1. 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

2. 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

3. Systemic Therapy for Breast Cancer
Endocrine Therapy
Chemotherapy
Biologically-targeted Therapy
New Strategies: Individualizing treatment to the cancer and the patient

4. 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

5. The Genomic Era Understanding the Genetic Changes in Each Individual Tumor
normal cell
atypical cell
cancer cell
Testing the acquired genetic makeup of the tumor can lead to more effective treatment strategies

6. Genomics of Breast Cancer: Breast Cancer is NOT One Disease!
Luminal Subtype A
Luminal Subtype B
Basal Subtype
Normal Breast–like
HER-2+
Subtypes vary with respect to:
Likelihood of recurrence
Sites of metastases
Response to treatment
A total of 115 breast cancer tumor tissues and 7 nonmalignant tissues were analyzed for characteristic patterns of gene expression measured by DNA microarrays applicable to classifying tumors into clinically relevant subgroups. Analysis was by hierarchical clustering based on patterns of expression of 534 “intrinsic” genes, delineated relative to 5 tissue subtypes:
One basal-like, 1 ErbB2 (HER2)-overexpressing (ERBB2+), 2 luminal-like (subtypes A and B), and 1 normal breast tissue–like
Slide shows the 5 recognized subgroups of coexpressed genes, with group C representing the ErbB2 (HER2)-overexpressing subgroup of genes.
Expression of the HER2 gene cluster is most pronounced in the ERBB2+ tissue subtype of tumors, hence its designation.
Results strongly support the contention that many breast cancer subtypes represent biologically distinct disease entities.
Sorlie et al, Proc Natl Acad Sci 100:8418, 2003
Sørlie et al. Proc Natl Acad Sci U S A. 2003;100:8418.

7. Clinically Available Molecular Profiling Assays in Breast Cancer
Genomic Health Oncotype Dx 21-Gene Recurrence Score Assay
Agendia Mammaprint 70-Gene Prognostic Signature Assay

8. 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
Extract tumor RNA
Surgical removal of tissue
Tumor evaluated for 21 genes
Recurrence score results
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)

9. 21 Gene Recurrence Score (RS) Assay: 16 Cancer Genes and 5 Reference Genes
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
ESTROGEN ER PR
Bcl2
SCUBE2
HER2
GRB7
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
INVASION
Stromolysin 3
Cathepsin L2
GSTM1
CD68
BAG1

10. 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
The Recurrence Score has been correlated with
Distant recurrence rate at 10 years assuming 5 years of tamoxifen treatment (the higher the score, the higher the distant recurrence rate)
Hormone therapy benefit (the lower the score, the greater the impact of tamoxifen (given for 5) years on 10 year distant recurrence-free survival)
Chemotherapy benefit (the higher the score, the greater the impact of chemotherapy on 10 year distant recurrence-free survival)
Lower RS
Less likelihood of recurrence
Greater tamoxifen benefit
No to minimal chemotherapy benefit
Higher RS
Greater likelihood of recurrence
Less tamoxifen benefit
Clear chemotherapy benefit

11. Endocrine Therapy

12. Aromatase inhibitors, ovarian suppression Cell Growth and Division
Estrogen and Breast Cancer
Aromatase inhibitors, ovarian suppression
SERMS, SERDS
Cell Growth and Division
Estrogen
Estrogen Receptor

13. 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

14. 5 years of adjuvant tamoxifen became standard in ER+ patients
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

15. Aromatase inhibitors block post-menopausal estrogen production
Anastrozole
Letrozole
Exemestane
Adrenal Hormones
Cortisol
Androstenedione
Aldosterone
Estrone
Testosterone
Aromatase inhibitors block post-menopausal estrogen production
Estradiol

16. Adjuvant Aromatase Inhibitors
Three Strategies
AIs as
Initial Therapy
AIs After
2-3 Yrs of TAM
AIs After
5 Years of TAM
TAM X 5 Yrs
TAM X 5 Yrs
AI X 5 Yrs
TAM X 5 Yrs
PLAC 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

17. 68 months follow-up:
17% relative reduction in events for A vs T
(3% absolute difference)
No difference in overall survival
Upfront Use of Aromatase Inhibitors vs. Tamoxifen ATAC Trial: Anastrozole vs. Tamoxifen Howell A et al, Lancet 365:60-62, BIG 1-98 Trial: Letrozole vs. Tamoxifen Thurlimann B et al, NEJM 353: , 2005
26 months follow-up:
19% relative reduction in events for L vs. T
(3% absolute difference)
No difference in overall survival

18. 42% decrease in breast cancer events
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: , 2005
30 months of follow-up:
42% decrease in breast cancer events
Node positive patients show statistically significant improvement in survival

19. Ovarian Ablation in Early Stage Breast Cancer Early Breast Cancer Trialists’ Collaborative Group 2000 (Oxford Overview) Overall Survival
Ablation vs. Not
Chemo/Ablation vs. Chemo
ablation
No ablation

20. Chemotherapy

21. EBCTCG (Oxford Overview) 2000 Chemotherapy vs. Not: Deaths (Overall 14
EBCTCG (Oxford Overview) Chemotherapy vs. Not: Deaths (Overall 14.8% +/- 2.1 reduction)
Entry Age Events/Women
Chemo Control
< / /908
(30.5%) (36.9%)
/ /2391
(27.2%) (32.7%)
/ /5143
(34.0%) (37.3%)
/ /4967
(37.9%%) (40.3%)
/ /610
(36.8%) (43.3%)
Ratio annual deaths
Chemo: Control
29%+/-7
26%+/-5
15%+/-3
7%+/-4
11%+/-11
0.5
1.0
1.5

22. 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
Disease-free survival
Overall survival
Control
1.0
1.0
<65% of dose
0.9
0.9
65-84% of dose
0.8
0.8
0.7
85% of dose
0.7
0.6
0.6
Probability of Overall Survival
Probability of Relapse-free Survival
0.5
0.5
0.4
20-year follow-up in 386 women randomized to no treatment following radical mastectomy (control, n = 179) versus radical mastectomy followed by 12 monthly cycles of adjuvant CMF (n = 207)
CMF = cyclophosphamide 100 mg orally days 1-14, methotrexate 40 mg/m2 IV days 1 and 8, fluorouracil 600 mg/m2 IV days 1 and 8. Cycles repeated every 4 weeks x 12
Reference:
Bonadonna G, Valagussa P, Moliterni A, et al. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. N Engl J Med 332: , 1995
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0.0
0.0 5 10 15 20 5 10 15 20
Years after Mastectomy
Years after Mastectomy

23. 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

24. 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 + T 175 mg/m2 q3 wks x 4
C 600 mg/m2 q3 wks x 4 No T
AC AC + T
DFS (5 yrs) 65% 70% HR = 0.83, p=0.0023
OS 77% 80% HR = 0.82, p=0.0064
n=3,121
BCIRG 001: TAC vs FAC in Breast Cancer Martin M, et al, N Engl J Med 2005
F 500 mg/m2 T (Docetaxel) 75 mg/m2
A 50 mg/m2 A 50 mg/m2
C 500 mg/m2 q3 wks x 6 C 500 mg/m2 q3 wks x 6
TAC FAC
DFS (55 months) 75% 68% HR = 0.72, p=0.001
OS % 81% HR = 0.7, p=0.008 vs
n=1,491

25. Biologic Therapy

26. 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

27. Adjuvant Chemotherapy +/- Trastuzumab: NSABP B-31 and N9831 Romond E et al, N Engl J Med 353, 2005
Number of patients
Risk of breast cancer recurrence reduced by 52% at 3 yrs
Risk of death decreased by 33% at 2 yrs

28. 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