Transcript Challenges in the Treatment of Breast Cancer: Overcoming

Clinical Updates
Hormonally Sensitive, Early-Stage Breast Cancer
Current Considerations in the Management of
Patients with Hormonally Sensitive
Early-stage Breast Cancer
Harold J. Burstein, MD, PhD
Dana-Farber Cancer Institute
Harvard Medical School
Boston, MA
Overview
• Case 1: Optimizing Therapy in Postmenopausal Women
– ER+, PR+, HER2 negative stage I breast cancer
• Case 2: Optimizing Therapy in Premenopausal Women
– Which patients with ER+ tumors should receive adjuvant
chemotherapy?
Case 1
• Postmenopausal Women
– T = 0.8 cm
– ER+
– PR+
– HER2 negative
– Stage I breast cancer
• What issues should be considered to optimize
endocrine therapy for postmenopausal women?
Key Issues in Adjuvant Endocrine Therapy
for Postmenopausal Women
• When to start an AI
• When to stop an AI
• Whether and how to use tamoxifen
– Tumor features (ER, PR, HER2)
– Clinical factors (patient preference, comorbidities)
– Pharmacogenomic factors
– Concurrent medication factors
• Minimizing side effects, esp. bones
• Late sequelae – good or bad – of AI therapy
Importance of Endocrine Therapy
• 2/3 of breast cancers are ER/PR+
• 3/4 of post-menopausal women have ER/PR+ tumors
• Overall little toxicity from endocrine treatment
• Significant benefit from optimizing use of endocrine
agents in the post-menopausal population
Adjuvant Endocrine Agents:
Tamoxifen
• Useful regardless of menopausal status
• In postmenopausal women:
– Reduces recurrence by 37 – 54%
– Reduces death by 11 – 33%
• Long-term side effects characterized
• Carryover effect documented
• Utility in sequence with AIs in post-menopausal women
Early Breast Cancer Trialists, Lancet 2005.
Adjuvant Endocrine Agents:
Aromatase Inhibitors
• Inhibit peripheral conversion of androgens to estrogens
by the aromatase enzyme
• 3 agents: anastrazole, letrozole, exemestane
• Utility of adjuvant AIs established through 3 trial
designs
– Upfront comparison with tamoxifen
• ATAC, BIG 1-98
– Sequential therapy after 2-3 years tamoxifen
• IES, ARNO/ABCSG, ITA
– Extended therapy after 5 years tamoxifen
• MA.17
Adjuvant Trials
AIs in Postmenopausal Women
Tamoxifen x 5 years
AI x 5 years
Upfront vs Tamoxifen
Tamoxifen x 5 years
Tamoxifen
AI
Sequential vs Tamoxifen
Placebo x 5 years
Tamoxifen x 5 years
AI x 5 years
Extended Rx, AI vs Placebo
5 years of AI is Established
• ATAC: 100 month follow-up
• Lower recurrence rate after
5 years, suggests carryover effect
• No new toxicity signals
• No OS benefits
Forbes et al, Lancet 2008
ATAC: 100 Month Follow-up
Forbes et al, Lancet 2008
Big 1-98: 5-year Analysis
DFS
OS
Coates, A. S. et al. J Clin Oncol; 25:486-492 2007
Coates et al, J Clin Oncol 2007;25:486-92
IES Update 2007
Coombes, et al. Lancet 2007;369:559
ARNO 95 / ABCSG 8 / ITA
Pooled Outcomes
Jonat, et al. Lancet Oncology 2006;7:991
MA.17
DFS
OS
Goss, P. E. et al. J. Natl. Cancer Inst. 2005 97:1262-1271;
doi:10.1093/jnci/dji250
ASCO Guidelines
“The Panel believes that optimal adjuvant hormonal
therapy for a postmenopausal woman with receptorpositive breast cancer includes an aromatase inhibitor
as initial therapy or after treatment with tamoxifen.
Women with breast cancer and their physicians must
weigh the risks and benefits of all therapeutic options.”
Winer, et al JCO 2004
The Debate
What is the Optimal Approach to the Use
of an AI in the Adjuvant Setting?
• Upfront AI x 5 years
– Proponents of an upfront AI cite early benefit and seek to
minimize risk of early relapse, hoping this will lead to longterm benefit
• Tamoxifen x 2 years followed by AI x 3-5 years
– Proponents of cross-over approach seek to minimize risk of
late recurrence by using two effective agents, hoping that
short-term losses will be more than compensated by longterm gains
BIG 1-98: Design
S
U
R
G
E
R
Y
R
R
A
A
N
N
D
D
O
O
M
Stratify
M
I
I
 Institution
Z
Z
E
 CT (Adjuvant/ E
Neoadjuvant)
-Prior
-None
-Concurrent
R
A
N
D
O
M
I
Z
E
2-Arm Option
A
Tamoxifen
N=911
B
Letrozole
N=917
N=1,828
Enrolled
1998-2000
4-Arm Option
N=8,010*
A
Tamoxifen
N=1548
B
Letrozole
N=1546
C Tamoxifen
Letrozole
N=1548
Letrozole
Tamoxifen
N=1540
D
0
2
Years
N=6,182
Enrolled
1999-2003
5
Previous Analyses:
Is 5 years Let superior to 5 years Tam as initial therapy?
• Primary Core Analysis (PCA), Median follow-up 26 months
• Monotherapy Arm Analysis, Median follow-up 51 months
*ITT:
excludes 18
patients who
withdrew
consent and
did not
receive
study
treatment
Summary of Previous Analyses
The PCA and monotherapy analyses showed that 5 years
upfront letrozole is significantly superior to 5 years of upfront
tamoxifen in terms of:
– Disease-free survival
– Time to distant recurrence
BIG 1-98 Collaborative Group, N Engl J Med 2005;353:2747-57
Coates et al, J Clin Oncol 2007;25:486-92
BIG 1-98 Monotherapy Update
Median Follow-up 76 months
*Let:Tam: breast cancer events, 321:363
second (non breast) malignancy, 101:115
deaths without prior cancer event, 87:87
Mouridsen HT, et al: SABCS 2008, Abstr. 13
BIG 1-98 Sequential Treatment
Disease-Free Survival
Mouridsen HT, et al: SABCS 2008, Abstr. 13
Sequential Treatment Comparisons
Median Follow-up 71 months
Tam→Let vs. Let
Let→Tam vs. Let
Mouridsen HT, et al: SABCS 2008, Abstr. 13
Breast Cancer Events
TamLet vs. Let
Overall
By Nodal Status*
*42% of the population is node positive; 58% node negative
Mouridsen HT, et al: SABCS 2008, Abstr. 13
Breast Cancer Events
LetTam vs. Let
Overall
By Nodal Status*
*42% of the population is node positive; 58% node negative
Mouridsen HT, et al: SABCS 2008, Abstr. 13
Conclusions
For postmenopausal women with endocrine-responsive
breast cancer
• Updated results of BIG 1-98 suggest superior overall survival with
letrozole compared with tamoxifen
• Adjuvant endocrine therapy should start with letrozole especially for
patients at higher risk for early recurrence
• Patients commenced on letrozole can be switched after 2 years to
tamoxifen, if required
• Safety is consistent with known safety profiles of each agent (data
not shown)
• Improved therapeutic approaches beyond five years are required to
control late relapses
Mouridsen HT, et al: SABCS 2008, Abstr. 13
Duration of Therapy
The Natural History of
HR+ Breast Cancer is Very Long
•
ER+ tumors demonstrate a
relatively constant hazard of
regression over time
•
After TAM x 5 years, over half of
all recurrences occur in years 6-15
(EBCTCG, Lancet 2005)
•
MA-17: risk of recurrence was
approx 2-3% each year on
placebo arm (Ingle, SABCS 2005)
•
With 5-8 years follow-up, none of
the AI trials are truly mature
Saphner et al, JCO 1996
ATTom Results 2008
Gray et al, ASCO 2008
How Long Should AI Be Administered
If Started After Tamoxifen?
• No direct evidence for more than 2-3 years of an AI
after a 2-3 years of tamoxifen, BUT…
– In MA-17, a 5 year course of an AI is safe and data through 4
years of follow-up demonstrate ongoing effectiveness
– In IES, benefit of E over T appears to be largely while patients
are on treatment
• Given these data, a 5 year course of AI treatment is
reasonable when switching to AI after 2-3 years of
tamoxifen
Ongoing Studies to Establish Optimal
Duration of AI Therapy: MA.17R
AI x 5y
Tam x 2y
Letrozole x 5y
AI x 5y
Placebo x 5y
Tamoxifen x 5y
Letrozole x 5y
Ongoing Studies to Establish
Optimal Duration of AI Therapy
> 10,000 pts will be studied
– NSABP B42
• Letrozole vs placebo;
N = 3,800
– SALSA
• Anastrazole 2y vs 5y;
N = 3,500
– SOLE
• 5y continuous vs
intermittent letrozole
– Dutch
• Anastrazole 3y vs
6y, N = 1,800
– GIM4
• Letrozole 2y vs
letrozole 5y;
N = 4,000
Can we identify which tumors and
which patients will benefit most from
the different strategies at our disposal?
Heterogeneity of ER+ Breast Cancer
Tumors
Patients
• HER2 status
• Variability in drug
metabolism
• PR status
• Grade
• Luminal A vs B, or other
genetic signature
– CYP2D6
• Risk of toxicity
• …and more
• …and more
And the lists will grow much longer in the years ahead
Risk of Distant Recurrence Using Oncotype DX
(21-Gene RS) in Patients Treated with
Anastrozole or Tamoxifen: ATTAC Study
• Objective was to evaluate the prognostic ability of 21-gene RS
assay in patients treated in ATAC study
• RS score was predictive of risk of recurrence in postmenopausal
patients with ER+ with either node negative or node positive
disease being treated with either tamoxifen or anastrozole
Rate of Distant Recurrence at 9 Years
Population
N
Low RS
Intermediate RS
High RS
Lymph Node Negative
872
4%
10%
22%
• Tamoxifen
432
3%
10%
30%
• Anastrozole
440
4%
11%
12%
Lymph Node Positive
306
16%
27%
46%
• Tamoxifen
152
14%
28%
42%
• Anastrozole
154
17%
25%
50%
Dowsett et al. SABCS 2008, Abstract 53
CYP2D6 and Tamoxifen Pharmacogenetics
CYP2D6 and Tamoxifen Metabolism
Goetz, M. P. et al. J Clin Oncol; 23:9312-9318 2005
CYP2D6 and Tamoxifen Metabolism
CYP2D6 Polymorphism
Jin, JNCI 2005
Concomitant Drug Use and CYP2D6
Jin, JNCI 2005
Clinical Evidence
Tamoxifen Pharmacogenetics and Clinical Outcomes
DFS
OS
Goetz, et al JCO 2005
Clinical Evidence
Tamoxifen Pharmacogenetics and Clinical Outcomes
Goetz, et al JCO 2005
AI Toxicities
• Arthralgias
• Sexual Dysfunction
• Osteoporosis
AI Toxicities
TEAM Trial
Jones, S. E. et al. J Clin Oncol; 25:4765-4771 2007
AI Trials Summary
Trial
Timing
Comparison
HRQOL
Endocrine Symptom
ATAC
Post surg
A vs. T
No effect
 Vag dryness, sexual
dysfunction
TEAM
Post surg
E vs. T
NA
 Vag dryness,
bone/muscle aches
IES
>2-3 Tam yrs
E vs. T
No effect
---
No effect
 Vasomotor
symptoms, bodily pain,
sexual dysfunction
MA.17
> 5 yrs Tam
L vs. Pl
From Whalen, 2006
Vaginal Estrogens for Genitourinary
Symptoms Related to AI Therapy
• Common complaint in postmenopausal women; aggravated
by estrogen deprivation of AI
• Topical / intravaginal estrogens may alleviate sx
• Are they safe?
• Kendall, SABCS 2005: E2 levels in women receiving
concurrent AI treatment and Vagifem 25 mg PV BIW
Estradiol Levels
AI
LET
LET
LET
ANA
BL
<3
<3
3.5
<3
Day 14
220
232
77
46
Day 28
40
31
16
2.4
AI Arthralgia Syndrome
Common complaint
• Symmetric
• Hands, feet, pelvis/hip, arms
• Pathognomonic criteria:
– “I aged overnight.” “I feel like an old lady.”
– Squeezing hands/joints gesture
• Etiology unclear
ATAC
Arthralgia Incidence over Time
Sestak, et al. Lancet Oncology 2008
Diagnosis: AI-associated Joint Symptoms
Pts referred to rheumatology at Michigan and Hopkins
Diagnosis
Bursitis
Trochanteric
Number of patients (%)
8 (21.1%)
6 (15.8%)
Carpal tunnel syndrome
8 (21.1%)
Osteoarthritis
11 (28.9%)
Knee
3 (7.9%)
Hand
2 (5.3%)
Tendonitis
14 (36.8%)
Rotator cuff/shoulder
8 (21.2%)
Wrist
3 (7.9%)
Elbow
2 (5.3%)
Patellofemoral syndrome
7 (18.4%)
AI Arthralgia Syndrome
Practical Suggestions
1. Alert patients to this side effect
2. Reassure patients that this is not associated with
destructive arthritis and that most cases are mild and
abate over time
3. Encourage weight reduction and regular exercise
4. For more severely affected patients, suggest AI
withdrawal to gauge relationship to treatment
5. Options: tamoxifen, other AIs, none
Fracture Rates in Adjuvant AI Trials
Aromatase
Tamoxifen /
Inhibitor
Placebo
ATAC
340 (11%)
BIG 1-98
IES
ABCSG/
ARNO
MA.17
% Increase
Reference
237 (7.7%)
43%
Howell et al 2005
228 (5.8%)
162 (4.1%)
41%
Thurlimann et al
2005
162 (7.0%)
111 (4.9%)
45%
Coombes et al
2006
34 (2.0%)
16 (1.0%)
113%
Jakesz et al 2005
137 (5.3%)
119 (4.6%)
15%
Perez et al 2006
Influence of Different AI Strategies on BMD
% change
In BMD from
baseline
4
3
2
1
0
-1
-2
-3
-4
-5
-6
-7
-8
x
ATAC
x
x
IES
MA-17
x
0
1
2
3
4
Anastrazole (ATAC)
Exemestane (IES)
Tamoxifen (ATAC)
Tamoxifen (IES)
5
x
x
6
7
Years
x Placebo (MA-17)
x Letrozole (MA-17)
Coleman et al Lancet Oncology 2007
ATAC: Annual Bone Fracture Rates
ATAC Trialists, Lancet Oncology 2008;9:45
Bone Health Guidelines
• Consider bone health when choosing adjuvant
endocrine therapies
• Check BMD at baseline when initiating AI therapy
• Recheck BMD at 1-2 years
• Initiate therapy for osteporosis / osteopenia according
to standard guidelines derived from normal
postmenopausal patient experience
• Interventions that “work” in general population with
osteopenia / osteoporosis also work in breast cancer
survivors
Case 2
• Premenopausal Women, 35 years old
– T = 1.5 cm
– ER+
– PR+
– HER2 negative
– Grade 2
– LVI+
• Which patients with ER+ tumors should receive
adjuvant chemotherapy?
Case 2
Optimizing Therapy in Premenopausal Women
Q: Which patients with ER+ breast cancer should receive
chemotherapy?
A: Those patients…
• where tumor is not eradicated by surgery, or radiation, or
adjuvant endocrine therapy, and
• where tumor is sensitive to chemotherapy, and
• where the patient is not likely to suffer gravely from other medical
conditions before breast cancer recurrence, and
• where the realistic benefits outweigh the risks of chemotherapy.
The Dilemma
Just exactly who are those patients?
Current Recommendations for
Chemotherapy for ER+ Breast Cancer
NIH Consensus Conference 2000
• LN+
• LN – if T > 1 cm
NCCN 2006
• LN+
• LN – if T > 1cm
• Consider for LN – if 0.6 to 1.0 cm
St. Gallen 2005 (endocrine responsive)
• LN + (>4 LN if HER2 negative, any if HER2+)
• Consider for LN – if: T > 2 cm, or grade 2-3, or LVI+, or
HER2+, or age < 35 years
Why Not Just Give
Chemotherapy to Everyone?
• Early Breast Cancer Trialists’ Group overview suggests
benefit for chemotherapy irrespective of ER status,
tamoxifen treatment, nodal status, or age
• Landmark trials show benefit of chemotherapy for women
with breast cancer compared to tamoxifen alone
– Postmenopausal node positive (SWOG 8814)
– Pre/postmenopausal node negative (NSABP B-20)
• 2nd / 3rd generation trials of optimal chemotherapy show
gains in outcome for ER+ and ER- tumors
Why Not Just Give
Chemotherapy to Everyone?
The studies have major limitations
that affect their application to patients in 2000
1.
Chemotherapy-induced amenorrhea
2.
Treatment regimens not contemporary
e.g. chemotherapy without endocrine therapy
3.
ER status
positive vs negative vs low/poor vs missing
4.
Patient age
5.
Absolute vs. relative benefit
Why Not Just Give
Chemotherapy to Everyone?
The studies have major limitations that affect
their application to patients in 2006
1.
Evolving taxonomy of breast cancer
Biological subsets of breast cancer defined by pathological
markers or gene expression arrays
2.
Quantitative levels of ER / PR
3.
Introduction of HEr testing and anti-HER2 therapy
4.
Neoadjuvant chemotherapy studies demonstrate lower
chance of pCR in ER+ in patients
5.
Lack of molecular predictors for chemotherapy benefit
Clinical Breast Cancer Subsets
ER+
65-75%
All Breast Cancer
HER2+
15-20%
Basaloid
15%
Adjuvant Treatment for a 2 x 2
Marker Model of Breast Cancer
HER2+
ER +
ER --
Trastuzumab Chemo
Trastuzumab Chemo
Endocrine
Endocrine
HER2 -
± Chemo
Chemo
Candidate Gene Selection
From ~40,000 genes
384 cancer-related
genes*
*Sources include:
1) Sotiriou et al., Breast Cancer Res Treat 4:R3, 2002
2) Scherf et al., Nat Genetics 24:236-44, 2000
3) Lamendola et al., Cancer Res 63:2200-5, 2003
4) Chang et al., Lancet 362:362-9, 2003
5) Staunton et al., Proc Natl Acad Sci U S A 98:10787-92, 2001
16 Cancer and 5 Reference Genes
ESTROGEN
PROLIFERATION
Best RT-PCR performance
and most robust predictions
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
GSTM1
HER2
CD68
GRB7
HER2
BAG1
ER
PR
Bcl2
SCUBE2
INVASION
Stromolysin 3
Cathepsin L2
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
Single Gene Analysis in ER+, Tam+
Patients from Multiple Studies
The Recurrence Score (RS)
• The recurrence score unscaled is defined as:
RSu= 0.47 x HER2 Group Threshold Score
– 0.34 x ER Group Score
+ 1.04 x Proliferation Group Threshold Score
+ 0.10 x Invasion Group Score
+ 0.05 x CD68 – 0.08 x GSTM1 – 0.07 x BAG1
• Then the RSu is rescaled to be between 0 and 100:
RS=(Rsu-6.7) x 20 and
If RS<0, then RS=0;
If RS>100, then RS=100.
• Classification into three groups:
Low risk group:
Intermediate risk group:
High risk group:
if RS<18;
if 18≤RS<31;
if RS≥31.
Genomic Health-NSABP B-14
Prospective Clinical Validation Study
• Objective
– Validate Recurrence Score as predictor of distant recurrence in N-, ER+,
Tamoxifen-treated patients
• Design
– Pre-specified 21 gene assay, algorithm, endpoints, analysis plan
– Blinded laboratory analysis of three 10 micron tumor block sections
B-14
Placebo--Not Eligible
Randomized
Registered
Tamoxifen--Eligible
Tamoxifen--Eligible
B14-Results
DRFS - All 668 Patients
100%
90%
80%
70%
10 year DRFS = 85%
60%
50%
DRFS
40%
30%
20%
10%
0%
0
2
4
6
8
Years
10
12
14
16
Oncotype DX™
Validation Study B-14
Rates of Distant Recurrence at 10 Years by RS Risk Category
Paik et al. NEJM 2004;351:2817
Oncotype DX™ NSABP B-14:
RS Subgroups by Patient Age
All patients (N = 668)
All Pts
59
Age <40
Age 40–50
Low Risk (RS <18)
Int Risk (RS 18-30)
High Risk (RS ≥31)
16
10
33
135
66
29
40
Age 50–60
Age >60
173
81
48
44
301
175
62
64
40%
60%
80% 100%
% Distant Recurrence-free at 10 Years
Oncotype DX™ NSABP B-14:
RS Subgroups by Tumor Grade
All Patients
N = 668
Well
224
166
41
17
Moderate
296
139
80
77
Poor
148
33
28
87
All Pts
Low Risk (RS<18)
Int Risk (RS 18-31)
High Risk (RS≥31)
20%
40%
60%
80%
100%
% Distant Recurrence-free at 10 Years
Recurrence Score and HER2 Status
HER2 Status
RS Result
FISH +
FISH -
Low
0
334
Intermediate
5
142
High
50
129
Recurrence Score as a Continuous Predictor
40%
Intermediate
Risk Group
Distant Recurrence at 10 Years
Low Risk Group
35%
High Risk Group
30%
25%
20%
15%
10%
5%
95% CI
0%
0
5
10
15
20
25
30
Recurrence Score
35
40
45
50
Recurrence Score as a Continuous Predictor
40%
Intermediate
Risk Group
Low Risk Group
Distant Recurrence at 10 Years
35%
High Risk Group
My RS is 30, What is the chance of
recurrence within 10 yrs?
30%
25%
20%
15%
10%
5%
95% CI
0%
0
5
10
15
20
25
30
Recurrence Score
35
40
45
50
Chemotherapy Response and Oncotype DX
NSABP Study B-20
Design:
Tam + MF
Randomized
Tam + CMF
Tam
Objective:
Determine the magnitude of the chemotherapy benefit as a function of 21 gene
Recurrence Score assay
NSABP B-20
Outcome by Recurrence Score
Overall
Int risk 18-30
Low risk < 18
High risk > 30
Paik, S. et al. J Clin Oncol; 24:3726-3734 2006
Linear fit of Distant Recurrence as a Continuous
Function of RS for TAM and TAM + Chemo
Paik, S. et al. J Clin Oncol; 24:3726-3734 2006
1.00
Disease-Free Survival by Treatment
Disease-free survival
0.25
0.50
0.75
SWOG 8814
Postmeno, ER+, LN+
Tam ± CAF
Stratified log-rank p = 0.97 at 10 years
Tamoxifen (n=55, 15 events)
CAF-T
(n=91, 26 events)
0.00
Albain, et al. SABCS 2007
Low risk (RS < 18)
0
2
4
6
8
10
Disease-Free Survival by Treatment
Disease-Free Survival by Treatment
1.00
1.00
0.25
Stratified log-rank p = 0.033 at 10 years
0
2
4
6
Years since registration
8
0.75
0.50
Stratified log-rank p = 0.48 at 10 years
Tamoxifen
CAF-T
0.00
Tamoxifen (n=47, 26 events)
CAF-T
(n=71, 28 events)
Intermediate risk (RS 18-30)
0.25
0.50
0.75
Disease-free survival
High risk (RS ≥31)
0.00
Disease-free survival
Years since registration
10
0
2
4
(n=46, 22 events)
(n=57, 20 events)
6
Years since registration
8
10
TAILORx
Sparano, J. A. et al. J Clin Oncol; 26:721-728 2008
Genomic Health-NSABP B-14
Prospective Clinical Validation Study
• Objective
– Validate Recurrence Score as predictor of distant
recurrence in N-, ER+, Tamoxifen-treated patients
• Design
Placebo--Not Eligible
B-14
Randomized
Tamoxifen--Eligible
Registered
Tamoxifen--Eligible
•Pre-specified 21 gene assay, algorithm, endpoints, analysis plan
•Blinded laboratory analysis of three 10 micron tumor block sections
Benefit from Tamoxifen in the NSABP B14
1.0
0.8
0.8
0.6
0.6
0.4
DRFS
1.0
Low Risk (RS<18)
0.2
Placebo
Tamoxifen
N
171
142
0.0
0
2
4
6
0.4
Int Risk (RS 18-30)
N
85
Placebo
Tamoxifen 69
0.2
8
12
10
Years
14
0.0
16
0
2
4
1.0
6
8
Years
0.8
DRFS
DRFS
by Oncotype DX Recurrence Score
0.6
0.4
High Risk (RS≥31)
0.2
Placebo
Tamoxifen
N
99
79
0.0
0
2
4
6
8
Years
10
12
14
16
10
12
14
16
How Many Genomic Assays
Do We Need?
Multi-gene Arrays and Prediction of DFS in
Cohort of ER+ Breast Cancer
Fan C et al. N Engl J Med 2006;
355:560-569
ASCO Tumor Marker Panel
Multiparameter Gene Expression Analysis for Breast Cancer
• Oncotype DX™ can be used to determine prognosis in newly
diagnosed patients with node-negative, estrogen-receptor positive
breast cancer who will receive tamoxifen. Indications:
– To predict risk of recurrence in patients considering treatment with tamoxifen
– To identify patients who are predicted to obtain the most therapeutic benefit from
adjuvant tamoxifen and may not require adjuvant chemotherapy
– Patients with high recurrence scores appear to achieve relatively more benefit
from adjuvant chemotherapy (specifically CMF) than from tamoxifen
• Conclusions may not be generalizable to hormonal therapies other
than tamoxifen, or to other chemotherapy regimens.
• Several other multi-parameter assays have been reported and a few
are commercially available, including Mammaprint and the
Rotterdam Signature. However, the Committee felt that the precise
clinical utility and appropriate application for these other assays were
insufficiently defined to recommend their use.
ASCO 2007; available at http://jco.ascopubs.org/cgi/content/full/25/33/5287
Case 2 Summary
Optimizing Therapy in Premenopausal Women
• Traditional criteria for recommending chemotherapy in
ER+ breast cancer relate to risk of recurrence, not
chemotherapy sensitivity
– T, N stage
– Age
• Chemotherapy benefits vary from tumor to tumor, and
thus patient to patient
• Genomic assays can inform the likelihood of sensitivity
to chemotherapy
Clinical Updates
Hormonally Sensitive, Early-Stage Breast Cancer
Current Considerations in the Management of
Patients with Hormonally Sensitive
Early-stage Breast Cancer
Concluding Remarks