1. Optimizing Treatment for Her 2 Positive Early Stage Breast Cancer Patients
Sunil Verma MD, MSEd, FRCPC
Medical Oncologist
Chair, Breast Medical Oncology
Sunnybrook Odette Cancer Centre
Associate Professor, University of Toronto

2. Outline Overview of Adjuvant EBC Her 2 Positive Trials
Duration of Therapy
< 1cm Node Negative
Role of Non-Anthracycline based chemotherapy
Incorporation of other Anti Her2 Therapies

3. Outline Overview of Adjuvant EBC Her 2 Positive Trials
Duration of Therapy
< 1cm Node Negative
Role of Non-Anthracycline based chemotherapy
Incorporation of other Anti Her2 Therapies

4. Four pivotal trials in over patients established trastuzumab as the standard of care for HER2-positive EBC
HERA (ex-USA)1
BCIRG 006 (global)2
Observation
IHC/FISH N = 5102
FISH N = 3222
1 year
1 year
2 years
1 year
NCCTG N9831 (USA)3
NSABP B-31 (USA)3
References
Gianni L, Dafni U, Gelber RD, et al. Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244.
Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365:12731283.
Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373.
IHC/FISH N = 2101
IHC/FISH N = 1944
1 year
1 year
1 year
Chemotherapy +/- radiotherapy
Doxorubicin + cyclophosphamide
Docetaxel + carboplatin
Docetaxel
Trastuzumab
Paclitaxel
1. Gianni L, et al. Lancet Oncol 2011; 12:236244; 2. Slamon D, et al. N Engl J Med 2011; 365:12731283; 3. Perez EA, et al. J Clin Oncol 2011; 29:33663373.
IHC, immunohistochemistry; FISH, fluorescence in situ hybridisation.

5. Her 2 EBC Adjuvant Trastuzumab Trials Timeline
1998
US approval: HER2-positive MBC1
2006
EU/US approval: HER2-positive EBC3
EMA approval: concurrent trastuzumab + chemotherapy in EBC4
2000
EU approval: HER2-positive MBC2
2010
2011
2012
2013
References
Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344:783792.
Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol 2005; 23:42654274.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353:16591672.
Perez EA, Suman VJ, Davidson NE, et al. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol 2011; 29:44914497.
Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 2013 [Epub ahead of print].
HERA 2-year results published5
1. Slamon DJ, et al. N Engl J Med 2001; 344:783792; 2. Marty M, et al. J Clin Oncol 2005; 23:42654274;
3. Piccart-Gebhart MJ, et al. N Engl J Med 2005; 353:16591672; 4. Perez EA, et al. J Clin Oncol 2011; 29:44914497; 5. Goldhirsch A, et al. Lancet 2013 [Epub ahead of print].
BC, breast cancer; EBC, early breast cancer; EMA, European Medicines Agency; MBC, metastatic breast cancer.

6. DFS and OS benefits demonstrated during long-term follow-up in the the four pivotal clinical trials of trastuzumab for 1 year
DFS OS
Study
Follow-up
(years) N HR
p value
HERA1–4
CT+/–RTH vs. CT+/–RT 1
3387
0.54
<
0.76
0.26 2
3401
0.64
0.66
0.0115 4
0.85
0.1087 8
0.0005
NCCTG N9831/ NSABP B-315–7 ACTHH vs. ACT
3351
0.48 –
4045
0.52
< 0.001
0.61
8.4
4046
0.60
0.63
BCIRG 0068
ACTHH vs. ACT
5.5
3222
TCH vs. ACT
0.75
0.04
0.77
References
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353:16591672.
Smith I, Procter M, Gelber RD, et al. HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 369:2936.
Gianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244.
Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 2013 [Epub ahead of print].
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:16731684.
Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373.
Romond EH, Suman VJ, Jeong J-H, et al. Trastuzumab plus Adjuvant Chemotherapy for HER2-positive Breast Cancer: Final Planned Joint Analysis of Overall Survival from NSABP B-31 and NCCTG N9831. Cancer Res 2012; 72 (Suppl 3): Abstract S5-5 (and associated oral presentation).
Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365:12731283.
1. Piccart-Gebhart MJ, et al; N Engl J Med 2005; 353: ; 2. Smith I, et al. Lancet 2007; 369:29-36; 3. Gianni L, et al; Lancet Oncol 2011; 12: ; 4. Goldhirsch A, et al. Lancet 2013 [Epub ahead of print]; 5. Romond EH, et al. N Engl J Med 2005; 353: ; 6. Perez EA, et al. J Clin Oncol 2011; 29: ; 7. Romond EH, et al. SABCS 2012 (abstract S5-5; oral presentation);
8. Slamon D, et al. N Engl J Med 2011; 365:
CT, chemotherapy; DFS, disease-free survival; H, trastuzumab; HR, hazard ratio; OS, overall survival; RT, radiotherapy; T, taxane.

7. The survival benefit is maintained irrespective of hormone receptor status
1 year of trastuzumab better
Observation better
DFS events, n
DFS HR (95% CI)
ER-negative and PgR-negative
73 vs. 133
0.52 (0.39, 0.69)
ER-negative and PgR-positive
7 vs. 8
0.67 (0.24, 1.84)
ER-positive and PgR-negative
15 vs. 29
0.63 (0.34, 1.17)
ER-positive and PgR-positive
28 vs. 38
0.61 (0.38, 1.00)
126 vs. 190
0.63 (0.50, 0.78)
12 vs. 12
0.77 (0.34, 1.74)
26 vs. 39
0.82 (0.50, 1.34)
46 vs. 61
0.63 (0.43, 0.93)
ER- and PgR-negative
1.00
ER- or PgR-positive
81.6 vs. 69.4
0.66 (0.57, 0.76)
ER- or PgR-positive*
89.4 vs. 77.2
0.57 (0.46, 0.69)*
0.65
0.61
HERA
1 year vs. obs: 1 year follow-up1
0.0
0.5
1.0
1.5
2.0
HERA
1 year vs. obs: 2 years’ follow-up2
0.0
0.5
1.0
1.5
2.0
NCCTG N9831/ NSABP B-31 4 years’ follow-up4
0.0
0.5
1.0
1.5
2.0
References
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353:16591672.
Smith I, Procter M, Gelber RD, et al. HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 369:2936.
Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 2013 [Epub ahead of print].
Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373.
Romond EH, VJ Suman VJ, Jeong J-H, et al. Trastuzumab plus adjuvant chemotherapy for HER2-positive breast cancer: Final planned joint analysis of overall survival (OS) from NSABP B-31 and NCCTG N9831. Cancer Research 2012; 72 (15 December suppl): Abstract S5-5 (and associated oral presentation).
NCCTG N9831/ NSABP B years’ follow-up5
0.0
0.5
1.0
1.5
2.0 HR
1. Piccart-Gebhart MJ, et al. N Engl J Med 2005; 353:16591672; 2. Smith I, et al. Lancet 2007; 369:2936; 3. Goldhirsch A, et al. Lancet 2013 [Epub ahead of print]; 4. Perez EA, et al. J Clin Oncol 2011; 29:33663373; 5. Romond EH, et al. SABCS 2012 (Abstract S5-5; oral presentation).
* OS
ER, oestrogen receptor; obs, observation; OS, overall survival; PgR, progesterone receptor.

8. NCCTG N9831/NSABP B-31: Cumulative incidence of distant recurrence as a first event
ER- and/or PgR-positive
ER- and PgR-negative 25
22.3%
AC→T
21.5%
AC→T 20
Δ = 9.6%
Δ = 9.6% 15
12.7%
11.9%
Cumulative incidence (%) 10
AC→TH
AC→TH
Reference
Romond EH, VJ Suman VJ, Jeong J-H, et al. Trastuzumab plus adjuvant chemotherapy for HER2-positive breast cancer: Final planned joint analysis of overall survival (OS) from NSABP B-31 and NCCTG N9831. Cancer Research 2012; 72 (15 December suppl): Abstract S5-5 (and associated oral presentation). 5 N
events N
events
AC→T
1105
216
AC→T
911
175
AC→TH
1110
124
AC→TH
917
103 2 4 6 8 10 2 4 6 8 10
Years from randomisation
Romond EH, et al. SABCS 2012 (Abstract S5-5; oral presentation).

9. Cumulative incidence (%)
Key trials showed a consistent safety and tolerability profile with trastuzumab for 1 year, with a low cumulative incidence of cardiac events after long-term follow-up1–7
Time (years)
Cumulative incidence (%)
3.3%
0.8%
0.4%
2.8%
2.0%
N9831 ACTH (n = 570)1
BCIRG 006 ACTH (n = 1068)2
BCIRG 006 TCH (n = 1056)2
N9831 ACTH (n = 710)1
HERA CTH (n = 1682)3,6,7
Adjuvant studies:
Cardiac events: NYHA class III/IV or severe symptomatic congestive heart failure or cardiac death
References
Perez EA, Suman VJ, Davidson NE, et al. Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 Adjuvant Breast Cancer Trial. J Clin Oncol 2008; 26:12311238.
Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365:12731283.
Procter M, Suter TM, de Azambuja E, et al. Longer-term assessment of trastuzumab-related cardiac adverse events in the Herceptin Adjuvant (HERA) Trial. J Clin Oncol 2010; 28:34223428.
Gianni L, Dafni U, Gelber RD, et al. Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244.
Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373.
Suter TM, Procter M, van Veldhuisen DJ, et al. Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. J Clin Oncol 2007; 25:38593865.
Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 2013 [Epub ahead of print].
1. Perez EA, et al. J Clin Oncol 2008; 26:12311238.
2. Slamon D, et al. N Engl J Med 2011; 365:12731283; 3. Procter M, et al. J Clin Oncol 2010; 28:34223428; 4. Gianni L, et al. Lancet Oncol 2011; 12:236244; 5. Perez EA, et al. J Clin Oncol 2011; 29:33663373; 6. Suter TM, et al. J Clin Oncol 2007; 25:38593865;
7. Goldhirsch A, et al. Lancet 2013 [Epub ahead of print].
NYHA, New York Heart Association.

10. Outline Overview of Adjuvant EBC Her 2 Positive Trials
Duration of Trastuzumab Therapy
< 1cm Node Negative
Role of Non-Anthracycline based chemotherapy
Incorporation of other Anti Her2 Therapies

11. Several ongoing trials are investigating the optimal duration of trastuzumab in EBC
Reported
Ongoing
Trastuzumab for <1 year vs. trastuzumab for 1 year
Trastuzumab for 2 years vs. trastuzumab for 1 year
6 months
9 weeks
2 years
1 year (standard of care)
HERA 1 year vs. observation7–9
PHARE 6 months vs. 1 year1
SOLD4 9 weeks vs. 1 year
HERA 2 years vs. 1 year6
NCCTG N983110
HORG 6 months vs. 1 year2
SHORT-HER 9 weeks vs. 1 year5
References
Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol 2013; 14:741–748.
ClinicalTrials.gov. Six vs 12 months of trastuzumab with docetaxel following FEC as adjuvant treatment in N+ breast cancer. Available at: (Accessed July 2013).
Earl HM, Cameron DA, Miles D, et al. PERSEPHONE: Duration of trastuzumab with chemotherapy in women with HER2-positive early breast cancer—six versus twelve months. J Clin Oncol 2013; 31 (20 May suppl): Abstract TPS667.
ClinicalTrials.gov. The synergism or long duration (SOLD) study. Available at: (Accessed July 2013).
ClinicalTrials.gov. combination chemotherapy and trastuzumab in treating women with stage I, Stage II, or Stage III HER2-Positive Breast Cancer. Available at: (Accessed July 2013).
Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 2013 [Epub ahead of print].
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353:1659–1672.
Smith I, Procter M, Gelber RD, et al; HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 369:2936.
Gianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244.
Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:3366–3373.
Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365:12731283.
NCCN Clinical Practice Guidelines in Oncology. Breast Cancer V Available at (Accessed 27 August 2013).
Senkus E, Kyriakides S, Penault-Llorca F, et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013 [Epub ahead of print].
Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer Ann Oncol 2013 [Epub ahead of print].
NSABP B3110
PERSEPHONE 6 months vs. 1 year3
FinHer 9 weeks vs. chemo
BCIRG 00611
Trastuzumab for 1 year remains the standard of care in EBC, as recommended by international guidelines12–14
1. Pivot X, et al. Lancet Oncol 2013; 14:741–748; Earl HM, et al. ASCO 2013 (Abstract TPS667); Goldhirsch A, et al. Lancet 2013 [Epub ahead of print]; 7. Piccart-Gebhart MJ, et al. N Engl J Med 2005; 353:1659–1672; 8. Smith I, et al. Lancet 2007; 369:2936; 9. Gianni L, et al. Lancet Oncol 2011; 12:236244; 10. Perez EA, et al. J Clin Oncol 2011; 29:3366–3373; 11. Slamon D, et al. N Engl J Med 2011; 365:12731283;
12. NCCN Clinical Practice Guidelines in Oncology; Breast Cancer V1.2013; 13. Senkus E, et al. Ann Oncol 2013 [Epub ahead of print]; 14. Goldhirsch A, et al. Ann Oncol 2013 [Epub ahead of print].

12. Years from randomisation Years from randomisation
FinHer: No statistically significant improvement in DDFS or OS with 9 weeks of trastuzumab vs. chemotherapy alone
DDFS OS
100 80 60 40 20 1 2 3 4 5 6 7
OS (%)
Years from randomisation
95.7%
90.5%
82.3%
91.3%
DDFS (%)
Years from randomisation
90.4%
77.6%
73.0%
83.3%
100 80 60 40 20 1 2 3 4 5 6 7
Chemotherapy
Trastuzumab 9 weeks + chemotherapy
Reference
Joensuu H, Bono P, Kataja V, et al. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial. J Clin Oncol 2013; 27:5685–5692.
Patients
Events HR
(9 weeks vs. none)
95% CI
p value
9 weeks
115 22
0.65
(0.38, 1.12)
0.12
Chemo
116 31
Patients
Events
HR (9 weeks vs. none)
95% CI
p value
9 weeks
115 12
0.55
(0.27, 1.11)
0.094
Chemo
116 21
CI, confidence interval; DDFs, distant disease-free survival.
Joensuu H, et al. J Clin Oncol 2009;27:5685–5692.

13. Years from randomisation Years from randomisation
HERA: Trastuzumab for 2 years was as efficacious as the standard 1 year of treatment, with no additional benefit
DFS1
OS2
100 80 60 40 20 1 2 3 4 5 6 7 8 9
OS (%)
Years from randomisation
97.4%
96.5%
91.4%
92.6%
86.4%
87.6%
Trastuzumab 1 year
Trastuzumab 2 years
DFS (%)
Years from randomisation
89.1%
86.7%
81.0%
81.6%
75.8%
76.0%
100 80 60 40 20 1 2 3 4 5 6 7 8 9
Trastuzumab 1 year
Trastuzumab 2 years
References
Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 2013 [Epub ahead of print].
Goldhirsch A, Piccart-Gebhart MJ, Procter M, et al. HERA TRIAL: 2 Years Versus 1 Year of Trastuzumab after Adjuvant Chemotherapy in Women with HER2-Positive Early Breast Cancer at 8 Years of Median Follow Up. 35th Annual San Antonio Breast Cancer Symposium 2012 (abstract S5-2 and associated oral presentation).
Patients
Events
HR (2 vs. 1 year)
95% CI
p value
2 years
1553
367
0.99
(0.84, 1.14)
0.86
1 year
1552
Patients
Events
HR (2 vs. 1 year)
95% CI
p value
2 years
1553
196
1.05
(0.86, 1.28)
0.63
1 year
1552
186
1. Goldhirsch A, et al. Lancet 2013 [Epub ahead of print];
2. Goldhirsch A, et al. SABCS 2012 (Abstract S5-2; oral presentation).

14. Months from randomisation Months from randomisation
PHARE: Non-inferiority of 6 months vs. 1 year of trastuzumab was not demonstrated
DFS OS
100 80 60 40 20 12 24 36 48
Months from randomisation
OS (%)
Months from randomisation
Trastuzumab 1 year
Trastuzumab 6 months
100 80 60 40 20 48 36 24 12
Trastuzumab 1 year
Trastuzumab 6 months
DFS (%)
Reference
Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol 2013; 14:741–748.
Patients
Events
HR (6 months vs. 1 year)
95% CI
p value
6 months
1690 93
1.46
(1.06, 2.01)
0.03
1 year 66
Patients
Events
HR (6 months vs. 1 year)
95% CI
p value
6 months
1690
219
1.28*
(1.05, 1.56)
0.29
1 year
175
HR (95% CI): 1.46 (1.06, 2.01)
(above the prespecified non-inferiority CI of 1.15)
Pivot X, et al. Lancet Oncol 2013;14:741–748.

15. Outline Overview of Adjuvant EBC Her 2 Positive Trials
Duration of Therapy
< 1cm Node Negative
Role of Non-Anthracycline based chemotherapy
Incorporation of other Anti Her2 Therapies

17. Trastuzumab in T1a/b, N0 French Retrospective Study (n=97)

18. Trastuzumab in < 1cm, N+ BCIRG 006

25. Summary
< 1cm node negative patients should be considered for trastuzumab
One has to weigh potential toxicity and absolute benefit, especially for T1a tumors
Paclitaxel + Trastuzumab may be a very effective and well tolerated approach for T1 N0 Her 2 positive tumors or for patients not deemed to be suitable for anthracyclines and docetaxel based regimens

26. Outline Overview of Adjuvant EBC Her 2 Positive Trials
Duration of Therapy
< 1cm Node Negative
Role of Non-Anthracycline based chemotherapy
Incorporation of other Anti Her2 Therapies

27. DFS and OS benefits demonstrated during long-term follow-up in the the four pivotal clinical trials of trastuzumab for 1 year
DFS OS
Study
Follow-up
(years) N HR
p value
HERA1–4
CT+/–RTH vs. CT+/–RT 1
3387
0.54
<
0.76
0.26 2
3401
0.64
0.66
0.0115 4
0.85
0.1087 8
0.0005
NCCTG N9831/ NSABP B-315–7 ACTHH vs. ACT
3351
0.48 –
4045
0.52
< 0.001
0.61
8.4
4046
0.60
0.63
BCIRG 0068
ACTHH vs. ACT
5.5
3222
TCH vs. ACT
0.75
0.04
0.77
References
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353:16591672.
Smith I, Procter M, Gelber RD, et al. HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 369:2936.
Gianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244.
Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 2013 [Epub ahead of print].
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:16731684.
Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373.
Romond EH, Suman VJ, Jeong J-H, et al. Trastuzumab plus Adjuvant Chemotherapy for HER2-positive Breast Cancer: Final Planned Joint Analysis of Overall Survival from NSABP B-31 and NCCTG N9831. Cancer Res 2012; 72 (Suppl 3): Abstract S5-5 (and associated oral presentation).
Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365:12731283.
1. Piccart-Gebhart MJ, et al; N Engl J Med 2005; 353: ; 2. Smith I, et al. Lancet 2007; 369:29-36; 3. Gianni L, et al; Lancet Oncol 2011; 12: ; 4. Goldhirsch A, et al. Lancet 2013 [Epub ahead of print]; 5. Romond EH, et al. N Engl J Med 2005; 353: ; 6. Perez EA, et al. J Clin Oncol 2011; 29: ; 7. Romond EH, et al. SABCS 2012 (abstract S5-5; oral presentation);
8. Slamon D, et al. N Engl J Med 2011; 365:
CT, chemotherapy; DFS, disease-free survival; H, trastuzumab; HR, hazard ratio; OS, overall survival; RT, radiotherapy; T, taxane.

28. BCIRG 006 DFS

29. BCIRG 006 DFS by Nodal Positivity

35. Which patients should we considered for a non-anthracycline based anti Her 2 alternative option?
Patients with cardiac risk factors or underlying cardiac disease
Patients where the absolute benefit of adjuvant therapy may be low
T1a, T1b tumors
Older patients (?>70 years of age)

36. Outline Overview of Adjuvant EBC Her 2 Positive Trials
Duration of Therapy
< 1cm Node Negative
Role of Non-Anthracycline based chemotherapy
Incorporation of other Anti Her2 Therapies

37. Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting
First results from the phase III ALTTO trial (BIG 02-06; NCCTG 063D) comparing one year of anti-HER2 therapy with lapatinib alone (L), trastuzumab alone (T), their sequence (TL) or their combination (L + T) in the adjuvant treatment of HER2-positive <br />early breast cancer (EBC)
Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

38. Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting
Slide 5
Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

39. Distribution of the Stratification Factors by Treatment Arm
Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

40. Distribution of patient characteristics by Treatment Arm
Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

41. ALTTO vs. Neo-ALTTO

42. DISEASE-FREE SURVIVAL (DFS) ANALYSIS
Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

43. DFS BY Hormone Receptor Status
Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

44. OVERALL SURVIVAL (OS) ANALYSIS
Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

45. Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting
PROPORTION OF PATIENTS RECEIVING ≥ 85% OF THE PLANNED DOSE OF ANTI-HER2 DRUGS
Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

46. MAIN DIFFERENCES IN AEs BY TREATMENT ARM
Presented By Martine Piccart-Gebhart at 2014 ASCO Annual Meeting

47. Bottom Line There is no role for Lapatinib in the adjuvant setting
Why is ALTTO negative?
The ‘Ceiling Effect’
OS > 95% in the control arm
low risk patient population
very effective and well-tolerated control arm
Dose Delivery in the experimental arm
Is it related to MOA for TKI

48. Outline Overview of Adjuvant EBC Her 2 Positive Trials
Duration of Therapy
< 1cm Node Negative
Role of Non-Anthracycline based chemotherapy
Incorporation of other Anti Her2 Therapies
Future Directions and Concluding Remarks

49. Future Questions in EBC
Which is the best combination of targeted agents?
Lapatinib and Trastuzumab
Pertuzumab and Trastuzumab
?T-DM1 and Pertuzumab
Do we need to offer patients one year of Herceptin or one year of combined blockade?
? Role of anti-HER2 agents in HER2 1+ or 2+ patients

50. Improving the outcome of EBC patients A Cost-Effective Approach
Which patients are ‘cured’ with surgery alone?
Which patients are cured with surgery and traditional chemotherapy?
Which patients require trastuzumab, only for a short duration i.e. 9 weeks or 6 months?
Which patients don’t benefit from chemotherapy and trastuzumab?

51. Conclusion
There is continued and maintained benefit with adjuvant trastuzumab
Duration of Trastuzumab remains to be fully defined
At present one year is standard of treatment
Identifying the patients who are at a greater risk
Address those who remain at high risk
The focus needs to be on how we can gain better outcomes with less toxicity
Integration of novel therapies vs. conventional traditional chemotherapy