1. 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

2. 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?

3. 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?

4. 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

5. 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

6. 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.

7. 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

8. Adjuvant Trials AIs in Postmenopausal Women
Tamoxifen x 5 years
Upfront vs Tamoxifen
AI x 5 years
Tamoxifen x 5 years
Sequential vs Tamoxifen
Tamoxifen AI
Placebo x 5 years
Tamoxifen x 5 years
AI x 5 years
Extended Rx, AI vs Placebo

9. 5 years of AI is Established
ATAC: 100 month follow-up
Lower recurrence rate after 5 years, suggests carry-over effect
No new toxicity signals
No OS benefits
Forbes et al, Lancet 2008

10. ATAC: 100 Month Follow-up
Forbes et al, Lancet 2008

11. Big 1-98: 5-year Analysis DFS OS
Coates et al, J Clin Oncol 2007;25:486-92
Coates, A. S. et al. J Clin Oncol; 25:

12. IES Update 2007
Coombes, et al. Lancet 2007;369:559

13. ARNO 95 / ABCSG 8 / ITA Pooled Outcomes
Jonat, et al. Lancet Oncology 2006;7:991

14. MA.17
DFS OS
Goss, P. E. et al. J. Natl. Cancer Inst : ;
doi: /jnci/dji250

15. ASCO Guidelines
“The Panel believes that optimal adjuvant hormonal therapy for a postmenopausal woman with receptor-positive 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

16. 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 long-term 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 long-term gains

17. BIG 1-98: Design 2-Arm Option 4-Arm Option Previous Analyses:
RANDOMI ZE
RANDOMI ZE
2-Arm Option A
N=911
N=1,828
Enrolled
Tamoxifen B
SURGERY
Stratify
Institution
CT (Adjuvant/ Neoadjuvant)
-Prior
-None
-Concurrent
Letrozole
N=917
4-Arm Option
N=8,010*
RANDOMI ZE A
Tamoxifen
N=1548 B
Letrozole
N=1546
N=6,182
Enrolled
*ITT: excludes 18 patients who withdrew
consent and did not receive study treatment C
Tamoxifen
Letrozole
N=1548 D
Letrozole
Tamoxifen
N=1540 2 5
Years
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 17

18. 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:
Coates et al, J Clin Oncol 2007;25:486-92

19. 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 19

20. BIG 1-98 Sequential Treatment Disease-Free Survival
Mouridsen HT, et al: SABCS 2008, Abstr. 13 20

21. Sequential Treatment Comparisons Median Follow-up 71 months
Tam→Let vs. Let
Let→Tam vs. Let
Mouridsen HT, et al: SABCS 2008, Abstr. 13

22. 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 22

23. 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

24. 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 24

25. Duration of Therapy

26. 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

27. ATTom Results 2008
Gray et al, ASCO 2008

28. 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

29. Ongoing Studies to Establish Optimal Duration of AI Therapy: MA.17R
AI x 5y
Letrozole x 5y
Tam x 2y
AI x 5y
Placebo x 5y
Tamoxifen x 5y
Letrozole x 5y

30. 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
After some duration tam or AI

31. Can we identify which tumors and which patients will benefit most from
the different strategies at our disposal?

32. Heterogeneity of ER+ Breast Cancer
Tumors
HER2 status
PR status
Grade
Luminal A vs B, or other genetic signature
…and more
Patients
Variability in drug metabolism
CYP2D6
Risk of toxicity
…and more
And the lists will grow much longer in the years ahead

33. Rate of Distant Recurrence at 9 Years
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%
30%
Anastrozole
440
11%
12%
Lymph Node Positive
306
16%
27%
46%
152
14%
28%
42%
154
17%
25%
50%
Dowsett et al. SABCS 2008, Abstract 53

34. CYP2D6 and Tamoxifen Pharmacogenetics

35. CYP2D6 and Tamoxifen Metabolism
Goetz, M. P. et al. J Clin Oncol; 23:

36. CYP2D6 and Tamoxifen Metabolism CYP2D6 Polymorphism
Jin, JNCI 2005

37. Concomitant Drug Use and CYP2D6
Jin, JNCI 2005

38. Clinical Evidence Tamoxifen Pharmacogenetics and Clinical Outcomes
DFS OS
Goetz, et al JCO 2005

39. Clinical Evidence Tamoxifen Pharmacogenetics and Clinical Outcomes
Goetz, et al JCO 2005

40. AI Toxicities
Arthralgias
Sexual Dysfunction
Osteoporosis

41. AI Toxicities TEAM Trial
Jones, S. E. et al. J Clin Oncol; 25:

42. AI Trials Summary Trial Timing Comparison HRQOL Endocrine Symptom ATAC
Post surg
A vs. T
No effect
 Vag dryness, sexual dysfunction
TEAM
E vs. T NA
 Vag dryness, bone/muscle aches
IES
>2-3 Tam yrs
---
MA.17
> 5 yrs Tam
L vs. Pl
 Vasomotor symptoms, bodily pain, sexual dysfunction
From Whalen, 2006

43. 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 BL Day Day 28
LET <
LET <
LET
ANA <

44. 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

45. ATAC Arthralgia Incidence over Time
Sestak, et al. Lancet Oncology 2008

46. Diagnosis: AI-associated Joint Symptoms Pts referred to rheumatology at Michigan and Hopkins
Number of patients (%)
Bursitis
8 (21.1%)
  Trochanteric
6 (15.8%)
Carpal tunnel syndrome
Osteoarthritis
11 (28.9%)
  Knee
3 (7.9%)
  Hand
2 (5.3%)
Tendonitis
14 (36.8%)
  Rotator cuff/shoulder
8 (21.2%)
  Wrist
  Elbow
Patellofemoral syndrome
7 (18.4%)

47. AI Arthralgia Syndrome
Practical Suggestions
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

48. Fracture Rates in Adjuvant AI Trials
Aromatase
Inhibitor
Tamoxifen /
Placebo
% Increase
Reference
ATAC
340 (11%)
237 (7.7%)
43%
Howell et al 2005
BIG 1-98
228 (5.8%)
162 (4.1%)
41%
Thurlimann et al 2005
IES
162 (7.0%)
111 (4.9%)
45%
Coombes et al 2006
ABCSG/
ARNO
34 (2.0%)
16 (1.0%)
113%
Jakesz et al 2005
MA.17
137 (5.3%)
119 (4.6%)
15%
Perez et al 2006

49. Influence of Different AI Strategies on BMD
Years 4 3 2 1 -1 -2 -3 -4 -5 -6 -7 -8 x
% change
In BMD from
baseline
Anastrazole (ATAC)
Tamoxifen (ATAC)
Tamoxifen (IES)
Exemestane (IES)
Letrozole (MA-17)
Placebo (MA-17)
ATAC
IES
MA-17
Coleman et al Lancet Oncology 2007

50. ATAC: Annual Bone Fracture Rates
ATAC Trialists, Lancet Oncology 2008;9:45

51. 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

52. 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?

53. Q: Which patients with ER+ breast cancer should receive 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.

54. The Dilemma Just exactly who are those patients?

55. Current Recommendations for Chemotherapy for ER+ Breast Cancer
NIH Consensus Conference 2000
LN+
LN – if T > 1 cm
NCCN 2006
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

56. 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

57. Why Not Just Give Chemotherapy to Everyone?
The studies have major limitations
that affect their application to patients in 2000
Chemotherapy-induced amenorrhea
Treatment regimens not contemporary
e.g. chemotherapy without endocrine therapy
ER status
positive vs negative vs low/poor vs missing
Patient age
Absolute vs. relative benefit

58. Why Not Just Give Chemotherapy to Everyone?
The studies have major limitations that affect
their application to patients in 2006
Evolving taxonomy of breast cancer
Biological subsets of breast cancer defined by pathological markers or gene expression arrays
Quantitative levels of ER / PR
Introduction of HEr testing and anti-HER2 therapy
Neoadjuvant chemotherapy studies demonstrate lower chance of pCR in ER+ in patients
Lack of molecular predictors for chemotherapy benefit

59. Clinical Breast Cancer Subsets
65-75%
All Breast Cancer
HER2+
15-20%
Basaloid
15%

60. Adjuvant Treatment for a 2 x 2 Marker Model of Breast Cancer
HER2+
Trastuzumab Chemo
Endocrine
HER2 -
± Chemo
Chemo

61. Candidate Gene Selection From ~40,000 genes
Cancer Literature
Microarray
Data*
Genomic
Databases
384 cancer-related
genes*
Molecular
Biology
*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: , 2001

62. 16 Cancer and 5 Reference Genes
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
ESTROGEN ER PR
Bcl2
SCUBE2
INVASION
Stromolysin 3
Cathepsin L2
HER2
GRB7
BAG1
GSTM1
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
CD68
Best RT-PCR performance
and most robust predictions

63. Single Gene Analysis in ER+, Tam+ Patients from Multiple Studies

64. 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
x Proliferation Group Threshold Score
x Invasion Group Score
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: if RS<18;
Intermediate risk group: if 18≤RS<31;
High risk group: if RS≥31.

65. 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
Randomized
Registered
Placebo--Not Eligible
Tamoxifen--Eligible
B-14

66. B14-Results
DRFS - All 668 Patients
10 year DRFS = 85%

67. Oncotype DX™ Validation Study B-14
Rates of Distant Recurrence at 10 Years by RS Risk Category
Paik et al. NEJM 2004;351:2817

68. Oncotype DX™ NSABP B-14: RS Subgroups by Patient Age
All patients (N = 668)
All Pts
Low Risk (RS <18)
Int Risk (RS 18-30)
High Risk (RS ≥31)
Age >60
Age 50–60
Age 40–50
Age <40
40% % % 100%
% Distant Recurrence-free at 10 Years

69. Oncotype DX™ NSABP B-14: RS Subgroups by Tumor Grade
All Patients
N = 668
Well
Moderate
Poor
All Pts
Low Risk (RS<18)
Int Risk (RS 18-31)
High Risk (RS≥31)
20% % % 80% %
% Distant Recurrence-free at 10 Years

70. Recurrence Score and HER2 Status
RS Result
FISH +
FISH -
Low
334
Intermediate 5
142
High 50
129

71. Recurrence Score as a Continuous Predictor
95% CI

72. Recurrence Score as a Continuous Predictor
My RS is 30, What is the chance of recurrence within 10 yrs?
95% CI

73. 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

74. Outcome by Recurrence Score
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:

75. Linear fit of Distant Recurrence as a Continuous Function of RS for TAM and TAM + Chemo
Paik, S. et al. J Clin Oncol; 24:

76. SWOG 8814 Postmeno, ER+, LN+ Tam ± CAF
Disease-Free Survival by Treatment
1.00
SWOG 8814
Postmeno, ER+, LN+
Tam ± CAF
Albain, et al. SABCS 2007
Low risk (RS < 18)
0.75
Disease-free survival
0.50
Stratified log-rank p = 0.97 at 10 years
0.25
Tamoxifen (n=55, 15 events)
CAF-T (n=91, 26 events)
0.00 2 4 6 8 10
Years since registration
Disease-Free Survival by Treatment
Disease-Free Survival by Treatment
1.00
1.00
Intermediate risk (RS 18-30)
High risk (RS ≥31)
0.75
0.75
Disease-free survival
Disease-free survival
0.50
0.50
Stratified log-rank p = at 10 years
Stratified log-rank p = 0.48 at 10 years
0.25
0.25
Tamoxifen (n=47, 26 events)
Tamoxifen (n=46, 22 events)
CAF-T (n=71, 28 events)
CAF-T (n=57, 20 events)
0.00
0.00 2 4 6 8 10 2 4 6 8 10
Years since registration
Years since registration

77. TAILORx
Sparano, J. A. et al. J Clin Oncol; 26:

78. 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
B-14
Tamoxifen--Eligible
Randomized
Registered
Placebo--Not Eligible
Pre-specified 21 gene assay, algorithm, endpoints, analysis plan
Blinded laboratory analysis of three 10 micron tumor block sections

79. Benefit from Tamoxifen in the NSABP B14
by Oncotype DX Recurrence Score
Low Risk (RS<18) N
171
142 2 4 6 8 14 16
Years
0.0
0.2
0.4
0.6
0.8
1.0
DRFS
Placebo
Tamoxifen 12 10
Int Risk (RS 18-30) N 85 69 2 4 6 8 14 16
Years
0.0
0.2
0.4
0.6
0.8
1.0
DRFS
Placebo
Tamoxifen 12 10
High Risk (RS≥31) N 99 79 2 4 6 8 14 16
Years
0.0
0.2
0.4
0.6
0.8
1.0
DRFS
Placebo
Tamoxifen 12 10

80. How Many Genomic Assays Do We Need?

81. Multi-gene Arrays and Prediction of DFS in Cohort of ER+ Breast Cancer
Fan C et al. N Engl J Med 2006;
355:

83. 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

84. 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

85. Hormonally Sensitive, Early-Stage Breast Cancer
Clinical Updates
Hormonally Sensitive, Early-Stage Breast Cancer
Current Considerations in the Management of Patients with Hormonally Sensitive Early-stage Breast Cancer
Concluding Remarks