0
T0-3 N2; T3N1
any T4
any N3
M1
0% risk
* Our patient
80% risk
Drugs Are Used to Prevent Relapse,
Improve Cure
• Treat at time of diagnosis to prevent
relapse (often from 2 – 15 years later)
• Evolving since 1970s
– Tamoxifen (antiestrogen)
– Chemotherapy
– Other drugs in investigation (more later…)
• Effective in early breast cancer
Possible Outcome of 10 Women
Treatment of breast
only
7 Cancer relapse
3 Cured
Treatment of breast
and body with drugs
4 Cancer relapse
3 More cured
Oxford Overview 2000:
Tamoxifen (5 years)
Years 0-1
Years 2-4
Years 5-9
Years 10+
Total
Reduction in Annual Odds:
Recurrences
Breast Deaths
51%
32%
45%
31%
30%
17%
17%
26%
40.3%
30.7%
ATAC Trial: Aromatase Inhibitors in Adjuvant
Therapy
Proportion event free (%)
100
95
Anastrozole
Tamoxifen
90
Combination
85
HR
AN vs TAM
Comb vs TAM
80
0.78
1.02
95.2% CI
0.65–0.93
0.87–1.21
p-value
0.006
0.773
0
0
6
12
18
24
30
36
42
Time to event (months)
Curves truncated at 42 months
N
ER+/PR+ 5704
ER+/PR- 1370
A
T
C
7% 8% 8%
9% 17% 19%
A vs. T (HR)
0.82 (0.65-1.03)
0.46 (0.33-0.71)
Long Term Impact of Adjuvant Chemo
34% reduction
in relapse risk
26% reduction
in risk of death
Bonadonna G et al. NEJM 1995
Tamoxifen and Chemotherapy
%  relapse %  death
< 50
Chemo/tam v tam
21
25
Tam/chemo v chemo
40
39
Chemo/tam v tam
19
11
Tam/chemo v chemo
54
49
50+
Possible Outcome of 10 Women
Treatment of breast
only
7 Cancer relapse
3 Cured
Didn’t need
further therapy
Treatment of breast
and body with drugs
Drug choice?
4 Cancer relapse
3 More cured
Can we categorize tumors
better regarding prognosis?
Yes, molecular classification
Cancers Have Many Mutations that Alter
the Function of Genes
Genes and Cancer: Clinical Utility
• Mutations in Cancer Cells:
– Vary from Cancer to Cancer
– Alter Gene Expression
Can we analyze 10,000-20,000 expressed
genes in a single tumor and devise a new
molecular classification of human cancer?
What Are Gene Expression Arrays?
• A method that allows examination of the
products of many genes from one cancer
simultaneously
• Simultaneous examination allows visualization
of patterns of change
• It also allows determination of genes and
groups of genes that work together
A 20,000 Gene Microarray
Gene Expression: cDNA
Microarrays
Molecular Portrait of Breast Cancers
Basal-like
HER-2
“Normal”
Sorlie T et al, PNAS 2001
Luminal B
Luminal A
Subtypes and Prognosis
Sorlie T et al, PNAS 2001
Carolina Breast Cancer Study (CBCS)
Population-based case-control study with deliberate
oversampling of premenopausal and AfricanAmericans
Courtesy of R. Millikan
Phase I 1993-96, 657/851 cases with relevant data
40% African-American, 50% < 50yo
Basal-like breast cancers (BBC): ER-/PR-/H2-CK5/6 or HER1+
Tumor Subtypes, Race and Menopause
Premen
AA
Postmen
AA
Premen
nonAA
Postmen
nonAA
p-value*
Luminal
36%
59%
51%
58%
0.001
BBC**
39%
14%
16%
16%
0.001
HER2+
19%
23%
24%
22%
0.79
** BBC= triple negative and either CK5/6 or HER1+
Update from Carey LA et al. Proc ASCO ‘04
*chi square
Basal-like Breast Cancer and BRCA1
= BRCA1+
Sorlie T et al. PNAS 03
Subtypes and Response to Chemotherapy
Clinical RR to AC
Basal-like
HER2+
Luminal
N
Overall RR
Clinical CR
Clinical PR
28
22
55
24 (86%) ¥
15 (68%)
33 (60%)
9 (32%) ¥
4 (18%)
3 (5%)
15 (54%)
11 (50%)
30 (55%)
Pathologic stage post-chemotherapy
Basal-like
HER2+
Luminal
N
0
I
II
III
27
22
55
8 (30%)
6 (27%)
7 (13%)
6 (22%)
3 (14%)
7 (13%)
7 (26%)
9 (41%)
20 (36%)
6 (22%)
4 (18%)
21 (38%)
Basal-like and HER2 that failed to achieve pCR
Appear to relapse early and often.
*¥ p < 0.05
Carey LA, SABCS 04
Oncotype Dx Genes
+ 1.04
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
INVASION
Stromolysin 3
Cathepsin L2
Best RT-PCR performance
and most robust predictors
- 0.34
+ 0.47
HER2
GRB7
HER2
ESTROGEN
ER
PR
Bcl2
SCUBE2
GSTM1
CD68
BAG1
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
Paik et al, NEJM 2004
B-14: Placebo versus Tamoxifen
by RS Category
1.0
1.0
142
0.8
0.8
171
69
0.6
85
DRFS
DRFS
0.6
0.4
0.4
Low Risk (RS<18)
0.2
Int Risk (RS 18-30)
0.2
Placebo
Tamoxifen
Placebo
Tamolxifen
0.0
0.0
2
4
6
8
10
12
14
16
0
2
4
Years
6
8
Years
1.0
0.8
99
79
0.6
DRFS
0
High Risk (RS≥31)
0.4
0.2
Placebo
Tamoxifen
0.0
0
2
4
6
8
Years
10
12
14
16
10
12
14
16
B-20: Tamoxifen Alone vs Tamoxifen + old
style chemo (MF/CMF)
96%
95%
1.0
0.9
0.8
0.6
0.6
DRFS
0.7
0.5
Low Risk
0.4
89%
90%
0.9
0.7
Intermed. Risk
0.5
0.4
0.3
0.3
0.2
0.2
Low Risk Patients (RS < 18)
Tam + Chemo
Tam
0.1
p = 0.76
0
2
4
6
8
10
p = 0.71
Int Risk (RS 18 - 30)
Tam + Chemo
Tam
0.1
0.0
0.0
12
0
2
Years
4
6
8
10
12
Years
1.0
88%
0.9
0.8
0.7
60%
0.6
DRFS
DRFS
0.8
1.0
0.5
0.4
High Risk
0.3
0.2
High Risk Patients (RS  31)
Tam + Chemo
Tam
0.1
p = 0.001
0.0
0
2
4
6
Years
8
10
12
Tam + chemo
Tam alone
Herceptin®: Humanized Anti-HER-2 Mouse
Monoclonal Antibody
• Targets HER-2 protein
overexpressed in 25%
of human breast cancer
HER2 epitopes recognized by
hypervariable murine
antibody fragment
Human
IgG-1
Baselga. San Antonio Breast Cancer Symposium 2000.
• 95% human, 5%
murine
– Negligible HAMA
– Recruits immune
effector mechanisms
• Little toxicity, acute or
chronic
1.0
BCIRG 006: Disease Free Survival
0.8
91%
86%
86%
80%
77%
84% AC->TH
80% TCH
0.7
73% AC->T
0.6
Patients Events
1073 147
1074 77
1075 98
AC->T
AC->TH HR (AC->TH vs AC->T) = 0.49 [0.37;0.65] P<0.0001
TCH
HR (TCH vs AC->T) = 0.61 [0.47;0.79] P=0.0002
0.5
% Disease Free
0.9
93%
0
1
2
3
Year from randomization
4
5
What About Myc?
• Overexpression in
breast cancer  poor
prognosis
• Transcriptional
regulator
• Myc induction 
apoptosis in normal
cells
• Myc mutants or p53
mutants lose apoptotic
signal
Suppression of Apoptosis Results in cMYC-triggered
Progression
proliferation
c-MYC on
Adult
pancreatic
islet ß-cells
Apoptosis
blocked (for
example by
HER2)
invasion
angiogenesis
No proliferation
or apoptosis
Adapted from S. Paik
Pelengaris et al, Cell 2002
cMYC co-amplification in NSABP B-31 (N=1549)
cMYC not amplified (N=1078)
cMYC amplified* (N=471)
~ 35%
* FISH (Vysis)
* > 5 average hybridization signal per nuclei/60 nuclei
Courtesy S. Paik
100
Time to First Recurrence
(N=1549)
90
MYC+,AC->TH
80
MYC-,AC->TH
70
Reversed by
trastuzumab
MYC-,AC->T
60
MYC+,AC->T
Poor prognosis, like B28
50
P interaction = 0.007
0
1
2
3
4
5
Suppression of anti-apoptotic signal from HER2 with
trastuzumab induce cMYC to trigger apoptosis
Apoptosis
DNA damage by chemotherapy required??
Intact p53 required??
cMYC
overexpression
due to gene
amplification
trastuzumab
HER2
overexpression
Proliferation,
invasion,
angiogenesis
How to Make “Prognosis” More
Complex
And useful…
Not all relapses are equal – 10% of
metastatic breast cancer patients are
alive 10 years later.
Who are they?
Recurrence Risk over Time
0
5 yr
65%
10 yr
20%
16 yr
15%
Median survival :
16 mo.
28 mo.
>42 mo.
CALGB 7541, pers comm, Ray Weiss MD, Walter Reed Hospital, 10/97.
Annual Risk of Death and Phenotype
Hess et al. Breast Cancer Research Treatment 2003
Sites of Relapse and Phenotype
ER+
ER-
Discovery Sample Set
340 samples from UNC
337 samples from the NKI
(L.J. van’t Veer, M. van de Vijver)
DWD combined = 677 arrays
470 patients/tumors with RFS and OS
B. Weigelt et al., Molecular Portraits and
70-gene prognosis signature are preserved
throughout the metastatic process
of breast cancer, Cancer Research,
65, 9155-8 (2005).
Analyzed this sample set using an
expanded Intrinsic/UNC gene list of 2000
genes plus 30 important breast cancer
genes added in
The Next Challenge
As molecular tools become more sophisticated,
use them to:
• Provide more meaningful prognostication
(already happening)
• Provide information about tailored therapies to
improve cure or, if that isn’t possible, survival.
Metastatic Spread
• Described to patients as sequential process
dependent upon tumor size, LN and time to
diagnosis = incorrect
• Size, lymph node status and other
prognostic factors are likely proxies for a
biologically complicated process dependent
upon the patient, the tumor, and the normal
tissues.
Metastatic Prognosis
 Average survival ~ 40 m (highly variable),
~10% > 10y survival
 Sites: locoregional > bone > lung > liver > CNS
 Locoregional/bone only- more indolent course
 Treatment depends on:
–
–
–
–
Site(s)
Disease pace
ER/PR status
Patient age and health
What Controls Metastasis?
• Tumor factors:
– growth factors, apoptosis, angiogenesis,
metastasis suppression genes, basement
membrane/ECM factors
– Breast cancer is metastatic 10% at diagnosis,
25% over time. Other tumors differ.
• Local microenvironment
– Cytokines and growth factors, cell-cell
interactions, other?
Invasion and Metastasis
Cancer-cell arrest in Muscle
secondary sites
Primary tumor
Liver
Clinically undetectable
Proliferate
Proliferate
Extravasate
Dormant
Die
“Dormant”
Die
Clinically
detectable
Treatment for Metastatic Disease
• Targeted therapy
– Hormones
• Antiestrogens
• Aromatase inhibitors
– Herceptin / trastuzumab, Tykerb/lapatinib if
HER-2 overexpressing
• Bisphosphonates
• Chemotherapy
– Non cross-resistant drugs together or in
sequence
How Do Cancers Grow?
• Unlimited proliferation
– Self-sufficiency in growth signals
– Insensitivity to anti-growth signals
• Functional immortality
– Evading apoptosis
– Limitless replication potential
• Angiogenesis
Can we exploit these in treatment?
Rationale for Targeted Therapies
• Chemotherapy affects both tumor cells and
normal cells
• Targeted therapies are drugs designed
specifically to attack a tumor characteristic
– More effective
– Less toxic to normal cells
• Tamoxifen was our first targeted therapy,
Herceptin the other for breast cancer
HER2, EGFR inhibitors
Bevacizumab
HER-2, other EGFR
?Angiogenesis
factors
?matrix, ECM
proteins
Multiple cell cycle and other genes
Tamoxifen, aromatase inhibitors
PS341
ER
Bcl-2, etc.
p53
Apoptosis
ERE
mito
Apoptosis
Cell cycle
Nucleus
1st Line Chemo/Herceptin: Survival
1.0
Overall survival
0.8
Cumulative % of patients on
CT alone crossing over
to Herceptin at progression†
Month
%
RR = 0.80
p = 0.046
0.6
25.1 mo
0.4
5
15
25
40
20.3 mo
0.2
24
62
65
72
Herceptin + CT (n = 235)
CT (n = 234)
0.0
0
10
No. at risk:
H + CT 235
CT 234
192
160
Slamon et al. N Engl J Med. 2001;344:783.
20
30
Months
134
96
116
76
40
11
13
50
* Median follow-up: 35 mo (range: 30–51).
† These patients are still reported in the
CT arm despite crossover to Herceptin.
Selected Targeted Therapies
Anti-ErbB (HER1-2) receptor Mabs
ligand
(trastuzumab, 2C4,cetuximab. EMD 7200,
Abx=EGF)
1 2
Grb2
Sos
K K
Shc
Shc
Grb2
Sos
PI3K
Anti-HER1, HER2, HER4 tyrosine
Kinase inhibitors (ZD1839, OSI-774,
EKB-569, GW-2016, CI-1033)
Ras
RAS farnesyl transferase inhibitors
(BMS-214662, R115777)
PTEN
Akt
Raf
RAF inhibitors
(BAY 43-9006)
mTOR
FKHR
GSK3
Bad
MEK1/2
MAPK
p27
mTOR inhibitors
(CCI-779, RAD)
MEK inhibitors
(CI-1040)
Cyclin D1
Cell cycle
progression
Survival
Proliferation
Apoptosis (Programmed Cell Death)
Apoptosis Induction:
Therapeutic Possibilities
•
•
•
•
•
•
•
p53 induction (gene therapy)
Bcl-2 inhibition (antisense therapy)
Death signaling (TRAIL mimics)
Caspase activation
Bax mimics
HDAC inhibitors
NF-kB inhibitors
Angiogenesis
Angiogenesis: development of new blood vessels from
existing vasculature
Central Concept: any increase in tumor size must be
preceded by an increase in tumor vasculature. This
increase in tumor vasculature is stimulated by the tumor.
VEGF Is a Key Mediator of
Angiogenesis
Upstream activators
of VEGF synthesis
Downstream
signaling pathways
rhuMAb VEGF (Recombinant Humanized
Monoclonal Antibody to VEGF)
 Humanized to avoid
immunogenicity (93%
human, 7% murine).
 Recognizes all isoforms of
vascular endothelial growth
factor, Kd= 8 x 10-10M
 Terminal half life 17-21
Days
 Works in Colon, Lung cancer
Agents Targeting the VEGF Pathway
Anti-VEGF
antibodies
VEGF
Soluble
VEGFRs
(bevacizumab)
(VEGF-TRAP)
Other biologics (indirect):
Anti-HER2
Anti-HER1
mTOR inhibition
Anti-VEGFR
antibodies
(IMC-1121b)
P
P
P
P
VEGFR-1
P
P
VEGFR-2
Endothelial cell
Adapted from Podar and Anderson. Blood.
2005;105:1383.
P
P
Small-molecule
VEGFR inhibitors
Usually
multitargeted
(PTK787, SU11248, ZD6474, BAY 43-9006, AG013736)
Antiangiogenesis Agents and Synergy with
Chemotherapy
Angiogenesis
inhibitor
..
...........
..
...
.....
Abnormal
environment,
Direct effects
Chemotherapy
VEGFR1, 2
cancer cell
Antiangiogenic Therapies Normalize
Vasculature Structure and Function
Normal
Abnormal
Tumor
formation
Jain. Science. 2005;307:58.
Normalized
Antiangiogenic
therapy
Vessel Abnormalities are Also Reversible
with Treatment of the Tumor
Abnormal vessels
Courtesy Elizabeth Bullitt
Normalization with treatment
with lapatinib
Weekly Paclitaxel + Bevacizumab ↑ PFS
Which patients got the most benefit?
Pac. + Bev. 11.4 months
1.0
Paclitaxel
6.11 months
PFS Probability
0.8
HR = 0.51 (0.43-0.62)
0.6
Log Rank Test p<0.0001
0.4
0.2
0.0
0
Miller K, SABCS 05
6
12
18
Months
24
30
484 events reported
Issues in Targeted Therapy
• Likelihood of success high, if:
– Target actually responsible for tumor growth
or survival, AND
– Drug actually does what it’s supposed to
• Likelihood of toxicity generally low
– MOST of the time
– Drugs typically can be given as long as
needed
New drugs for breast cancer
1980s
1990s: Chemotherapy:
• Mitoxantrone
•
•
•
•
•
•
•
1990s: Hormones:
•
•
•
•
Letrozole
Anastrozole
Exemestane
Zoladex
Paclitaxel
Docetaxel
Epirubicin
Navelbine
Gemcitabine
Liposomal Doxorubicin
Capecitabine
1990s: Bisphosphonates 1990s: Biologic therapy:
• Trastuzumab
Breast Cancer Mortality
Thanks
for
hanging
in
there…
Impact of Screening on Stage at Diagnosis
247 women age 40-49
Buseman S. et al. Cancer 2003
Invasive Breast Cancer
• Infiltrating ductal, lobular, or mix most
common (95%). Rare sarcoma/phyllodes,
lymphoma etc.
• Special histology - better prognosis (pure
tubular, cribriform, papillary,
mucinous/colloid)
• Inflammatory – poor prognosis
– Dermal lymphatic invasion
– E-cadherin, Rho GTPases unusually
expressed
Infiltrating ductal carcinoma,
invading and replacing breast
stroma
Prevention
• Tamoxifen (Fisher B et al. JNCI 1998;90:1371)
– Invasive and noninvasive  ~50%
– Pro: breast, bone. Con: endometrium, DVT
• Prophylactic mastectomy (Hartmann LC et al. NEJM
1999;340:7)
– Retrospective data:  ~90%
• Prophylactic oophorectomy (Rebbeck TR et al. JNCI
1999;91:1442)
– Retrospective data:  ~50%
Goal of sentinel lymphadenectomy: To
abandon routine full axillary dissections in
breast cancer patients
Impact of BM and LN mets
HER-2, other EGFR
?Angiogenesis
factors
?matrix, ECM
proteins
Multiple cell cycle and other genes
ER
Bcl-2, etc.
p53
Apoptosis
ERE
mito
Apoptosis
Cell cycle
Nucleus
Treatment to Prevent Relapse
• Conventional
– Tamoxifen 40-50% decreased risk (if ER-positive)
– Chemotherapy 30% decreased risk
– Combined in sequence is better than either alone
• Promising, under investigation
–
–
–
–
Oophorectomy (premenopausal, ER-positive)
Aromatase inhibitors (postmenopausal, ER-positive)
Herceptin
Bisphosphonates
• Timing of treatments
– Neoadjuvant therapy
Gene arrays identify which genes differ
from “normal”
Computers determine the genes that
are the most helpful
Bioinformatics Selects Informative Genes
Prediction of Clinical Outcome:
The Potential Power of Microarrays
Van de Vijver et al. NEJM 2002
Notes on Gene Arrays
• The ability to metastasize is in part an early and
inherent property of a breast cancer.
• Only 2 groups have demonstrated this approach
– needs further validation
• Gene expression arrays have technical issues that
must be resolved before clinically useful.
• ALL this knowledge derived from tumor bank
samples and clinical studies!
Preoperative Chemotherapy
Allows:
1. Less Surgery
2. Testing Tumor Sensitivity to Drugs
Preoperative
Chemotherapy
Response Rate as Surrogate for Survival
Lumpectomy
Mastectomy
Inflammatory
Disease
Cance, Carey and friends, Ann Surg, 2002
Preoperative Chemotherapy Also Allows
Research into Tumor Characteristics
Responsible for Drug Sensitivity
Preoperative
Chemotherapy
Genetic characteristics can
be measured here…
And compared with response
to specific drugs here
Goal: treatment specific to what that patient needs.
Metastatic Approach
• Local/regional: surgery + radiation +/- chemo
or hormones
• Bone: hormone + bisphosphonate
• Lung: chemo or hormone therapy
• Liver: chemotherapy
• Brain: Solitary metastasis - consider surgery +
radiation, multiple - whole brain radiation
Endocrine vs Chemotherapy
Endocrine
Chemo
RR
25-45%
50-60%
Time to resp
8-12 wk
6-8 wk
Resp duration
12-16 m
8-12 m
Toxicity
Minimal
Mod-severe
Hormone Therapy
 Estrogen sources:
 ovaries (premenopausal)
 adrenal androgens converted by aromatase
 Premenopausal paradigm
 oophorectomy  Tam  progestin
 chemical (LHRH agonists), radiation,
surgical castration methods
 Postmenopausal paradigm
 Tam  aromatase inhibitor  progestin 
androgen
Chemotherapy in St IV disease
 Polychemotherapy > monotherapy for
response, survival benefit less clear
  Dose intensity =  effectiveness
  Effectiveness =  toxicity
 Multiple agents with different
mechanisms available
Chemotherapy Types in Breast Cancer
• Anthracyclines (DNA intercalators, topo II
inhibitors etc: doxorubicin, epirubicin,
mitoxantrone sort of)
• Taxanes (microtubule stabilizers: docetaxel,
paclitaxel)
• Alkylators (cyclophosphamide, platinums)
• Antimetabolites (fluorouracil, capecitabine,
methotrexate)
• Vinca alkaloids (microtubule inhibitors:
vinorelbine)
Therapeutic Surgery
• Modified radical mastectomy
– Breast, pectoral fascia, lower axillary lymph nodes
EQUALS
• Breast conservation with radiation (BCT)
– Lumpectomy with axillary node removal
– (sometimes not feasible)
IS BETTER THAN
• Breast conservation w/o radiation
– in breast recurrence up to 30%
Axillary node surgery
• Axillary dissection = removal of level I
and II lymph nodes. If negative,
likelihood of level 3 + < 5%.
• Purpose:
– Decreases local recurrence
– Prognostication
• Morbidity 5-10%: lymphedema, pain
Radiation Therapy
• Lumpectomy
– alone - 30% recur
– Radiation standard of care (510% local recurrence)
• Post-mastectomy
– T3, >3 LN - standard of care
– larger T2, 1-3 LN - controversial
• Overgaard M et al. NEJM 1997
• Ragaz J et al. NEJM 1997
– Ongoing Intergroup study
Local Treatment Morbidity
•
•
•
•
•
•
•
Lymphedema
Pneumonitis (RT)
Brachial plexopathy
RT osteonecrosis
Pericarditis
Secondary tumor (RT)
Postmastectomy pain
5-10%
1%
0.25%
1%
0.4%
0.2%
1-5%
Advances in Surgical Therapy
• Sentinel lymphadenectomy
– No need for full axillary dissection if
negative, minimizes toxicity such as
lymphedema
– Allows greater scrutiny of a few lymph nodes
• Neoadjuvant (preoperative) therapy
– Permits breast conservation by downstaging
Advances in Radiotherapy:
• Tailor Radiotherapy to Risk
– Adjuvant post-mastectomy treatment of select patients
improves survival
– Focusing on tumor bed in select patients may allow
rapid, convenient treatment
• Reduce ToxicityAdjuvant
– Conformal 3-D radiotherapy
– Partial breast treatment
Tailor Radiotherapy to Risk:
Tumor-targeted Treatment
Hormonal Risk Factors
• Early menarche (1-2% extra lifetime risk)
• Nulli- or late parity (~2% extra risk)
• Late menopause (½ - 1% extra risk/yr)
• Hormone replacement (½-1% extra risk/yr)
• Obesity (postmenopausal)
• Possible: no/less lactation
• Probably not: abortion, OCP
Benign and Preneoplastic
Breast Diseases
• Proliferation without atypia, minimal increase in
risk
• Proliferation with atypia, aka atypical hyperplasia.
Risk: 1%/yr.
• Lobular carcinoma in situ (LCIS). Risk: 1.3% /yr.
• Ductal carcinoma in situ (DCIS) = preneoplastic
lesion, must be treated aggressively.
Breast Cancer Risk Factors: Age
Risk factors
 Age: 1/3 pre-, 2/3 postmenopausal
 Race: white > black, Hispanic, Asian
 Positive family history (overall RR 2)
 Hormonal: estrogen exposure
 Breast disease (abnormal histology)
 Radiation therapy to chest
Solid DCIS,
uniform
monotonous
cell population
SCREENING
Mammography
• 8 randomized controlled trials
• U.S. Preventive Services Task Force
– Recommends yearly after age 40
– Studies reviewed 2/02
• Quality control issues
– FDA certification for facilities
– No similar certification for mammographers
Issues in Mammography Surveillance
• Technical limitations in premenopausal
• Aggressiveness of “interval” cancers
• Not all cancers are visible or palpable
Future Directions
• Digital approaches to lesion identification
• New technology: MRI
– Expensive
– Lots of “false positives”
MRI Measurements Pre/post Therapy
Pre-chemotherapy
LD=47 mm
Post-chemotherapy
(AC, 4 cycles)
LD=16 mm
Proportional risk : adjuvant chemo
(1995 Overview)
age
<40
40-49
50-59
60-69
Overall
%  relapse %  death
37
27
34
27
22
14
18
8
24
15
HER-2/neu Amplicon
*
*
*Coamplification of topo II and HER2
in HER2-amplified breast cancers
* Topo II is a target of anthracyclines
Jarvinen TA, et al Am J Pathol 2000
1.0
DFS Topo II Amplified vs NonAmplified All Patients
0.9
0.8
% Disease Free
Amplified
0.7
Non amplified
Patients
0.6
744
1376
Events Topo II
57
191
Amplified
Non amplified
Logrank P<0.001
0.5
0
1
2
3
Year from randomization
4
5
1.0
DFS Amplified Topo II by Arm
0.8
AC->T
TCH
Patients
AC->T
AC->TH
TCH
23
13
21
Logrank P= 0.24
0.6
227
265
252
Events Treatment
0.5
% Disease Free
AC->TH
0
6
12
18
24
30
Months
36
42
48
54
0.8
AC->TH
TCH
0.6
Patients Events Treatment
458
472
446
92
45
54
AC->T
AC->TH
TCH
Logrank P= <0.001
AC->T
0.0
% Disease Free
1.0
DFS Non-Amplified Topo II by Arm
0
6
12
18
24
30
Months
36
42
48
54
Steps in Metastasis
Efficiency
Intravasation
-
Impact on met
ability?
+
Circulation
+
-
Arrest in target
+
-
Extravasation
+
-
Survival
-
+
Growth
-
+
Persistence
-
+
From Chambers AF et al, Breast Cancer Research 2001