1. Optimizing Treatments for Early-Stage Breast Cancer
Experts Review
Clinical Application of Evolving Treatment Paradigms
Optimizing Treatments for Early-Stage Breast Cancer
Hyman B. Muss, MD
Professor of Medicine
University of Vermont
Fletcher Allen Health Care
Burlington, VT

2. Case 1
A 70-year old women in excellent health sees you in consultation for a 1.3 cm, moderately differentiated, infiltrating ductal carcinoma of the right breast
Sentinel nodes were negative
ER and PR positive
HER-2 negative by FISH

3. Case 1
Which of the following would you use or recommend to help make treatment recommendations?
Adjuvant! Online to estimate the value of endocrine therapy and chemotherapy
Oncotype DX® testing
All of the above
None of the above

4. Case 1
Which of the following would you use or recommend to help make treatment recommendations?
Adjuvant! Online to estimate the value of endocrine therapy and chemotherapy
Oncotype DX® testing
All of the above
None of the above
Recommended Approach:
Calculate treatment benefit from Adjuvant!
Oncotype® testing unless patient adamantly against chemotherapy
Neither Adjuvant! or Oncotype® are correct all the time and in 10% to 20% of patients may give opposite estimates

5. Adjuvant. Online Results 70-Year old with 1
Adjuvant! Online Results 70-Year old with 1.3 cm N-MDIDC, ER+/PR+/HER2-
From adjuvantonline.com; excellent health, TC 2nd gen chemo, OS 12% die of other causes
Adjuvantonline.com

6. Oncotype DX® 21 Gene PCR Assay
PROLIFERATION (5)
Ki-67, STK15,Survivin
Cyclin B1, MYBL2
RS =
Coefficient x Expression Level
x HER2 Group Score
x ER Group Score
x Proliferation Group Score
x Invasion Group Score
x CD68
x GSTM1
x BAG1
ESTROGEN (4)
ER, PR, Bcl2, SCUBE2
INVASION (2)
Stromolysin 3,Cathepsin L2
HER2 (2)
GRB7,HER2
Category
RS (0-100)
Mets 10y
Low risk
<18
0-11%
Int risk
≥18 to <31
12-21%
High risk
≥31
22%+
OTHER (3)
GSTM1, CD68, BAG1
REFERENCE (5)
β-actin, GAPDH. RPLPO
GUS,TFRC
Paik S, et al: NEJM 2004

7. Oncotype RS as a Continuous Predictor
RS is 30, What is the chance of recurrence within 10 yrs
if you take tamoxifen?
95% CI
Paik S, et al: NEJM 2004

8. Adjuvant! vs Oncotype DX
Correlation of Risk Indices
Concordance = 48%
Bryant J: St Gallen 2005

9. Case 1
(continued)
You present the patient with adjuvant online and oncotype results. She declines chemotherapy or entry into a clinical trial. What endocrine therapy would you suggest for this patient?
Tamoxifen
Aromatase inhibitor
Give patient both options and mutually decide?

10. Case 1
(continued)
You present the patient with adjuvant online and oncotype results. She declines chemotherapy or entry into a clinical trial. What endocrine therapy would you suggest for this patient?
Tamoxifen
Aromatase inhibitor
Give patient both options and mutually decide?
Recommended Approach:
Offer both options to patient

11. Case 1 Clinical Course The patient elects to take tamoxifen
You plan to switch her to an AI in two years
She declines and takes tamoxifen for five years
She is now 75-years old, healthy and has no toxicity with endocrine therapy

12. Tamoxifen x 5 Years ↓ Annual Odds Of Recurrence/Death (15-yr Follow-up)
EBCTG Lancet 2005 12

13. AI vs Tamoxifen Initial Rx
ATAC [anastrozole vs tamoxifen (T) vs both]
100 month follow
BIG (letrozole vs T vs L>T vs T>L)
Both show
3-5% improvement in RFS with AI
No improvement OS
No predictive marker for AI vs T 13

14. ATAC at 100 Months Anastrozole N = 3,125 Tamoxifen N = 3,116 HR/P
Disease-Free
74.2%
70.1%
.85/.003
Distant Mets
13.2%
15.6%
.84/.02
Contralateral BC
2.5%
4.2%
.60/.004
Overall Survival
79.9%
80.0%
1.0/.99
There is carryover effect years 5-9 (like tamoxifen)
No difference in MI for A vs T
Yearly fracture rate: A vs T = 2.9% vs 1.9% (Hip NS)
Endometrial cancer rates lower A vs T
Forbes et al SABCS 2007; abstract 41(revision to abst); Lancet Oncol. 2008;9:45-53 14

15. 5-year diff (L-T) = -3.2% (SE = 1.1)
BIG 1-98: Time to Relapse
7.9%
6.0%
10.2% L T 10 5 15 20
Proportion Relapse (%)
Years From Randomization 2 3 4 1
5-year diff (L-T) = -3.2% (SE = 1.1)
Cum. inc. P = .005
13.4%
Big 1-98 shows an almost identical pattern.
Of course, the appearance of an excess of relapses during the second year may reflect subclinical events during the first, so that we cannot safely conclude that switching at 1 year would not have incurred at least some of the later deficit.
Coates AS et al. J Clin Oncol 2007; 25:486 15 15

16. Switch to AI After 2-3 Years of Tamoxifen?
IES, BIG, ITA, ARNO/ABCSG 16

17. Intergroup Exemestane Study (IES) Trial Design
Post Treatment Follow-up
10,335*
Diagnosis
Tamoxifen R A N D O M I Z E
Exemestane
2,352
2,372
2-3 years
2-3 years study treatment
Total 5 years endocrine therapy
Start of study
Coombes et al. Presented at ASCO 2006 (abstract LBA527); Lancet 2007 17

18. IES at 56 Months (Events) Tam N = 2,372 Exemestane N = 2,352 HR P
Absolute
Difference
DFS
455
354
.76
0.0001
3.3% OS
261
222
.85
.05
1.6%
Coombes et al Lancet 2007

19. Case 1 (continued) After 5 years of tamoxifen, what would you do?
Discontinue endocrine therapy
Continue tamoxifen
Suggest consideration of an aromatase inhibitor
Other

20. Case 1 (continued) After 5 years of tamoxifen, what would you do?
Discontinue endocrine therapy
Continue tamoxifen
Suggest consideration of an aromatase inhibitor
Other
Recommended Approach:
She has an estimated survival of 12 years
Review tamoxifen and AI data
Suggest that patient consider AI therapy for five years
Preventing recurrence improves QOL
Toxicity should be minimal

21. Tamoxifen Duration: ATLAS Adjuvant Tamoxifen, Longer vs Shorter
Randomized trial
Tamoxifen 5 vs. 10 yrs
38 countries and 420 hospitals
11,500 patients (~follow-up 4.2 yrs/pt)
Data reasonably complete for first 10 yrs
ER+ 59%, others unknown
1,300 recurrences yr 5-9
Peto et al SABCS 2007, Abstract 48 LBA 21

22. Tamoxifen Duration: ATLAS Adjuvant Tamoxifen, Longer vs Shorter
RFS significantly better for longer tam
Recurrence T vs none: 739 vs 835
12% risk reduction for 5 more yrs (P = .0005)
Overall Survival and BC mortality lower but not significant
Safe but more endometrial cancer
Await year data
Peto et al SABCS 2007, Abstract 48 LBA 22

23. NCIC MA.17: Trial Design Tamoxifen Randomization Placebo daily
(all patients disease-free)
Placebo daily
Letrozole 2.5 mg daily
~ 5 years
5 years extended adjuvant
0-3 months
N = 2,593
N = 2,594
Primary end point: DFS
Secondary end points: OS/rate of contralateral breast cancer/safety/QOL
Goss PE et al: J Natl Cancer Inst 97:1262, 2005

24. Overall Survival MA-17 (30 Months)
P = 0.04
Node Positive
Node Negative
P = 0.34
Goss PE et al: J Natl Cancer Inst 97:1262, 2005 24

25. MA-17 Toxicity Letrozole Placebo P % Hot Flashes 58 54 .003 Fatigue 39NS
Vaginal Bleeding 6 8
.005
Arthritis 5
.07
Arthralgia 25 21
<.001
Myalgia 15 12
.004
High Cholesterol 16
Fractures
5.3
4.6
0.25
Cardiac Events
5.8
5.6
.76
Goss PE et al: J Natl Cancer Inst 97:1262, 2005 25

26. Case 2
A 58-year old women with well controlled hypertension sees you in consultation for a 1.8 cm, moderately differentiated, infiltrating ductal carcinoma of the left breast
Sentinel nodes were negative
ER and PR positive
HER-2 negative by FISH

27. Case 2
You’ve sent her tumor for Oncotype testing and are awaiting results. What is her estimated 10-year overall survival if you treated her with endocrine therapy alone?
85%
75%
65%
55%

28. Case 2
You’ve sent her tumor for Oncotype testing and are awaiting results. What is her estimated 10-year overall survival if you treated her with endocrine therapy alone?
85%
75%
65%
55%
Answer:

29. Case 2 Clinical Course She is randomized to chemotherapy
You offer her an ongoing clinical trial for patients with node negative tumors and she declines
I would offer her a second generation chemotherapy regimen as per Dr. Ravdin (adjuvantonline.com)

30. Adjuvant. Online Results 58-year old with 1
Adjuvant! Online Results 58-year old with 1.8 cm N-MDIDC, ER+/PR+/HER2-
From Adjuvantonline; minor problems, TC 2nd gen chemo, OS 8% die of other causes

31. Intergroup – PACCT TAILORx Trial
(Randomization ~ 4,390)
Node Negative ER+
Oncotype DX® Assay
RS < 11
Hormone
Therapy
Risk < 6%
RS 11-25
Randomize
Hormone Rx
vs.
Chemotherapy + Hormone Rx
Risk 6-17%
RS > 25
Chemotherapy +
Hormone Rx
Risk 18+%

32. Adjuvant! Online Dr. Ravdin
CT*4
1st
2nd
3rd

33. AC vs TC: US Oncology 9735 Are Anthracyclines Essential?D O M I Z E
Doxorubicin 60 mg/m2 IV Day 1
Cyclophosphamide mg/m2 IV Day 1
Every 21 days X 4 Cycles AC
Docetaxel 75 mg/m2 IV Day 1
Cyclophosphamide mg/m2 IV Day 1
Every 21 days X 4 Cycles TC
Jones SE, et al. SABCS Abstract 12.

34. Disease-free Survival by Treatment
Jones SE, et al. SABCS Abstract 12.

35. Overall Survival by Treatment
Jones SE, et al. SABCS Abstract 12.

36. Overall Survival by Treatment and by Age Group
Insert graphics here
Jones SE, et al. SABCS Abstract 12.

37. Grade 3-4 Hematologic Toxicity by Treatment and Age (%)
< 65 Years
≥ 65 Years TC AC
Adverse Event
428 Pts
78 Pts
82 Pts
Anemia
< 1 1 5
Neutropenia 60 54 52 59
Thrombocytopenia
Febrile Neutropenia 4 2 8
Jones SE, et al. SABCS Abstract 12.

38. Case 3
A 47-year old women in otherwise good health sees you in consultation for a 2.1 cm moderately differentiated infiltrating ductal carcinoma of the left breast
One of 3 sentinel nodes were positive
Axillary dissection revealed 2 other positive nodes of 16 removed
ER positive
PR negative
HER-2 positive (IHC 3+)
She declines participation in a clinical trial

39. Which of the following regimens would you recommend?
Case 3
Which of the following regimens would you recommend?
AC and trastuzumab
TC and trastuzumab
Docetaxel, carboplatin and trastuzumab (TCH)
AC (either q 3 weeks or dose-dense) followed by paclitaxel and trastuzumab (TH)
Other

40. Which of the following regimens would you recommend?
Case 3
Which of the following regimens would you recommend?
AC and trastuzumab
TC and trastuzumab
Docetaxel, carboplatin and trastuzumab (TCH)
AC (either q 3 weeks or dose-dense) followed by paclitaxel and trastuzumab (TH)
Other
Recommended Approach:
AC → TH (but TCH is a reasonable alternative)
Monitor cardiac function every 3 months
Add endocrine therapy after completion of chemotherapy/RT

41. Efficacy: Adjuvant Trastuzumab
One Year Duration
9 weeks
Telli, M. L. et al. J Clin Oncol; 25: 41

42. Kaplan-Meier Estimates of Disease-free Survival
(Panel A) and Overall Survival (Panel B)
Romond, E. H. et al. N Engl J Med 2005;353:

43. (Panels A and C) and Overall Survival (Panels B and D)
Effects of Single-Agent Docetaxel or Vinorelbine and Trastuzumab on the Kaplan-Meier Estimates of Recurrence-free Survival
(Panels A and C) and Overall Survival (Panels B and D)
Among Women with Breast Cancer
“Finnish Trial”
9 wks of trastuzumab
Only 39 recurred or died (small #) of 232 HER2+ randomized
Joensuu H et al. N Engl J Med 2006;354:

44. BCIRG: Disease-Free Survival (2nd Interim Analysis)
0.5
0.6
0.7
0.8
0.9
1.0 1 2 3 4 5
Patients
Events
1073
192
AC  T
1074
128
AC  TH
1075
142
TCH
81%
87%
86%
77%
83%
82%
93%
92%
HR (AC  TH vs AC  T) = 0.61 [0.48;0.76] P<0.0001
HR (TCH vs AC T) = 0.67 [0.54;0.83] P=0.0003
Year from randomization
Absolute DFS benefit (from years 2 to 4):
ACTH vs ACT: 6%
TCH vs ACT: 5%

45. Is Adjuvant Herceptin Needed For All Breast Cancer Patients?
Speculation ! (Ravdin)
60-Year Old Women. ER+, Her2+, average comorbidity.
Competeing mortality about 8%. To Get Tam + CA * 4, T * 4q3w
HER2 FISH+; Additional RR conferred by HER2: 1.5
Baseline 10 Year OS
With Tam and Chemo
Added Herceptin
Benefit Due to Herceptin
NP (1-3) T2
45 %
64 %
72 %
8 %
NN T2
59 %
74 %
79 %
5 %
NN T1c
81 %
86 %
88 %
2 %
NN T1ab
90 %
91 %
1 %
Risk of developing CHF 5%, 2/3 have symptoms resolve in 6 months.
Cardiac status at 10 years??

46. Issues for HER2+ Disease
Optimal duration
Role of anthracyclines (TCH)
Role of trastuzumab (Topo 2 ↑)
Cardiac Protection and monitoring
ACE inhibitors/beta-blockers up front?
Role of lapatinib
New agents

47. Case 4
A 67-year old women with well controlled adult onset diabetes sees you in for a 1.8 cm poorly differentiated infiltrating ductal carcinoma of the left breast
One of 2 sentinel nodes were positive (2.1 mm metastatic deposit)
Subsequent axillary dissection revealed 8 other negative nodes
ER negative
PR negative
HER2 negative
She declines participation in a clinical trial

48. Which of the following regimens would you recommend?
Case 4
Which of the following regimens would you recommend? AC TC
Docetaxel, doxorubicin and cyclophosphamide
AC followed by paclitaxel (dose dense)
AC (dose-dense or q 3 weeks) followed by weekly paclitaxel x 12
Other

49. Which of the following regimens would you recommend?
Case 4
Which of the following regimens would you recommend? AC TC
Docetaxel, doxorubicin and cyclophosphamide
AC followed by paclitaxel (dose dense)
AC (dose-dense or q 3 weeks) followed by weekly paclitaxel x 12
Other
Recommended Approach:
Chemotherapy regimen consisting of an anthracycline and taxane
Although she is older, she is in good health and should get similar benefits from these more intensive regimens as younger patients

50. ER Poor Chemo vs Not RFS OS All HR Absolute benefit <50 15% N+ .73
12%
.75 8%
50-69
58% N+
.82
10%
.87 6%
All P-values <.01
Lancet 371;29 January 2008 50

51. Kaplan-Meier Curves for Disease-free Survival According to Estrogen-Receptor (ER) Status in the 3 Studies
CAF 3 Doses
AC ± T
DD v Q3wk
ER-
ER+
Berry, D. A. et al. JAMA 2006;295:

52. Overall Survival for All Patients by Chemotherapy Intensity and Age Group
Muss HB et al. JAMA 2005;293:

53. Classification of Breast Cancer for Clinical Trials
Old
New
Node −
Node +
ER and PR
ER and PR
HER2

54. ER neg ER pos
Sorlie, et al. PNAS 2001

55. Overall and Relapse Free Survival by Tumor Types Defined with Gene Expression Patterns
Sorlie, et al. PNAS 2001.

56. Divide by ER and HER-2 and Conquer! (from Winer)
ER+/HER2-
(low grade; luminal A)
HER2- / ER-
(Triple Negative)
ER+/HER2-
(high grade; luminal B)
HER2+
ER+/ER-
Adapted with permission from E. Winer.

57. Optimizing Treatments for Early-Stage Breast Cancer
Experts Review
Clinical Application of Evolving Treatment Paradigms
Optimizing Treatments for Early-Stage Breast Cancer
Concluding Remarks