Kesho Conference

1. Breast Cancer 2014
S D Moodley
Wits Donald Gordon
Medical Centre

2. MBC milestones

3. Tamoxifen in MBC
1973
Ward
Ward. Br Med J 1973; 1: 13-14
60-77%
Stable disease or response
Tamoxifen monotherapy

4. CMF in MBC
33%
3 months
Overall response rate
Median survival
1976
Canellos
CMF vs L-phenylalanine mustard
Canellos et al. Cancer 1976; 38: 1882-1886
C, cyclophosphamide;
M, methotrexate;
F, 5-fluorouracil

5. Paclitaxel in MBC
First publication: Nabholtz et al. Proc Am Soc Clin Oncol 1993; 12: abs 42
1993
CA139-048
29%
4.2months
Paclitaxel monotherapy high vs low dose
Latest data (175 mg/m2 dose)
Overall response rate
Time to progression
Nabholtz et al. J Clin Oncol 1996; 14: 1858-1867

6. Aromatase inhibitors
in MBC
First publication: Jonat et al. Proc Am Soc Clin Oncol 1995; 14: abs 130
4.2 months Median survival
Buzdar et al. Cancer 1998; 83: 1142-1152
1995
Latest data
Arimidex Study Group trials 3 and 4
Anastrozole vs megestrol acetate

7. Docetaxel in MBC
First publication: Chan et al. Proc Am Soc Clin Oncol 1997; 16: abs 540
14.5% Overall response rate
1997
TAX 303
Docetaxel vs doxorubicin
2.7 months Median survival
TAX 304
Nabholtz et al. J Clin Oncol 1999; 17: 1413-1424
Latest data
Docetaxel vs mitomycin C + vinblastine
First publication: Nabholtz et al. Proc Am Soc Clin Oncol 1997; 16: abs 519
Latest data
Chan et al. J Clin Oncol 1999; 17: 2341-2354

8. Herceptin in MBC
First publication: Slamon et al. Proc Am Soc Clin Oncol 1998; 17: 98a, abs 377
1998
H0648g
Herceptin + chemotherapy vs chemotherapy
Herceptin Latest data + paclitaxel vs paclitaxel (HER2 IHC 3+ )
32% Overall response rate
7 months Median survival
Smith. Anticancer Drugs 2001; 12 (Suppl 4): S3-S10

9. EBC milestones

10. Adjuvant CMF
21%
Risk of recurrence
Bonadonna et al. BMJ 2005; 330: 217
1976
The CMF programme
CMF vs observation
C, cyclophosphamide;
M, methotrexate;
F, 5-fluorouracil
First publication: Bonadonna et al. N Engl J Med 1976; 294: 405-410
Latest data
29%
Risk of death

11. Adjuvant tamoxifen
36%
29%
Risk of recurrence
Risk of death
First publication: Lancet 1983; 1: 257-261
Br J Cancer 1988; 57: 608-611
1983
Latest data
NATO trial
Tamoxifen vs observation

12. Adjuvant anthracyclines
First publication: Levine et al. J Clin Oncol 1998; 16: 2651-2658
Risk of recurrence
Latest data
Levine et al. J Clin Oncol 2005; 23: 5166-5170
1998
NCIC MA.5
CEF vs CMF
24%
C, cyclophosphamide;
E, epirubicin;
F, fluorouracil;
M, methotrexate

13. Adjuvant taxanes
18%
Risk of recurrence
Risk of death
1998
CALGB 9344
AC→P vs AC
First publication: Henderson et al. Proc Am Soc Clin Oncol 1998; 17: 101a, abs 390A
17%
Latest data
A, doxorubicin;
C, cyclophosphamide;
P, paclitaxel
Henderson et al. J Clin Oncol 2003; 21: 976-983

14. Adjuvant aromatase inhibitors
First publication: Baum et al. Breast Cancer Res Treat 2001; 69: 210, abs 8
13% Risk of recurrence
2001
ATAC
Anastrozole vs tamoxifen
Howell et al. Lancet 2005; 365: 60-62
Latest data

15. Adjuvant Herceptin
36%
34%
Risk of recurrence
Risk of death
First presentation: Piccart-Gebhart et al. ASCO 2005
Smith et al. Lancet 2007; 369: 29-36
Latest data
3 further large studies have also demonstrated similar significant reductions in risk of relapse and risk of death
Romond et al. N Engl J Med 2005; 353: 1673-1684; Slamon et al. SABCS 2006; abs 52
2005
HERA
1-year Herceptin vs observation after chemotherapy

16. Herceptin landmarks
Defined as key studies in the evolution of Herceptin therapy
The data shown are from themost mature analyses available from these trials

17. Preclinical evidence for targeting HER2
Anti-HER2 monoclonal antibodies revert transformed
cells to non-transformed phenotype
Drebin et al. Cell 1985; 41: 697-706
1985

18. HER2 amplified in 15 to 30% of breast cancers
Link between HER2 expression and breast cancer
progression established
Slamon et al. Science 1987; 235: 177-182
1987

19. Herceptin + chemotherapy in MBC
First publication: Slamon et al. Proc Am Soc Clin Oncol 1998; 17: 98a, abs 377
1998
H0648g
Herceptin + chemotherapy vs chemotherapy
Herceptin Latest data + paclitaxel vs paclitaxel (HER2 IHC 3+ )
32% Overall response rate
7 months Median survival
Smith. Anticancer Drugs 2001; 12 (Suppl 4): S3-S10

20. First-line Herceptin monotherapy in MBC
2000
First publication: Vogel et al. Proc Am Soc Clin Oncol 2000; 19: 71a, abs 376
Vogel et al. Oncology 2001; 61 (Suppl 2): 37-42
Latest data
26%
Overall response rate
24 months
Median survival
H0650g

21. Herceptin + docetaxel in MBC
First publication: Extra et al. Breast Cancer Res Treat 2003; 82: 47, abs 217
2003
M77001
Herceptin + docetaxel vs docetaxel
8.5 months Median survival
Marty et al. J Clin Oncol 2005; 23: 4265-4274
Latest data
27% Overall response rate

22. Herceptin + anastrozole in MBC
Herceptin + anastrozole vs anastrozole
2.4 months Progression-free survival
Kaufman et al. Ann Oncol 2006; 17 (Suppl 9): LBA2
2006
TAnDEM
14.8% Clinical benefit rate

23. Adjuvant Herceptin
36%
34%
Risk of recurrence
Risk of death
First presentation: Piccart-Gebhart et al. ASCO 2005
Smith et al. Lancet 2007; 369: 29-36
Latest data
3 further large studies have also demonstrated similar significant reductions in risk of relapse and risk of death
Romond et al. N Engl J Med 2005; 353: 1673-1684;
Slamon et al. SABCS 2006; abs 52
2005
HERA
1-year Herceptin vs observation after chemotherapy

24. Herceptin® (trastuzumab)
for adjuvant therapy of
HER2-positive early breast
cancer (EBC)

25. Treatment guidelines
for HER2-positive EBC
Adjuvant
therapy Recommended patient groups Administration
1. Goldhirsch et al 2011; 2. Aebi et al 2011; 3. www.nccn.org
St.
Gallen1
1 year of
Herceptin®
(trastuzumab)
• HER2-positive tumours ≥1 cm
• HER2-positive node-negative tumours 0.51.0 cm
(pT1b)
• Excludes: HER2-positive node-negative tumours
0.10.5 cm (pT1a)
• Preferred: concurrent use of Herceptin®
(trastuzumab) with chemotherapy
• Acceptable: chemotherapy followed by
Herceptin® (trastuzumab) sequentially
ESMO2
1 year of
Herceptin®
(trastuzumab)
• HER2-positive tumours ≥1 cm
• Use of Herceptin® (trastuzumab) should be discussed
with patients with small node-negative HER2-positive
breast cancers
• Herceptin® (trastuzumab) may be started in
parallel with a taxane
• Herceptin® (trastuzumab) should not be given
concurrently with an anthracycline outside
the context of a clinical trial
NCCN3
1 year of
Herceptin®
(trastuzumab)
• Category 1 recommendation: patients with
HER2-positive tumours >1 cm
• Category 2A recommendation: patients with
HER2-positive node-negative tumours 0.6‒1.0 cm
• HER2-positive node-negative pT1a or pT1b tumours:
use of Herceptin® (trastuzumab) to be based on
individual benefit:risk
• Preferred: doxorubicin and
cyclophosphamide followed by concurrent
administration of Herceptin® (trastuzumab)
with taxane
• Preferred: docetaxel, carboplatin and
Herceptin® (trastuzumab), other regimen see
at NCCN
• Acceptable: chemotherapy followed by
Herceptin® (trastuzumab) sequentially
Herceptin® (trastuzumab) recommended
across international guidelines

26. Key Herceptin® (trastuzumab)
studies in HER2-positive EBC
CT, chemotherapy (*selected from a list of approved regimens consisting of ≥4 cycles);
RT, radiotherapy
1. Gianni et al 2011; 2. Slamon et al 2011; 3. Perez et al 2011
Study N Treatment arms
Follow-up
(years)
HERA1 5102
CT* ± RT  observation
CT* ± RT  Herceptin® (trastuzumab) 1 year
CT* ± RT  Herceptin® (trastuzumab) 2 years
4
BCIRG
0062 3222
AC  docetaxel
AC  docetaxel+Herceptin® (trastuzumab)  Herceptin®
(trastuzumab)
Docetaxel+carboplatin+Herceptin® (trastuzumab) 
Herceptin® (trastuzumab)
5
NCCTG
N98313 3505
AC  paclitaxel
AC  paclitaxel  Herceptin® (trastuzumab)
AC  paclitaxel+Herceptin® (trastuzumab)  Herceptin®
(trastuzumab)
4
NSABP
B-313 2101
AC  paclitaxel
AC  paclitaxel+Herceptin® (trastuzumab)  Herceptin®
(trastuzumab)
4
Extensive clinical programme involving >12,000 patients

27. HERA (BO16348)
HERceptin Adjuvant (HERA): a randomised
three-arm multicentre comparison of 1
year and
2 years of Herceptin® (trastuzumab) versus
no Herceptin® (trastuzumab) in women
with HER2-positive primary breast cancer
who have completed adjuvant
chemotherapy

28. HERA: study design
*Stratification factors: nodal status, adjuvant
CT regimen, hormone receptor status and
endocrine therapy, age, region
R
A
N
D
O
M
I
S
A
T
IO
N
Observation
(n=1698)
1 year of Herceptin®
(trastuzumab)
8 mg/kg6 mg/kg
3-weekly schedule
(n=1703)
2 years of Herceptin®
(trastuzumab)
8 mg/kg6 mg/kg
3-weekly schedule
(n=1701)
C
R
O
S
S
O
V
E
R
(n=885)
Piccart-Gebhart et al 2005: Smith et al 2007; Gianni et al 2011
HER2-positive
invasive EBC
(N=5102)*
Surgery +
(neo)adjuvant
CT±RT

29. HERA: endpoints I
• Primary endpoint
– Disease-free survival (DFS)
• Herceptin® (trastuzumab) 1 year vs observation
• Herceptin® (trastuzumab) 2 years vs observation
• Secondary endpoints include:
– Overall survival (OS) and cardiac safety
• Herceptin® (trastuzumab) 1 year vs observation
• Herceptin® (trastuzumab) 2 years vs observation
– DFS, OS, RFS, DDFS, TTR, TTDR, cardiac safety,
overall safety
• Herceptin® for 1 year vs Herceptin® for 2 years
– Safety and tolerability of Herceptin®
– Cardiac dysfunction of Herceptin® vs observation
Piccart-Gebhart et al 2005: Smith et al 2007; Gianni et al 2011

30. HERA: disease-free survival at all
time points
Consistent disease-free survival benefit for
Herceptin® (trastuzumab) vs observation
Median
follow-up
CI, confidence interval;
HR, hazard ratio
DFS benefit
Favours
Herceptin®
(trastuzumab)
Favours no
Herceptin®
(trastuzumab)
1. Piccart-Gebhart et al 2005; 2. Smith et al 2007; 3. Gianni et al 2011
1 year1
2 years2
4 years3
Number of DFS events
Herceptin® (trastuzumab)
vs observation
127 vs 220
p<0.0001
218 vs 321
p<0.0001
369 vs 458
p<0.0001
0 1 2
HR (95% CI)

31. HERA: overall survival at all
time points
Overall survival benefit for Herceptin® (trastuzumab)
loses significance at 4 years due to extensive crossover
No. of deaths
Herceptin® (trastuzumab)
vs observation
29 vs 37
p=0.26
Median
follow-up
20051
1 year
59 vs 90
p=0.0115
182 vs 213
p=0.1087
20062
2 years
20083
4 years
OS benefit
Favours
Herceptin®
(trastuzumab)
0 1 2
Favours
observation
HR (95% CI)
1. Piccart-Gebhart et al 2005; 2. Smith et al 2007; 3. Gianni et al 2011

32. HERA: adverse events and cardiac
endpoints
Low incidence of cardiac adverse events with
Adverse event (AE), n (%)
Herceptin® (trastuzumab)
Observation*
(n=1719)
Herceptin®
(trastuzumab)
1 year (n=1677)
Patients with ≥1 Grade 3/4 AE 131 (8) 239 (14)
Patients with ≥1 SAE 129 (8) 199 (12)
Fatal AEs 6 (0) 12 (1)
Treatment withdrawals – 176 (11)
Cardiac endpoints
Cardiac death 1 (0) 0
Symptomatic CHF (II, III and IV)† 2 (0) 33 (2)‡
Confirmed significant LVEF drop§ 13 (1) 62 (4)
Herceptin® (trastuzumab) discontinued due to
– 87 (5)
cardiac problems
Any type of cardiac endpoint 14 (1) 75 (5)
*Crossover patients were censored from the date of starting Herceptin® (trastuzumab);
†Not including cardiac death
‡20 New York Heart Association II and 13 New York Heart Association III and IV
§ Asymptomatic or mildly symptomatic Gianni et al 2011

33. BCIRG 006
Multicentre Phase III randomised trial comparing
doxorubicin and cyclophosphamide followed by
docetaxel (ACT) with doxorubicin and
cyclophosphamide followed by docetaxel and
Herceptin® (trastuzumab) (ACTH) and with
docetaxel, carboplatin and Herceptin®
(trastuzumab) (TCH) in the treatment of node-positive
and high-risk node-negative adjuvant
patients

34. BCIRG 006: study design
6 x T + C
ACT
AC  TH
TCH
1 year of Herceptin® (trastuzumab)
HER2-positive
Node-positive or
high-risk
node-negative EBC
N=3222
Stratified by nodes and hormone-receptor
status
4 x AC  4 x T
1 year of Herceptin® (trastuzumab)
AC: Doxorubicin 60 mg/m2 + cyclophosphamide 600 mg/m2 q3w x 4
T: Docetaxel 100 mg/m2 q3w x 4 (75 mg/m2 q3w x 6 when combined with carboplatin)
C: Carboplatin AUC 6 q3w x 6
H: Herceptin® (trastuzumab) was administered weekly during chemotherapy (4 mg/kg loading dose, then
2 mg/kg qw), followed by 6 mg/kg q3w as monotherapy for a total treatment duration of 12 months
Slamon et al 2011
4 x AC  4 x T

35. BCIRG 006:
end points and analyses
• Primary
– Disease-free survival (DFS)
• Local/regional/distant
recurrence
• 2nd primary invasive
cancers
• Death due to any cause
• Secondary
– Overall survival (OS)
– Safety
– Pathological and molecular
markers for predicting
efficacy
1st interim efficacy
analysis after
322 DFS events (23 months)1
2nd interim efficacy
analysis after
462 DFS events (36 months)2
3rd interim efficacy
analysis after
656 DFS events (65 months)3
1. Slamon et al 2005; 2. Slamon et al 2006; 3. Slamon et al 2011

36. Alive and disease-free (%)
BCIRG 006: disease-free survival
at 5 years of follow-up
Slamon et al 2011
Years from randomisation
ACTH 84%
TCH 81%
ACT 75%
Significant disease-free survival benefit with
Herceptin® (trastuzumab) in both regimens
0 1 2 3 4 5 6
100
80
60
40
20
0
n Events HR 95% CI p value
ACTH 1074 185 0.64 0.53‒0.78 <0.001
TCH 1075 214 0.75 0.63‒0.90 0.04
ACT 1073 257 1 (ref) − −

37. BCIRG 006: overall survival at 5
ACTH 92%
TC H 91%
ACT 87%
years of follow-up
Years from randomisation
Slamon et al 2011
Significant overall survival benefit with
Herceptin® (trastuzumab) at long-term follow-up
n Events HR 95% CI p value
ACTH 1074 94 0.63 0.48‒0.81 <0.001
TCH 1075 113 0.77 0.60‒0.99 0.0038
ACT 1073 141 1 (ref) − −

38. BCIRG 006: summary of efficacy
endpoints at 5-year follow-up
Consistent efficacy benefit of Herceptin® (trastuzumab) with
anthracycline-based and non-anthracycline-based regimens
185 vs 257 0.64 (0.530.78)
Slamon et al 2011
No. events
Herceptin®
(trastuzumab)
vs observation
HR
(95% CI)
214 vs 257 0.75 (0.630.90)
0.0 0.5 1.0 1.5
DFS
OS
ACTH
TCH
ACTH
TCH
94 vs 141 0.63 (0.480.81)
113 vs 141 0.77 (0.600.99)
HR (95% CI)
Favours
Herceptin® (trastuzumab)
Favours
observation

39. BCIRG 006: Grade 3/4 non-haematological
adverse events
Low incidence of Grade 3/4 non-haematological AEs
Events, %
across treatment groups at 5 years of follow-up
*Statistically significantly fewer events
ACT
(n=1050)
ACTH
(n=1068)
TCH
(n=1056)
Arthralgia 3.2 3.3 1.4*
Myalgia 5.2 5.2 1.8*
Fatigue 7.0 7.2 7.2
Hand-foot syndrome 1.9 1.9 0.0*
Stomatitis 3.5 2.9 1.4*
Diarrhoea 3.0 5.6 5.4
Nausea 5.9 5.7 4.8
Vomiting 6.2 6.7 3.5*
Irregular menses 27.0 24.3 26.5
Slamon et al 2011

40. BCIRG 006: Grade 3/4
haematological adverse events
Similar incidence of Grade 3/4 haematological AEs
across treatment groups at 5 years of follow-up
Events, %
ACT
(n=1050)
ACTH
(n=1068)
TCH
(n=1056)
Neutropenia 63.3 71.5 65.9*
Leucopaenia 51.8 60.3 48.2*
Febrile neutropenia 9.3 10.9 9.6
Neutropaenic infection 11.1 11.9 11.2
Anaemia 2.4 3.1* 5.8
Thrombocytopenia 1.6 2.1* 6.1
*Statistically significantly fewer events Slamon et al 2011

41. BCIRG 006: cardiac deaths and congestive heart
failure (independently adjudicated)
Stable CHF rates at long-term follow-up
p=0.0121 p<0.001
Slamon et al 2009; Slamon et al 2011
Events, n
ACT
(n=1050)
ACTH
(n=1068)
TCH
(n=1056)
Cardiac-related death
First analysis (23 months) 0 0 0
Second analysis (36 months) 0 0 0
Third analysis (65 months) 0 0 0
Cardiac left ventricular function (CHF) Grade 3/4
First analysis (23 months) 3 17 4
Second analysis (36 months) 4 20 4
Third analysis (65 months) 7 21 4

42. NCCTG N9831 and
NSABP B-31: combined analysis
NCCTG N9831: Phase III trial of doxorubicin and
cyclophosphamide (AC) followed by weekly paclitaxel with
or without Herceptin® (trastuzumab) as adjuvant treatment
for women with HER2 overexpressing
node-positive or high-risk node-negative breast cancer
NSABP B-31: A randomised trial comparing the safety and
efficacy of adriamycin and cyclophosphamide followed by
paclitaxel (ACT) to that of adriamycin and
cyclophosphamide followed by paclitaxel plus Herceptin®
(trastuzumab) (ACTH) in node-positive breast cancer
patients who
have tumours that overexpress HER2

43. Combined analysis: study
design
Concurrent administration of Herceptin® (trastuzumab)
AC
= AC (doxorubicin/cyclophosphamide 60/600 mg/m2 q3w × 4)
= T (paclitaxel 80 mg/m2/wk × 12)
= T (paclitaxel 175 mg/m2 q3w × 4 or 80 mg/m2 qw × 12)
= H (Herceptin® (trastuzumab) 4 mg/kg loading dose then 2 mg/kg qw × 52)
Perez et al 2011
Control group (n=2017): ACT
NCCTG N9831 Arm A (n=971)
NSABP B-31 Group 1 (n=1046)
Herceptin® (trastuzumab) group (n=2028): ACTH
NCCTG N9831 Arm C (n=973)
NSABP B-31 Group 2 (n=1055) T
H
AC
T
T
H
AC
T
AC
with paclitaxel

44. Combined analysis:
end points and analyses
• Primary
– Disease-free survival
(DFS)
• Local/regional/distant
recurrence
• Contralateral breast
disease (including DCIS)
• 2nd primary invasive
cancers
• Death due to any cause
• Secondary
– Overall survival (OS)
– Time to distant
recurrence (TTDR)
1st interim efficacy
analysis after
355 DFS events1
2nd interim efficacy
analysis after
619 DFS events2
3rd interim efficacy
analysis after
779 DFS events3
1. Romond et al 2005; 2. Perez et al 2007; 3. Perez et al 2011
DCIS, ductal carcinoma in situ

47. Further analysis
• 102 women (5%) assigned to treatment arm
did not receive trastuzumab because of
cardiac symptoms or decrease in LV function.
These patients were included in treatment
arm in the ITT analysis.
• 413 women (20.4%) assigned to control arm
received Trastuzumab after the first interim
analysis reported positive findings in 2005.
These patients were included in control arm
in the ITT analysis.

48. Combined analysis: independent
adjudication of cardiac events
Russell et al 2010
Incidence of symptomatic cardiac events with Herceptin® (trastuzumab)
is very low at 2.0%, and most patients recover with treatment
Patients ACT
(n=1755)
ACTH
(n=1799)
Confirmed cardiac
events*, n (%)
8 (0.5) 36 (2.0)
Symptomatic CHF 7 (0.4) 34 (1.9)
Probable cardiac death 1 (0.1) 2 (0.1)
Hospitalised 5 (0.3) 11 (0.6)
Recovery 7 36
AC, doxorubicin + cyclophosphamide; CHF, congestive heart failure; H, Herceptin® (trastuzumab); T, docetaxel.
* Confirmed by ACREC Committee

51. NCCTG N9831: disease-free survival for sequential
Herceptin® (trastuzumab)
ACTH
ACT
80.1%
71.8%
Years from
randomisation
Alive and disease-free
(%)
100
80
60
40
20
0
Disease-free survival benefit observed with
sequential treatment
n Events HR 95% CI p value*
1097 165 0.69 0.57−0.85 <0.001
1087 225
0 1 2 3 4 5 6
735
728
675
643
624
582
588
530
539
470
No.
at risk
1097
1087
389
330
*log-rank Perez et al 2011

52. ACTH
ACTH
Years from
randomisation
NCCTG N9831: disease-free survival for sequential vs
Alive and disease-free
(%)
100
80
60
40
20
0
Non-significant* disease-free survival benefit for
concurrent treatment
84.4%
80.1%
n Events HR 95% CI p value*
949 139 0.77 0.53−1.11 0.022
954 174
0 1 2 3 4 5 6
837
830
790
766
742
707
691
654
576
519
No.
at risk
949
954
334
288
concurrent Herceptin® (trastuzumab)
*Significant p value pre-defined as p=0.00116 Perez et al 2011

55. Summary of clinical trials

56. Consistent disease-free survival benefit for Herceptin®
(trastuzumab) 1 year
Study Follow-up HR
1 3387 0.54
HERA13 2 3401 0.64
4 3401 0.76
0.64
0 1 2
Favours
Herceptin® (trastuzumab)
Favours
observation
1. Piccart-Gebhart et al 2005; 2. Smith et al 2007; 3.Gianni et al 2011
4. Slamon et al 2011; 5. Romond et al 2005; 6. Perez et al 2011
BCIRG 0064
ACTHH vs ACT
TCH vs ACT
5
0.75
3222
(years)
N
Combined
analysis5,6
NCCTG N9831/
NSABP B-31)
2 3351 0.48
4 4045 0.52
HR (95% CI)

57. Study Follow-up HR
2 0.66
4 0.85
0.63
0.77
Consistent overall survival benefit with adjuvant
Herceptin® (trastuzumab)
3401
3401
5 3222
4 4045 0.61
0 1 2
HR (95% CI)
1. Smith et al 2007; 2. Gianni et al 2011
3. Slamon et al 2011; 4. Perez et al 2011
(years)
N
HERA1,2
BCIRG 0063
ACTHH vs ACT
TCH vs ACT
Combined
analysis4
NCCTG N9831/
NSABP B-31)
ACTHH
Favours
Herceptin® (trastuzumab)
Favours
observation

58. Low incidence of cardiac events
across studies
10
8
6
4
2
Cumulative incidence of cardiac events* with 1 year
of Herceptin® (trastuzumab)remains low with long-term follow-up
*Cardiac events: CHF or cardiac death
NSABP B-31 ACTH (n=947)1
NCCTG N9831 ACTH (n=570)2
NCCTG N9831 ACTH (n=710)2
BCIRG 006 ACTH (n=1068)3
HERA CTH (n=1682)4
BCIRG 006 TCH (n=1056)3
1. Rastogi et al 2007; 2. Perez et al 2008
3. Slamon et al 2011; 4. Procter et al 2010
3.3%
2%
0.4%
2.8%
0.8%
Time (years)
Cumulative incidence (%)
3.8%
0
0 1 2 3 4 5

59. Conclusions
Herceptin® (trastuzumab) for 1 year is the standard of care
for patients with HER2-positive EBC
• Disease-free survival and overall survival
benefits with Herceptin® (trastuzumab) are
maintained at long-term follow-up
– Herceptin® (trastuzumab) may be administered
either concurrently or sequentially with
chemotherapy, offering physicians different
options to suit individual patient needs
• Herceptin® (trastuzumab) is well tolerated with
a consistent safety and tolerability profile
– Cumulative incidence of cardiac events remains
low after
long-term follow-up
Gianni et al 2011; Perez et al 2011; Procter et al 2010; Russell et al 2010; Slamon et al 2011

60. PHARE* Trial results of subset
analysis comparing 6 to 12
months of trastuzumab in
adjuvant early breast cancer
Xavier Pivot, Gilles Romieu, Marc Debled, Jean-Yves Pierga, Pierre Kerbrat,
Thomas Bachelot, Alain Lortholary, Marc Espié, Pierre Fumoleau, Daniel Serin,
Jean-Philippe Jacquin, Christelle Jouannaud, Maria Rios, Sophie Abadie-Lacourtoisie,
Nicole Tubiana-Mathieu, Laurent Cany, Stéphanie Catala, David Khayat,
Iris Pauporté, Andrew Kramar
*lighthouse in French
Protocol of
Herceptin®
Adjuvant with
Reduced
Exposure

72. NOAH (MO16432) data:
Lancet 2010

73. NOAH (MO16432): Study
design
neo-adjuvant−adjuvant Herceptin® (trastuzumab) in patients with
locally advanced or inflammatory HER2-positive breast cancer
HER2-negative LABC
(IHC 0/1+)a
An international, open-label, Phase III study of
(n=117) (n=118) (n=99)
AT
q3w x 3 cycles
T
q3w x 4 cycles
CMF
q4w x 3 cycles
AT
q3w x 3 cycles
T
q3w x 4 cycles
CMF
(IHC 3+ or FISH-positive)
q4w x 3 cycles
HER2-positive LABC
Surgery followed by radiotherapyb
H + AT
q3w x 3 cycles
H + T
q3w x 4 cycles
H q3w x 4 cycles
+ CMF q4w x 3 cycles
H continued q3w
to week 52
19 crossed over to H
H, trastuzumab (8 mg/kg loading dose then 6 mg/kg);
AT, doxorubicin (60 mg/m2), paclitaxel (150 mg/m2); T, paclitaxel (175 mg/m2)
aA separate treatment group of HER2-negative patients received chemotherapy only
bHormone receptor-positive patients received adjuvant tamoxifen Gianni et al 2010

74. NOAH: Inclusion criteria
• Histologically proven locally advanced breast
cancer (T3N1/T4) or any T plus N2/N3, or any
T plus involvement of ipsilateral
supraclavicular nodes
• HER2-positive disease was defined as IHC 3+
overexpression or HER2 amplification by FISH
according to a central laboratory
– For the observational arm, HER2-negative disease
was defined as IHC 0 or 1+ on the basis of local
laboratory testing
• Mandatory hormone receptor assessment
• LVEF ≥55%
Gianni et al 2010

75. NOAH: Endpoints
Primary endpoint
• Event-free survival (EFS) defined as:
– Time from randomisation to disease recurrence or progression (local,
regional, distant or contralateral), or
– Death from any cause
Secondary endpoints
• Total pathological complete response in breast and axillary
nodes (tpCR)
• Pathological complete response in breast tissue (bpCR)
• Overall clinical response rates (ORR)
• Overall survival (OS)
• Safety and tolerability, including cardiac safety
Gianni et al 2010

76. NOAH: Baseline characteristics
HER2-positive patients
Gianni et al 2010
Herceptin® (trastuzumab)
+ chemotherapy
(n=117)
Chemotherapy
(n = 118)
Stage group, %
T4, non-inflammatory 42 43
Inflammatory disease 27 26
N2 or ipsilateral nodes 31 31
Hormone receptor status, %
ER- and/or PgR-positive 36 36
Both negative 64 64
Age group, %
<50 years 43 42
≥50 years 57 58

77. NOAH: EFS in the HER2-positive ITT
Significant EFS benefit with the addition of Herceptin® (trastuzumab)
to chemotherapy in HER2-positive patients
With Herceptin® (trastuzumab)
Number at risk
With Herceptin®
(trastuzumab)
Without Herceptin®
(trastuzumab)
ITT, intent to treat Gianni et al 2010

78. NOAH: EFS by subgroup in patients
with HER2-positive disease
EFS benefit of Herceptin® (trastuzumab) is maintained across patient
HR (95% CI)
subgroups in HER2-positive patients
ER, oestrogen receptor; PR, progesterone receptor; cN, clinical nodal stage;
bpCR, pathological complete response in breast tissue
Gianni et al 2010

79. NOAH: Overall survival in the
HER2-positive ITT population
Trend towards overall survival benefit with the addition of
Herceptin® (trastuzumab) to chemotherapy in HER2-positive patients
ITT, intent to treat Gianni et al 2010

80. NOAH: pCR rates in the ITT population
Significant improvement in pCR with addition of Herceptin® (trastuzumab) to
chemotherapy in HER2-positive treatment groups
ITT, intent to treat
bpCR, pathological complete response in breast tissue
tpCR, total pathological complete response (in breast and axillary nodes)
* Absence of invasive tumour cells Gianni et al 2010

81. NOAH: Selected Grade 3/4
adverse events
Low incidence of grade 3/4 adverse events with no
difference between HER2-positive or negative patients
HER2-positive HER2-negative
With H
(n = 115)
Without H
(n = 113)
Without H
(n = 99)
n (%) n (%) n (%)
Febrile neutropenia 2 (2%) 2 (2%) 2 (2%)
Neutropenia 3 (3%) 5 (4%) 2 (2%)
Diarrhoea 1 (1%) 4 (4%) 1 (1%)
Stomatitis 1 (1%) 4 (4%) 3 (3%)
Infection 0 (0%) 0 (0%) 1 (1%)
Pneumonia 1 (1%) 0 (0%) 0 (0%)
Arthralgia 0 (0%) 3 (3%) 3 (3%)
Myalgia 1 (1%) 1 (1%) 1 (1%)
Peripheral neuropathy 1 (1%) 2 (2%) 0 (0%)
H, Herceptin® (trastuzumab) Gianni et al 2010

82. NOAH: LVEF during and after
therapy
HER2-positive Herceptin® HER2-positive chemotherapy
(trastuzumab) + chemotherapy
LVEF
80
60
40
20
Gianni et al 2010

83. NOAH: Overview of safety and
tolerability
• Herceptin® (trastuzumab) was well tolerated and adverse events
were much the same in the three groups
• Safety and tolerability was consistent with the known profile of
Herceptin® (trastuzumab)
• One patient in each arm had an adverse event that resulted in
study drug discontinuation
• No increase in incidence of Grade 3 or 4 non-cardiac toxicities
with the addition of Herceptin® (trastuzumab) to chemotherapy
• Low incidence of symptomatic cardiac dysfunction (1.7%),
despite concurrent administration of Herceptin® (trastuzumab)
with doxorubicin
Gianni et al 2010

84. NOAH: Conclusions
• Results from the NOAH study
demonstrate the benefits of neo-adjuvant-
adjuvant Herceptin®
(trastuzumab) as a treatment option for
patients with HER2-positive LABC and
with IBC
– Neo-adjuvant Herceptin® (trastuzumab) with an
anthracycline- and taxane-containing chemotherapy
significantly extends EFS in patients with HER2-positive
disease
– The neo-adjuvant regimen with Herceptin® (trastuzumab) is
well tolerated with acceptable cardiac safety
LABC, locally advanced breast cancer
IBC, inflammatory breast cancer
EFS, event-free survival Gianni et al 2010