Breast Cancer
Systemic Therapy for Early
Stage Disease
Julie R. Gralow, M.D.
Director, Breast Medical Oncology, Seattle Cancer Care Alliance
Professor, Medical Oncology, University of Washington School of
Medicine
Member, Clinical Division, Fred Hutchinson Cancer Research Center
Adjuvant Systemic Treatment
of Breast Cancer
• Breast cancer is most often curable when
detected in early stages
• Micrometastases exist at the time of
diagnosis in many patients, leading to
eventual recurrence
• Adjuvant systemic therapy has been found
to prolong both overall and disease-free
survival in breast cancer patients
Systemic Therapy for Breast Cancer
Endocrine Therapy
Chemotherapy
Biologically-targeted Therapy
New Strategies: Individualizing treatment
to the cancer and the patient
Systemic Treatment of Early Stage Breast
Cancer
• THE PAST (2000 NCI Consensus Development
Conference on Adjuvant Breast Cancer)
– Chemotherapy should be offered to the majority of
women with early stage breast cancer regardless of
size, lymph node, menopausal or hormone receptor
status
• THE PRESENT AND FUTURE
– Individualizing estimates of recurrence risk and
chemotherapy benefit using genomic/molecular
profiling
– Many patients don’t need chemotherapy
The Genomic Era
Understanding the Genetic Changes in Each
Individual Tumor
normal cell
atypical cell
Genetic change
cancer cell
Genetic change
Testing the acquired genetic makeup of the tumor
can lead to more effective treatment strategies
Genomics of Breast Cancer:
Breast Cancer is NOT One Disease!
Luminal Luminal HER-2+Basal
Normal
Subtypes vary with
Subtype A Subtype B
Subtype Breast–like
respect to:
• Likelihood of
recurrence
• Sites of
metastases
• Response to
treatment
Sorlie et al, Proc Natl Acad Sci 100:8418, 2003
Clinically Available Molecular Profiling
Assays in Breast Cancer
Genomic Health Oncotype Dx 21-Gene
Recurrence Score Assay
Agendia Mammaprint 70-Gene Prognostic Signature
Assay
Who Doesn’t Need Chemotherapy?
Oncotype Dx 21-Gene Recurrence Score Assay
Developed to help define which “low risk” patients do not need
chemotherapy, and which may benefit
Fixed (stored) tissue
Surgical
removal of
tissue
Recurrence
score
results
Extract
tumor
RNA
Tumor
evaluated
for 21
genes
•In lymph node negative, ER+ breast cancer:
•20% recurrence with tamoxifen only (may benefit from chemo)
•80% won’t recur with tamoxifen only (won’t benefit from chemo)
21 Gene Recurrence Score (RS) Assay: 16
Cancer Genes and 5 Reference Genes
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
INVASION
Stromolysin 3
Cathepsin L2
ESTROGEN
ER
PR
Bcl2
SCUBE2
GSTM1
CD68
BAG1
HER2
GRB7
HER2
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
21-Gene Recurrence Score Assay
Results (Oncotype DX)
Recurrence Score in LN-, ER+ if 5 Years Tamoxifen
RS of 39 = 27% 10 yr
distant relapse rate
despite tamoxifen
Lower RS
Higher RS
• Greater likelihood of recurrence
• Less likelihood of recurrence
• Less tamoxifen benefit
• Greater tamoxifen benefit
• Clear chemotherapy benefit
• No to minimal chemotherapy benefit
Endocrine Therapy
Estrogen and Breast Cancer
Aromatase
inhibitors, ovarian
suppression
Estrogen
SERMS, SERDS
Estrogen
Receptor
Cell
Growth
and
Division
Endocrine Therapy in Breast Cancer
• Selective Estrogen Receptor Modulators
– tamoxifen
– toremifene
– raloxifene
• Aromatase inhibitors (postmenopausal)
– anastrozole
– letrozole
– exemestane
• Medical or surgical oophorectomy (premenopausal)
• Selective Estrogen Receptor Downregulators
– fulvestrant
• Others: Progestins, Estrogens, Androgens
Selective Estrogen Receptor Modulators
Early Breast Cancer Trialists’ Collaborative Group 2000
(Oxford Overview)
Tamoxifen vs. Nil: Disease-free Survival
ER Negative
ER Positive
tamoxifen
nil
ER status matters!!
5 years of adjuvant
tamoxifen became
standard in ER+ patients
Aromatase Inhibitors
Anastrozole
Letrozole
Exemestane
Cortisol
Adrenal Hormones
Androstenedione
Estrone
Aromatase inhibitors
block post-menopausal
estrogen production
Aldosterone
Testosterone
Estradiol
Adjuvant Aromatase Inhibitors
Three Strategies
AIs as
Initial Therapy
AIs After
2-3 Yrs of TAM
TAM X 5 Yrs
TAM X 5 Yrs
AIs After
5 Years of TAM
AI X 5 Yrs
TAM X 5 Yrs
AI X 5 Yrs
TAM X 2-3 AI X 2-3
ATAC and BIG1-98 studies
Reduction in recurrences
Survival benefit for
AI arm
PLAC X 5 Yrs
Upfront Use of Aromatase Inhibitors vs.
Tamoxifen
ATAC Trial: Anastrozole vs. Tamoxifen
Howell A et al, Lancet 365:60-62, 2005
68 months follow-up:
17% relative reduction in events for A vs T
(3% absolute difference)
No difference in overall survival
BIG 1-98 Trial: Letrozole vs. Tamoxifen
Thurlimann B et al, NEJM 353: 2747-57, 2005
26 months follow-up:
19% relative reduction in events for L vs. T
(3% absolute difference)
No difference in overall survival
Extended Adjuvant Hormonal Therapy
Trials
MA17 Trial: Letrozole vs. Placebo After
Completing 5 Years of Tamoxifen
Goss P et al, J Natl Cancer Inst 97: 1262-71, 2005
30 months of follow-up:
42% decrease in breast cancer events
Node positive patients show statistically significant
improvement in survival
Ovarian Ablation in Early Stage Breast Cancer
Early Breast Cancer Trialists’ Collaborative Group 2000
(Oxford Overview)
Overall Survival
Ablation vs. Not
ablation
No ablation
Chemo/Ablation vs. Chemo
Chemotherapy
EBCTCG (Oxford Overview) 2000
Chemotherapy vs. Not: Deaths
(Overall 14.8% +/- 2.1 reduction)
Entry Age
Events/Women
Ratio annual deaths
Chemo
Control
Chemo: Control
29%+/-7
< 40
293/960
335/908
40-49
50-59
(30.5%)
(36.9%)
674/2480
783/2391
(27.2%)
(32.7%)
1658/4880
(34.0%)
60-69
70+
1918/5143
2000/4967
(37.9%%)
(40.3%)
(36.8%)
15%+/-3
(37.3%)
1851/4886
210/570
26%+/-5
7%+/-4
264/610
11%+/-11
(43.3%)
0.5
1.0
1.5
Survival Relative to Delivered Dose
Adjuvant CMF Therapy - 20 Year Follow-up
Milan Study (N = 386)
Bonadonna G et al, N Engl J Med 1995
Overall survival
1.0
Control
1.0
0.9
<65% of dose
0.9
0.8
65-84% of dose
0.8
85% of dose
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Probability of Overall Survival
Probability of Relapse-free Survival
Disease-free survival
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.0
5
10
15
Years after Mastectomy
20
5
10
15
Years after Mastectomy
20
Anthracyclines vs. CMF
EBCTCG (Oxford Overview) 2006 Meta-Analysis
Presented ASCO Educational Session 2007
• Many studies
with relatively
low doses of
anthracyclines
included in
analysis
• Magnitude of
benefit
probably
underestimated
Adjuvant Taxanes
CALGB 9344: AC +/- Paclitaxel in LN+ Breast Cancer
Henderson IC et al, J Clin Oncol 2003
A 60 vs 75 vs 90 mg/m2 +
C 600 mg/m2 q3 wks x 4
DFS (5 yrs)
OS
AC
65%
77%
T 175 mg/m2 q3 wks x 4
n=3,121
No T
AC + T
70%
HR = 0.83, p=0.0023
80%
HR = 0.82, p=0.0064
BCIRG 001: TAC vs FAC in Breast Cancer
Martin M, et al, N Engl J Med 2005
F 500 mg/m2
vs
A 50 mg/m2
C 500 mg/m2 q3 wks x 6
DFS (55 months)
OS
TAC
75%
87%
T (Docetaxel) 75 mg/m2
A 50 mg/m2
C 500 mg/m2 q3 wks x 6
FAC
68%
81%
n=1,491
HR = 0.72, p=0.001
HR = 0.7, p=0.008
Biologic Therapy
HER-2 as a Target for Therapy
HER-2 Oncogene: amplified and
overexpressed in 20-25% of
breast cancer
HER-2
Trastuzumab (Herceptin)
Anti-HER-2 Antibody
cancer cell
nucleus
Lapatinib (Tykerb)
Dual HER-1/HER-2
Tyrosine Kinase Inhibitor
cell division
26
Adjuvant Chemotherapy +/Trastuzumab: NSABP B-31 and N9831
Romond E et al, N Engl J Med 353, 2005
300
250
Number
of
patients
200
Chemo Alone
150
Chemo +
Trastuzumab
100
50
0
Recurrence
Death
•Risk of breast cancer recurrence reduced by 52% at 3 yrs
•Risk of death decreased by 33% at 2 yrs
Adjuvant Therapy in Breast Cancer:
The Future
• Clinical features, stage and biology all contribute to
risk of recurrence!
• Endocrine therapy critical in ER+ breast cancer
• In chemotherapy-sensitive breast cancers,
anthracycline and taxanes both add to disease
control
• Many patients don’t need chemo!
• Trastuzumab significantly reduces breast cancer
recurrence and death in HER2+
• Ongoing prospective trials are integrating traditional
and novel markers of risk to better define tailored
options for early-stage breast cancer