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Advances in Breast Cancer
Detection and Management
January 7, 2009
Rowan T Chlebowski MD, PhD
Professor of Medicine
David Geffen School of Medicine at UCLA
Los Angeles Biomedical Research Institute
at Harbor-UCLA Medical Center
DISCLOSURE
• Dr. Chlebowski receives research support
from Amgen and is a consultant for
Amgen, Astrazeneca, Novartis, Eli Lily and
Wyeth.
LEARNING OBJECTIVES
• To become familiar with the Women’s
Health Initiative results and impact on
breast cancer incidents
• To become familiar with current issues
regarding breast cancer detection
• To become familiar with recent results
from the San Antonio Breast Cancer
Symposium
WHI Hormone Program Design
YES
N= 10,739
CEE (Conjugated equine
estrogens) 0.625 mg/d
Placebo
Prior
Hysterectomy
NO
N= 16,608
CEE 0.625 mg/d +
medroxyprogesterone
acetate (MPA) 2.5 mg/d
Placebo
* Initially: CEE only (N=331), CEE+MPA, or Placebo
WHI Writing JAMA 2002; 288: 321
Chlebowski JAMA 2003; 289: 3253
Available online @ http://jama.ama-assn.org/
Clinical Trial: Sensitivity Analysis CEE+MPA vs. Placebo Breast
Cancer Risk During Intervention and Postintervention
P-trend-diff = 0.005
HR=1.26
(0.73, 2.20)
HR=1.26(0.73,2.20)
P-trend-diff = 0.005
1
HR(time)
2
4
HR=1.62 (1.10,
2.39)
HR=1.62(1.10,2.39)
HR=1.26(0.73,2.20)
1
0.25
0.5
P Trend-Diff
0.005
Linear time varying Hazard Ratio during Clinical Trial
Linear time
varying
Hazard
Ratio
during Clinical Trial
Linear
time varying
Hazard Ratio
during Post-Intervention
HR(95%CI)
basedHazard
on events accumulated
in 6 monthPostintervention
window
Linear time
varying
Ratio during
HR (95% CI) based on events accumulated in each 6 month window
0.125
0.25
0.125
HR(time)
0.5
2
4
HR=1.62(1.10,2.39)
Linear time varying Hazard Ratio during Clinical Trial
Linear time varying Hazard Ratio during Post-Intervention
HR(95%CI) based on events accumulated in 6 month window
0
1
0
2
1
3
2
3
Trial Time(yrs)
Trial Time(yrs)
4
4
5
0
1
5
0
1
2
2
2.5
2.5
Post Intervention Time (yrs)
Post Intervention Time (yrs)
WHI Clinical Trial Ppts With Mammograms by
Year and Randomization Group
Ppt with Mammograms (%)
100
83 82
83 83
80 80
78 78
50
CEE+ MPA
Placebo
0
2 Yrs
Before
1 Yr
Before
1 Yr
After
Intervention End
Chlebowski RT, Kuller L, Prentice R, et al. SABCS 2008, Abstract 64
2 Yrs
Before
Conclusions
The increased breast cancer risk associated
with combined estrogen plus progestin use
declines markedly after therapy discontinuation
and is unrelated to mammography utilization
change
These findings support the hypothesis that the
recent reduction in breast cancer incidence
seen in the United States in certain age groups
is predominantly related to a decrease in
combined estrogen plus progestin use
Breast Cancer Screening
Early detection of breast cancer is accomplished
through screening
Screening is undertaken to evaluate an
asymptomatic population in order to detect
unsuspected disease at a time when cure is still
possible
Breast cancer screening involves:
mammography, ultrasound, MRI
Digital Mammography or Standard
Testing
• Women under 50 years of age
• Women who were premenopausal or
perimenopausal
• Women classified as having heterogeneously
dense or extremely dense breast tissue
Digital mammography performed significantly
better in the detection of breast cancer
Breast MRI: Screening
• 45 cancers
– 22 seen on MRI only
– 10 seen on MRI and mammography
– 8 seen only on mammography
– 4 interval cancers
– 1 cancer detected on CBE only
Kriege et al NEJM July 2004
Breast MRI: Screening
Saslow et al CA Cancer J Clin 2007;57:75-89
San Antonio Breast Cancer
Symposium Update
Trial ABCSG-12: Endocrine Therapy With or
Without Zoledronic Acid
ABCSG-12:
1801 patients, stage I/II
< 10 nodes, ER and/or PgR+
No adjuvant chemo
Bone substudy (N = 404)
Surgery
+ RT
Goserelin
3.6 mg
q28d
1533 centrally reviewed
BMD measurements, both
trochanter and spine
R
A
N
D
O
M
I
Z
E
Gnant M, et al. SABCS 2007 (Abstract 26)
N = 103
+ Tamoxifen 20 mg/d
N = 100
+ Tamoxifen 20 mg/d +
Zoledronic acid 4 mg q6m
N = 96
+ Anastrozole 1 mg/d
N = 105
+ Anastrozole 1 mg/d +
Zoledronic acid 4 mg q6m
ABCSG-12 Trial of Endocrine Therapy
With or Without Zoledronic Acid:
First Efficacy Results
Tamoxifen
Anastrozole
(n = 900)
(n = 903)
Disease-Free Survival
65 events
Recurrence-Free
Survival
Overall Survival
HR
P
Value
72 events
1.096
.593
64 events
72 events
1.116
.529
15 events
27 events
1.791
.065
ZA
No ZA
(n = 899)
(n = 904)
HR
P
Value
Disease-Free Survival
54 events
83 events
0.643
.011
Recurrence-Free
Survival
54 events
82 events
0.653
.014
Overall Survival
16 events
26 events
0.595
.101
Gnant et al. ASCO 2008; abstract LBA4.
FIRST (Fulvestrant fIRst-line Study
Comparing Endocrine Treatments)
Phase II, randomized, open-labeled, multi-center
Advanced breast
cancer
ER positive
First line
Fulvestrant HD
(500 mg/mos plus 500 mg D14)
Anastrozole 1 mg/d
Ellis et al SABCS 2008, Abst 6126
Kaplain Meier Plot for Time to
Progression (TTP)
d
Integrated meta-analysis on
6634 patients with early breast cancer
receiving neoadjuvant
anthracycline-taxane +/- trastuzumab
containing chemotherapy
von Minckwitz G, Kaufmann M, Kümmel S, Fasching P, Eiermann W,
Blohmer JU, Costa SD, Loibl S, Mehta K, Untch M
for the
AGO
and
Treatment Group Effects
Use of Trastuzumab
in Patients with HER2-Positive Tumors
45%
ypTis No
ypT0 No
P<0.001
40%
35%
13.4%
pCR
30%
25%
20%
5.6%
15%
10%
27.7%
17.1%
5%
0%
w ithout Trastuzumab
N=736
w ith Trastuzumab
* excluding patients with HER2 negative or HER2 unknown tumors
N=671
A Phase II Study of Trastuzumab-DM1
(T-DM1), a HER2 Antibody-Drug Conjugate, in Patients with
HER2-Positive Metastatic Breast Cancer (MBC): Interim
Results
 DM1 is conjugated to trastuzumab via a non-reducible
thioether bond to a linker molecule (MCC).1
Average number DM1 molecules/monoclonal antibody=3.5
1. Beeram M., et al. J Clin Oncol. 2008; 26 (May 20 suppl; abstr 1028).
Prior Chemotherapy and Anti-HER2
Therapy
Prior Therapy
N=112
Median number of chemotherapy agents for
metastatic disease (range)
3 (1–12)
Prior anthracycline, n (%)
76 (67.9)
Median duration of prior trastuzumab therapy,
weeks (range)
76.6 (3–660)
62 (55.4)
Patients on prior lapatinib therapy, n (%) Median
duration of lapatinib therapy, weeks (range)
26.3 (3–106)
Analysis of Efficacy: Antitumor Activity
Median follow-up, 4.4 mo (19 weeks)
Tumor Response as
Assessed by Investigators
N
Overall ORR†
n (%)
(95% CI)
Confirmed‡ ORR†
n (%)
(95% CI)
All efficacy evaluable patients*
107
42 (39.3)
(30.0, 49.0)
29 (27.1)
(19.4, 36.1)
Subset of patients with ≥6 months
follow-up or have discontinued
study treatment
76
33 (43.4)
(32.6, 54.9)
29 (38.2)
(27.3, 50.0)
ORR=Objective response rate
* Because of limited follow-up, 19 patients have only had 1 post-baseline tumor assessment
† PR+CR
‡ Confirmed Objective response: Complete or partial response determined on two consecutive
occasions 4 weeks apart