1. ASCO 2002 Advances in the Adjuvant Chemotherapy of Breast Cancer
Alessandro Riva, MD
Breast Cancer International Research Group

2. Adjuvant Chemotherapy NIH Consensus Conference: Nov, 2000
Polychemotherapy for women with T > 1 cm, regardless of nodal, menopausal, or hormone receptor status
Anthracycline-containing (ie, epirubicin or doxorubicin) regimens (4-6 cycles)
Taxanes not yet recommended: based on 3 phase III trials with paclitaxel
NIH Consensus Development Panel. J Natl Cancer Inst. 2001;93:

3. Adjuvant Chemotherapy EBCTCG Meta-Analysis: 1995, 2000
Reduction in Annual Odds, %
Therapy
Recurrence
Death
Polychemotherapy vs no chemotherapy (1995) (P < ) (P < )
Anthracyclines vs CMF (1995) (P = .006) (P = .02)
Anthracyclines vs CMF (2000) (P = .0005) (P < )
Taxanes vs. Not done Not done Anthracyclines

4. Adjuvant Paclitaxel in Breast Cancer Summary of Reported Trials
Sequential Regimens
Study
Regimen
No. of
Median
DFS OS
Pts
F/U
CALGB 9344
AC x 4
3,170 52 - mo
70%
81%
(Henderson, 2000)
AC x 4
P x 4 73 % 84 % P
=.032 P
=.074
NSABP B - 28
AC x 4
3,060 34 - mo
81%
90%
(Mamounas, 2000)
AC x 4
P x 4
81% 92 %
M.D. Anderson
FAC 4
FAC x 4
524 60 - mo
83% NR
(Buzdar, 2002)
P x 4
FAC x 4 86 %

5. Adjuvant Chemotherapy St
Adjuvant Chemotherapy St. Gallen Consensus: Feb, 2001 Taxanes not yet recommended
Goldhirsch et al. J Clin Oncol. 2001;19:

6. Adjuvant chemotherapy Major Areas of controversy (I)
Which patients should not be treated ?
Small primary tumor (Node neg., T< 1cm) ?
Elderly patients (> 70 years old) ?
ASCO 2002, Abs. 145: Epi-Dox+Tam vs. Tam
Which is the optimal duration of anthracycline-based therapy ?
3 months (4cy) vs. 5 to 6 months (6 cy)?
North American trial is planned

7. 4 cycles better than 6 cycles? Anthracycline vs. CMF
NSABP B-23 AC (4cy) = CMF (6cy)
Intergroup CAF (6cy) > CMF (6cy)
MA CEF (6cy) > CMF (6cy)
Danish-Swedish CEF (9cy) > CMF (9CY)

8. Adjuvant chemotherapy Major Areas of controversy (II)
Which is the best schedule of adjuvant chemo-hormonal therapy?
Sequential vs. concurrent?
ASCO 2002, Abs. 143 and 144
Which is the benefit of adding Taxanes?
Taxanes vs. no Taxanes ?
BCIRG 001, ASCO 2002, Abs. 141, TAC vs. FAC

9. BCIRG 001: Efficacy Summary
At 33 months median follow-up, TAC provides over FAC:
Primary endpoint: Disease-Free Survival
Overall 32% reduction (p=0.0011)
By nodal status : 50% reduction (p=0.0002)
4+: 14% reduction (p=0.33)
By hormonal status HR- : 38% reduction (p=0.005)
HR+: 32% reduction (p=0.02)
Relapse rate
Secondary endpoint: Overall Survival
Overall 24% reduction (p=0.11)
By nodal status : 54% reduction (p=0.006)
4+: No difference
Mortality rate

10. BCIRG 001 Disease Free Survival by HER2 status
Negative (FISH)
Positive (FISH)
100
100 90 90
TAC 80 80
% Alive and Disease Free
TAC 70
FAC 70 60 60 50
242 with missing FISH
RR = 0.74
p = 0.06 50
RR = 0.59
p = 0.02
FAC 40 40 12 24 36 48 12 24 36 48
Months
Months
N at Risk
N at Risk
TAC
485
467
433
102 1
TAC
138
131
118 32
FAC
478
455
402
108
FAC
148
135
107 26

11. BCIRG 001 Hematological Toxicity
Treated (n=1,480)
TAC n=744
FAC n=736 %
ANC <1000
65.1*
49.0
Febrile Neutropenia§
23.9*
2.4
Infection (Gr 3/4)
3.1
1.5
Septic Death
Anemia (Gr 3/4)
4.8*
2.2
Thrombocytopenia (Gr 3/4)
1.8
 Protocol required blood counts every 3 weeks
§ Gr 4 neutropenia at time of grade > 2 fever and i.v. antibiotics
* p0.05

12. TAC n=744 FAC n=736 % Nausea 5.1 9.5* Vomiting 4.3 7.3* Diarrhea 3.4*
BCIRG 001 Non-Hematological Toxicity Grade 3 or 4 with Incidence >1%
TAC n=744
FAC n=736 %
Nausea
5.1
9.5*
Vomiting
4.3
7.3*
Diarrhea
3.4*
1.0
Stomatitis
7.1*
2.0
Asthenia
11.2*
5.3
CHF
1.6
0.7
Premenopausal pts
n=383
n=375
Amenorrhea
51.4*
32.8
*p0.05

13. Year 2002 What do Taxanes add to anthracycline regimens?
Paclitaxel: CALGB 9344 (n=3170), NSABP B-28 (n=3060)
AC (60,600;4cy) vs. AC (60,600;4cy) ® P (4cy)
Docetaxel: BCIRG 001 (n=1491)
FAC (500,50,500;6cy) vs. TAC (75,50,500;6cy)

14. CALGB 9344/NSABP B-28 vs. BCIRG 001
Comparators
- Number of cycles: 4 (AC) vs. 6 (FAC)
- Total dose doxo: 240 vs. 300 mg/m2
Taxane containing arms
- Paclitaxel vs. docetaxel
- Sequential vs. combination
- 8 cycles (24 wks) vs. 6 cycles (18 wks)
Patient and tumor characteristics

15. Patient and Tumor Characteristics
CALGB 9344
NIH 11/00
(n=3170)
NSABP B-28
NIH 11/00
(n=3060)
BCIRG 001
ASCO 5/02
(n=1491)
Age<50
60%
51%
54%
1-3 Positive Nodes
46%
70%
62%
4+ Nodes
54%
30%
38%
T>2cm
63%
41%
60%
HR+
65%
66%
69%
%Tamoxifen
60%
84%
69%

16. CALGB 9344/NSABP B-28 vs. BCIRG 001
Use of Tamoxifen
CALGB 9344 and BCIRG 001:
- all patients HR+
- after chemotherapy
NSABP B-28:
- all patients > 50 yrs old
- all patients < 50 yrs and HR+
- concomitant with chemotherapy

17. Primary Endpoint: Disease-Free Survival
CALGB 9344
n=3170
CALGB 9344
n=3170
NSABP B-28
n=3060
BCIRG
001
n=1491
Med Follow-up
30mo
52mo
34mo
33mo
No. Events
624 (20%)
901 (28%)
551 (18%)
289 (19%)
Risk Reduction
Hazard Ratio
p-value
Log-rank
Cox model
22%
0.78
( ) NA
0.0022
13%
0.87
( ) NA
0.0324 7%
0.93
( )
0.38 NA
32%
0.68
( )
0.001
0.0002

18. Secondary Endpoint: Overall Survival
CALGB 9344
n=3170
CALGB 9344
n=3170
NSABP B-28
n=3060
BCIRG 001
n=1491
Med Follow-up
30mo
52mo
34mo
33mo
No. Events
Risk Reduction
Hazard Ratio
p-value
Log rank
Cox model
342 (11%)
26%
0.74
( ) NA
0.0065
589 (18%)
14%
0.86 NA
0.0746
269 (9%) 0%
1.00
( )
0.98 NA
133 (9%)
24%
0.76
( )
0.11
0.049

19. Absolute Differences Disease-Free and Overall Survival
% Patients Disease-Free
% Patients Alive
CALGB yr
AC ® P AC
% Difference 79 74 5 88 85 3
NSABP B-28 3-yr
BCIRG yr
TAC
FAC 82 8 92 87

20. Subgroup analyses: Hormone Receptor Status
CALGB 9344†
FDA 4/99
(n=3170)
BCIRG 001
ASCO 5/02
(n=1491)
Median Follow-up
DFS
Receptor Positive
Risk Reduction
Hazard Ratio
Receptor Negative
30mo 8%
0.92
( )
32%
0.68
( )
33mo
32%
0.68*
( )
38%
0.62**
( )
*p=0.02; **p=0.005
†Unplanned retrospective analysis

21. CALGB 9344 and NSABP B-28 Subgroup analysis
Relative Risk of Recurrence (95% CI)
Without Tam
With Tam
Adapted from the 2000 NIH Consensus Development Conference on Adjuvant Therapy for Breast Cancer.

22. Adjuvant Taxanes: Take home message
Adjuvant Taxanes improve DFS (Level 1 evidence?):
2 positive trials (CALGB 9344, BCIRG 001)
1 negative trial (NSABP B-28) but:
Tamoxifen concomitant to chemotherapy
Tamoxifen to all patients > 50 years old
Adjuvant Taxanes are becoming a reality for breast cancer patients:
Clinical practice
Comparators in the adjuvant trials
The full integration of adjuvant Taxanes need:
Longer follow up of the available studies: survival
Results from the completed trials (n=10,000 pts)

23. Adjuvant Taxanes-Combination Regimens Only docetaxel studies: PK rationale
ECOG (N+1-3, High risk N-, n=2,200, closed)
AT (4cy) vs. AC (4cy)
BIG (N+, n=2,900, closed)
AT (4cy) ® CMF (3cy) vs. AT (4cy) ® CMF (3cy)

24. OTHER ADJUVANT TRIALS WITH DOCETAXEL
SEQUENTIAL REGIMENS
ACCRUAL COMPLETED
BIG (N+) AC x 4  CMF x 3
AT x 4  CMF x 3
A x 4  CMF x 3
A x 3  T x 3  CMF x3 Italian Study (N>3) Epi x4  CMF x 4 Epi x4  T x 4  CMFx4
French Study (N+) FEC x 6 FEC x 3  T x 3
NSABP B-27 AC x 4  Surgery AC x 4  SurgeryT x 4
AC x 4  T x 4  Surgery
A = Adriamycin; C = Cyclophosphamide; M = Mitomycin C; F = 5 FU; T = Taxotere; E = Epirubicin

25. Adjuvant Taxanes Other open questions (I)
Which is the role of Taxanes in high risk node negative patients?
ECOG (AT vs. AC): High risk N- and N 1-3;
- n=2,200 (closed)
- is a subgroup analysis reliable enough?
GEICAM (TAC vs. FAC): High risk N-
- n=1,100 (ongoing)
- is the sample size large enough?

26. Adjuvant Taxanes Other open questions (II)
2. Which is the best Taxane?
Intergroup, AC ® T(weekly; q-3 weekly) vs.
AC ® P(weekly; q-3 weekly)
3. Which is the best schedule of a regimen containing Taxane and anthracycline ?
Sequential vs. combination (only docetaxel studies)
BCIRG 005, TAC (6) vs. AC (4) ® T (4)
NSABP B-30, TAC (4) vs. AT (4) vs. AC ® T

27. BCIRG ADJUVANT STUDIES INTEGRATION OF NEW AGENTS
Cytotoxic agents
Capecitabine (Planned)
Biologic agents
Trastuzumab (Ongoing)
TKIs (Planned)
Anti-VEGFs (Planned)

28. AC vs. A ® C Intergroup 0137, ASCO 2002, Abs 142
Patient population/Study design
N-, N1-3; n= 3176
AC (18 wks) vs. A (12 wks) ® C (6 wks)
Prophylactic G-CSF in both groups
Cumulative doses (mg/m2)
A=324 and C=7200 in both groups
Dose Intensity (mg/m2/wk)
AC: A=18; C=400
A ® C: A=27; C=1200

29. Adjuvant Taxanes Other open questions (II)
2. Which is the best Taxane?
Intergroup, AC ® T(weekly; q-3 weekly) vs.
AC ® P(weekly; q-3 weekly)
3. Which is the best schedule of a regimen containing Taxane and anthracycline ?
Sequential vs. combination (only docetaxel studies)
BCIRG 005, TAC (6) vs. AC (4) ® T (4)
NSABP B-30, TAC (4) vs. AT (4) vs. AC ® T