Transcript St. Gallen Geyer - Sisters Network

Adjuvant Therapy for Early
Breast Cancer Subtypes
Joyce O’Shaughnessy, MD
Baylor Sammons Cancer Center
Texas Oncology, PA
US Oncology
Dallas, TX
Encouraging…..
Peto, SABCS 2006
Sites of breast cancer metastases
CNS, brain
meninges
eyes (>20%)
bones (>60%)
lungs (>60%)
lymph nodes (>50%)
liver (>60%)
GI, peritoneum (>20%)
adrenals (~40%)
bones (>60%)
Traditional
approach
Node
negative
Node
positive
New Approach
HER-2+
Virulent
ER-, PRHER-2Basal-like
Virulent
ER++
Luminal A
Indolent
ER+
Luminal B
Virulent
Advances in Early Breast Cancer
• Adjuvant Herceptin for HER2+ disease
• Less adjuvant chemotherapy for
indolent, strongly ER+ disease
• Prolonged anti-estrogen therapy for
indolent, strongly ER+ disease
• Improving therapy for virulent ER, PR,
HER2-negative disease
HER2-Driven Breast Cancer
Fluorescence In Situ Hybridization (FISH)
HER-2
Adjuvant Herceptin + Chemotherapy
100
AC  T+ H
(n=1,989; 222 events)
92.3%
Alive and disease-free (%)
87.9%
80
86.4%
85.9%
77.6%
73.1%
60
AC  T
(n=1,979; 397 events)
N=619 events
HR*adj = 0.48 (95% CI: 0.41-0.57)
40
P < 0.00001
20
1,854
1,800
1,347
1,235
1
2
868
753
522
460
202
168
4
8
5
6
0
0
Perez E, et al. PASCO 2007
3
4
Follow-up (yrs)
Number
at risk
7
Despite 21% crossover!
Indolent ER and PR-Positive Breast Cancer
E2
ER
P
PR
Breast Cancer
•Tamoxifen and
Aromatase Inhibitorresponsive
More Virulent ER+ Breast Cancer
TAM
IGFR
Her-1 Her-2
ER
+
AIB1
An estrogen response
coactivator
PR
Schiff R, J Natl Cancer Inst 2003;95:353 - 361
Oncotype DX 21 Gene
Recurrence Score (RS) Assay
16 Cancer and 5 Reference Genes From 3 Studies
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
INVASION
Stromolysin 3
Cathepsin L2
HER2
GRB7
HER2
ESTROGEN
ER
PR
Bcl2
SCUBE2
GSTM1
CD68
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
RS = +
+
+
+
BAG1
0.47 x HER2 Group Score
0.34 x ER Group Score
1.04 x Proliferation Group Score
0.10 x Invasion Group Score
0.05 x CD68
0.08 x GSTM1
0.07 x BAG1
Category
RS (0 – 100)
Low risk
RS < 18
Int risk
RS ≥ 18 and < 31
High risk
RS ≥ 31
Recurrence Score in Node Negative, ER+ Patients
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
35
40
45
50
Recurrence Score
Paik S et al NEJM 2005
NCI Cooperative Groups TAILORx
Node-Negative, ER-Positive Breast Cancer
Register
Specimen
banking
21-Gene Recurrence
Score Assay
RS 11-25
RS <10
Hormone
Therapy
Registry
Randomize
Hormone Rx
vs
Chemotherapy +
Hormone Rx
Primary study group
RS >25
Chemotherapy
+
Hormone Rx
Annual Risk of Recurrence
For ER+ Patients
Percent Experiencing
Recurrence
12
9%
10
N=2257
10%
9%
8%
8
6
7%
7%
6%
6%
5%
5%
4%
3%
4
2
0
1
2
3
4
5
6
7
Years
Adapted from Saphner et al, JCO 1996
8
9 10 11 12
Benefit from Tamoxifen over 15 Years
Early Breast Cancer Trialists (Lancet 2005)
Adjuvant Trials of AIs in Postmenopausal Women
(Arimidex, Femara, Aromasin)
Tamoxifen x 5 years
Upfront AI vs Tamoxifen
AI x 5 years
Tamoxifen x 5 years
Tamoxifen
Sequential AI vs Tamoxifen
AI
Placebo x 5 years
Tamoxifen x 5 years
AI x 5 years
Extended Treatment Options in
ER+ Premenopausal Women
• Tamoxifen
• Tamoxifen + ovarian
suppression
IF POSTMENOPAUSAL, AI X 5 YEARS
Extended Treatment Options in ER+
Premenopausal Women
TAMOXIFEN x 5 YEARS
+/- Ovarian Suppression
Still Premenopausal
???????????
Continued tamoxifen
Oophorectomy or
Ovarian Suppression + AI
Basal-Like Breast Cancer (ER, PR, HER2-Negative)
Basal-like Tumors
Courtesy of Charles Perou, PhD
Breast Cancer Subtypes, Race and Age
Premenopausal
N
Basallike
HER2+
(ER-)
Luminal
A
Luminal
B
97
39%
9%
36%
9%
99
14%
7%
59%
16%
164
16%
6%
51%
18%
136
16%
6%
58%
16%
496
20%
7%
51%
16%
African-American
Postmenopausal
African-American
Premenopausal
non African-American
Postmenopausal
non African-American
TOTAL
P=0.0001
Carey LA et al, JAMA. 2006;295:2492-502
Chemotherapy Advances and ER-Negative Breast Cancer
ER-negative tumors = Basal-like and HER2+/ERReduction in Breast Cancer Recurrence
63%
70
60
50
40
36%
32%
25%
30
23%
14%
20
12%
ERER+
10%
10
0
8541
9344
9741
CALGB Trial
Overall
Berry DA et al, JAMA 2006
1.00
0.95
Adriamycin/Cytoxan
vs
Taxotere/Cytoxan
89%
0.90
TC
86%
P = 0.015
HR = 0.67
0.85
86%
AC
0.80
Disease-Free Survival
80%
0.75
DFS
0.70
0
12
24
36
48
60
72
M onths
1.00
94%
0.95
TC
0.90
93%
AC
0.85
87%
P = 0.131
HR = 0.76
0.80
Proportion Survivin
Jones et al, J Clin Oncol
2006
90%
OS
0.75
0.70
0
12
24
36
M onths
48
60
72
Preoperative ChemoRx in Basal-like Breast Cancer
T-FAC1
(N=82)
AC-T2
(n=107)
Luminal A/B
2/30 (7%)
4/62 (7%)
Normal-like
0/10 (0)
NA
HER2+/ER-
9/20 (45%)
4/11 (36%)
Basal-like
10/22 (45%)
9/34 (26%)
Regimen
Subtype
1 Rouzier et al, Clin Cancer Res 2005;
2 Carey LA et al, SABCS 2004
P<0.001
P=0.003
pCR (no residual disease in breast after
preoperative chemotherapy) defines risk of
recurrence
0.8
0.6
high-risk & no-pCR (125)
0.4
0.2
0.0
Prob Survival
1.0
high-risk & pCR (34)
Candidates for clinical trials for novel
therapies after surgery
0
Time (months)
20
40
60
80
100
PaikTime
NCI (months)
Preoperative Conference March 2007
Basal-Like Breast Cancer
Basal-like Tumors
Courtesy of Charles Perou, PhD
Cancer stem cells: are we missing the target?
Jones et al. JNCI 96:583, 2004
Courtesy of Jenny Chang, MD
Cancer stem cells: are we missing the target?
Jones et al. JNCI 96:583, 2004
Cancer stem cells: are we missing the target?
Jones et al. JNCI 96:583, 2004
Breast Stem Cell Survival
Notch
family
Hedgehog
family
Wnt
family
TGFβ
family
Growth Hormone
/Insulin-like GF
EGF
family
Estrogen
Progesterone
FGF
family
Self-renewal
Prolactin
Stem Cell
Modified from Clarke et al 2005
VEGF: Survival Factor for
Vasculature -- Avastin
Tumor
vessels
Normal
vessels
PARP Inhibitor + DNADamaging Chemotherapy
Basal Breast Cancer: Deficits in DNA Repair
Yap T ASCO 2007
Women’s Intervention Nutrition Study (WINS)
Evaluating Dietary Fat Reduction and Breast
Cancer Outcomes
Eligibility Criteria:
• Women 48-79 years
• Early breast cancer
R
A
N
D
O
M
I
Z
E
• Primary surgery ± RTx
• Systemic therapy (ER+:
tamoxifen/chemotherapy;
ER–: chemotherapy)
• Dietary fat intake > 20% of
calories
(n = 2437)
Dietary intervention: reduced fat
intake to about 35 fat grams/day
(15% kcals)
(n = 975)
Control
(n = 1462)
Primary Endpoint: Relapse-free survival
Randomization 60:40 within a year
from primary surgery
Chlebowski RT, et al. Breast Cancer Res Treat 2006; 100(suppl 1):S16 (abstract 32).
Change in BMI and Weight by Group
Variable
BMI (kg/m2)
Diet Minus Control Group
Year 1
Year 3
Year 5
-0.80
-0.77
(-1.1
(-1.3 to -0.3)
1.3 to -0.2)
(-1.9 to -0.4)
-5.0
-3.9
-6.0
(-8.0 to -2.1)
(-6.9 to -0.5)
(-9.9 to -1.9)
Weight (LBS)
All values, P < .005 versus control
BMI = Body Mass Index
All values for weight, P = .005, intervention versus control Information on weight and BMI was available for all
975 and 1462 women in the dietary intervention group and the control group, respectively, at baseline; for 854
and 1310 at year 1; 698 and 1044 at year 3; and 386 and 998 at year 5.
Chlebowski RT, et al. Breast Cancer Res Treat 2006; 100(suppl 1):S16 (abstract 32).
Relapse-Free Survival (ER+, PgR+)
HR 0.92; 95% CI, 0.71-1.19
Dashed line ---- Control
Solid line – Diet
;
Relapse-Free Survival (ER–, PgR–)
HR 0.46; 95% CI, 0.26-0.80
Dashed line ---- Control
Solid line – Diet
Fasting Insulin and Outcome in
Early Breast Cancer Patients
Goodwin, P, et al. J Clin Oncol 20:42-51, 2002
Goodwin, P. ASCO 2005
Body Mass Index and Outcome in
Early Breast Cancer Patients
Goodwin, P, et al. J Clin Oncol 20:42-51, 2002
Breast Cancer Lab Report of the Future
Jones, Mary A.
DOB: 4/22/47
MR#:555690
Dx: Breast cancer
Receptor status: ER-, Her2-, PR-, AR-
Activated pathway: Insulin-like growth factor receptor, AKT, mTOR
Basal-like Breast Cancer
Percentage of patients that have had this pathway activated in
breast cancer: 16%
Potential therapies:
RAD0001
Imatinib
Anti-IGFR antibody
Metformin
Exercise, low fat diet
Breast Cancer Mortality
Will the Progress Continue?
Clinical
Trials in
Breast
Cancer
Subtypes
Queensize panty
Hose –
one
size does
not fit
all !