Adjuvant Therapy for Early Breast Cancer Subtypes Joyce O

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Adjuvant Therapy for Early Breast Cancer
SubtypesJoyce OShaughnessy, MDBaylor Sammons
Cancer CenterTexas Oncology, PAUS
OncologyDallas, TX
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Encouraging..
Peto, SABCS 2006
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(No Transcript)
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Traditional approach
Node positive
Node negative
New Approach
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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

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HER2-Driven Breast Cancer
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Fluorescence In Situ Hybridization (FISH)

HER-2
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Adjuvant Herceptin Chemotherapy
100
86.4
80
77.6
73.1
60
AC ? T (n1,979 397 events)
Alive and disease-free ()
N619 events HRadj 0.48 (95 CI 0.41-0.57)
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P lt 0.00001
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Numberat risk
168
460
8
753
1,235
1,800
0
0
1
2
3
4
5
6
7
Follow-up (yrs)
Despite 21 crossover!
Perez E, et al. PASCO 2007
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Indolent ER and PR-Positive Breast Cancer
E2

• Breast Cancer
• Tamoxifen and Aromatase Inhibitor- responsive

ER
P
PR
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More Virulent ER Breast Cancer
TAM
IGFR
Her-1
Her-2
ER

AIB1
An estrogen response coactivator
PR
Schiff R, J Natl Cancer Inst 200395353 - 361
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Cross-talk between signal transduction and
endocrine pathways
IGFR
Trastuzumab
HER2
Plasma membrane
Anastrozole
Cell survival
p90RSK
Cell growth
Cytoplasm
Nucleus
Adapted from Johnston 2005
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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
ESTROGEN ER PR Bcl2 SCUBE2
BAG1
GSTM1
INVASION Stromolysin 3 Cathepsin L2
CD68
Category RS (0 100)
Low risk RS lt 18
Int risk RS 18 and lt 31
High risk RS 31
REFERENCE Beta-actin GAPDH RPLPO GUS TFRC
HER2 GRB7 HER2
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Recurrence Score in Node Negative, ER Patients
Paik S et al NEJM 2005
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RS as a Predictor of C/MF Chemotherapy Benefit in
Node (-), ER () Pts
Interm. Risk (RS 1830)

• Low Risk (RS lt 18)

10 yr
96
95
89
N Events 89 9 45
8
90
N Events 218 11 135
5
p 0.71
p 0.76
88
60
High Risk (RS 31)
N Events 117 13 47
18
p 0.001
Paik S, et al SABCS 2004
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NCI Cooperative Groups TAILORx
Node-Negative, ER-Positive Breast Cancer
Register Specimen banking
21-Gene Recurrence Score Assay
RS 11-25 Randomize Hormone Rx vs Chemotherapy
Hormone Rx
RS lt10 Hormone Therapy Registry
RS gt25 Chemotherapy Hormone Rx
Primary study group
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Annual Risk of Recurrence For ER Patients
N2257
10
9
9
8
7
7
6
6
5
5
4
3
Adapted from Saphner et al, JCO 1996
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Benefit from Tamoxifen over 15 Years Early
Breast Cancer Trialists (Lancet 2005)
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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
Sequential AI vs Tamoxifen
Tamoxifen

AI
Placebo x 5 years
Tamoxifen x 5 years
AI x 5 years
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Extended Treatment Options in ER Premenopausal
Women

• Tamoxifen

• Tamoxifen ovarian suppression

IF POSTMENOPAUSAL, AI X 5 YEARS
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Extended Treatment Options in ER Premenopausal
Women
TAMOXIFEN x 5 YEARS /- Ovarian Suppression
Still Premenopausal
??????????? Continued tamoxifen Oophorectomy
or Ovarian Suppression AI
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Basal-Like Breast Cancer (ER, PR, HER2-Negative)
Courtesy of Charles Perou, PhD
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Breast Cancer Subtypes, Race and Age
N Basal-like HER2 (ER-) Luminal A Luminal B
Premenopausal African-American 97 39 9 36 9
Postmenopausal African-American 99 14 7 59 16
Premenopausal non African-American 164 16 6 51 18
Postmenopausal non African-American 136 16 6 58 16
TOTAL 496 20 7 51 16
P0.0001
Carey LA et al, JAMA. 20062952492-502
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Chemotherapy Advances and ER-Negative Breast
Cancer
ER-negative tumors Basal-like and HER2/ER-
Reduction in Breast Cancer Recurrence
63
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32
25
23
14
12
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CALGB Trial
Berry DA et al, JAMA 2006
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Adriamycin/Cytoxan
vs Taxotere/Cytoxan
89
86
86
80
DFS
94
90
93
87
OS
Jones et al, J Clin Oncol 2006
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Preoperative ChemoRx in Basal-like Breast Cancer
Regimen Subtype T-FAC1 (N82) AC-T2 (n107)
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)
Plt0.001
P0.003
1 Rouzier et al, Clin Cancer Res 2005 2 Carey
LA et al, SABCS 2004
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pCR (no residual disease in breast after
preoperative chemotherapy) defines risk of
recurrence
high-risk pCR (34)
1.0
0.8
0.6
high-risk no-pCR (125)
Prob Survival
0.4
Candidates for clinical trials for novel
therapies after surgery
0.2
0.0
Time (months)
0
20
40
60
80
100
Time (months)
Paik NCI Preoperative Conference March 2007
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Basal-Like Breast Cancer
Courtesy of Charles Perou, PhD
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Cancer stem cells are we missing the target?
Jones et al. JNCI 96583, 2004
Courtesy of Jenny Chang, MD
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Cancer stem cells are we missing the target?
Jones et al. JNCI 96583, 2004
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Cancer stem cells are we missing the target?
Jones et al. JNCI 96583, 2004
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Breast Stem Cell Survival
Hedgehog family
Notch family
TGFß family
Wnt family
Growth Hormone /Insulin-like GF
EGF family
Estrogen
Progesterone
Self-renewal
FGF family
Stem Cell
Prolactin
Modified from Clarke et al 2005
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Primary Tumor Niche
Pre- Metastatic Niche
Fibronectin Id genes MMP-9 a4ß1 Osteopontin Cathep
sins VEGF bFGF
Fibronectin Id genes MMP-9 a4ß1 ? Osteopontin ?
Cathepsins
Peripheral Circulation
Sinusoidal Endothelial Cells
Bone Marrow Niches
HPC
Vascular Niche
ESC HSC MSC
megakaryocytes
Fibronectin Id genes MMP-9 sKitL a4ß1 Osteopontin
Cathepsins
Osteoblastic Niche
STROMA adipocytes
osteoblast osteoclast
fibroblasts
Trabecular Bone
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VEGF Survival Factor for Vasculature -- Avastin
Tumor vessels
Normal vessels
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PARP Inhibitor DNA-Damaging Chemotherapy
Basal Breast Cancer Deficits in DNA Repair
Yap T ASCO 2007
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Womens Intervention Nutrition Study (WINS)
Evaluating Dietary Fat Reduction and Breast
Cancer Outcomes

• Eligibility Criteria
• Women 48-79 years
• Early breast cancer
• Primary surgery RTx
• Systemic therapy (ER tamoxifen/chemotherapy
  ER chemotherapy)
• Dietary fat intake gt 20 of calories

RANDOMIZE
Dietary intervention reduced fat intake to
about 35 fat grams/day (15 kcals) (n 975)
Control (n 1462)
(n 2437)
Primary Endpoint Relapse-free survival
Randomization 6040 within a year from primary
surgery
Chlebowski RT, et al. Breast Cancer Res Treat
2006 100(suppl 1)S16 (abstract 32).
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Change in BMI and Weight by Group
Diet Minus Control Group Diet Minus Control Group Diet Minus Control Group
Variable Year 1 Year 3 Year 5
BMI (kg/m2) -0.80 (-1.3 to -0.3) -0.77 (-1.3 to -0.2) -1.1 (-1.9 to -0.4)
Weight (LBS) -5.0 (-8.0 to -2.1) -3.9 (-6.9 to -0.5) -6.0 (-9.9 to -1.9)
All values, P lt .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).
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Relapse-Free Survival (ER, PgR)
HR 0.92 95 CI, 0.71-1.19

Dashed line ---- Control
Solid line Diet

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Relapse-Free Survival (ER, PgR)
HR 0.46 95 CI, 0.26-0.80
Dashed line ---- Control

Solid line Diet
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Fasting Insulin and Outcome in
Early Breast Cancer Patients
Goodwin, P, et al. J Clin Oncol 2042-51, 2002
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Goodwin, P. ASCO 2005
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Body Mass Index and Outcome in
Early Breast Cancer Patients
Goodwin, P, et al. J Clin Oncol 2042-51, 2002
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Breast Cancer Lab Report of the Future
Jones, Mary A.
DOB 4/22/47 MR555690
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
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Breast Cancer MortalityWill the Progress
Continue?
Queen- size panty Hose one size does not
fit all !
Clinical Trials in Breast
Cancer Subtypes
2030
2010
2020