1. Roma 11 Giugno 2009 Teresa Gamucci Oncologia Medica Sora (FR)
St. Gallen March 11-14, 2009
Roma 11 Giugno 2009
Teresa Gamucci
Oncologia Medica
Sora (FR)

2. St. Gallen: Overview 11th international conference 4500 participants
“Primary Therapy of Early Breast Cancer: Evidence, Controversies, Consensus”
4500 participants
Expert panel includes 40 Top KOLs
22 EU, 13 US, 4 from other countries
Outcome to be published as expert consensus recommendations in Annals of Oncology later this year

3. Chemotherapy vs hormonal therapy

4. Use of Chemotherapy in Hormone Receptor-Positive Disease
Increasing attention to this topic
Need to identify patients who can be spared unnecessary chemotherapy toxicity
Decision based according to
Risk assessment (e.g. nodal status, grade)
Tumor biology
Genomic profiling

5. Chemo vs Hormones in Node+ ESBC: Top 5 EU

6. Country Specific Chemo vs. Hormones in Node+ ESBC

7. Oxford Overview SABCS 2007 7

8. Paradigm of Endocrine Responsiveness
Uncertain
Sure
Absent
ER and PR low/intermediate and/or any of these:
PgR absent
UPA / PAI-1 high
HER2 overexpressed
Increased proliferation
High grade
Both receptors high levels No
ER and PR absent
May not differ if N0 vs N+
Chemo only option
Chemo adds to hormonal
Consider chemo

9. Can We Identify HR+ Patients Who Do Not Need Chemotherapy
Old methods are still beneficial but insufficient
Grade
Nodal status
ER / PgR status
Increasing interest/evidence for molecular risk assessment
Biological markers ( Ki 67, mitotic index etc.)
New methodologies, e.g. multigene assays etc.

10. Use of Multigene Assays
Panel Vote 2009
The panel accepts the use of molecularly-based tools, if readily available, as an adjunct to high-quality standard histo-pathologic assessment in patients with ER+ breast cancer when the doctor and patient are uncertain or ambivalent about the administration of adjuvant chemotherapy
Optimally, the patient should be enrolled in appropriate trials
80% YES 18% NO

11. Anthracycline vs non-anthracycline regimens

12. Anthracycline vs Non-Anthracycline Regimens
Are anthracyclines a necessary component for effective chemo regimens?
NO 61% (but useful in some situations)
USON (TC vs. TAC) trial will answer the question (for HER2- population)

13. Anthracycline vs Non-Anthracycline Regimens
Are non-anthracycline regimens accepted as a standard treatment?
In HER2+ population:
2007: Slim majority found TCH to be an acceptable alternative
2009: Though BCIRG 006 not yet published, data accepted as solid proof
Is there a different standard chemo regimen for HER2+ disease? YES 33% NO 51%
In HER2- population:
Is TC x 4 a standard adjuvant regimen?
YES 43%

14. Stima dell’effetto epidemiologico di trastuzumab a 10 anni in 5 paesi europei
Il modello aveva lo scopo di valutare l’impatto a lungo termine della terapia del EBC con trastuzumab sul numero annuale di pazienti con trasformazione metastatica della malattia tra il 2005 e il 2015 in 5 Paesi Europei. Le conclusioni dello studio mostrano che il trattamento con trastuzumab dei EBC HER2+ potrebbe prevenire quasi casi di progressione di malattia metastatica nell’arco di 10 anni solo considerando 5 Paesi Europei, il che significa poter evitare un numero simile di decessi del tumore – abstract 6569 ASCO 2008

15. References
Joensuu H et al. Clin Cancer Res 2003; 9:
Norris B et al. Poster 2031 presented at the 29th SABCS, San Antonio, Texas, USA, December 2006.
Goldhirsch A et al. Ann Oncol 2007; 18:
St Gallen guidelines: HER2 positivity alone confers either intermediate- or high-risk status
Breast cancer-specific survival in T1pN0 cohort (Norris, et al)
1.0
0.8
0.6
0.4
0.2
HER2 negative
HER2 is recognised in guidelines as an independent risk factor
Even in T1N0 disease, HER2-positive status is associated with a significant risk of relapse
HER2 positive
Breast cancer- specific survival
Patients untreated with trastuzumab
p=0.031
Time (years)
Joensuu, et al. Clin Cancer Res 2003; Norris, et al. SABCS 2006 Goldhirsch, et al. Ann Oncol 2007

16. Più di 13.000 pazienti arruolate in 4 studi clinici multicentrici in adiuvante
HERA (ex-USA)
BCIRG 006 (global)
Observation
IHC / FISH (n=5,090)
FISH (n=3,222)
1 year
1 year
2 years
1 year
NCCTG N9831 (USA)
NSABP B-31 (USA)
IHC / FISH (n=3,505)
IHC / FISH (n=2,030)
A seguito dei dati molto favorevoli osservati dall’impiego di trastuzumab e chemioterapia in donne con carcinoma mammario metastatico, lo sviluppo di trastuzumab ha visto un rapidissimo reclutamento in 4 trial clinici maggiori di oltre pazienti
References
Piccart-Gebhart MJ et al. N Engl J Med 2005; 353:
Romond EH et al. N Engl J Med 2005; 353:
Slamon D et al. Abstract 52 presented at the 29th SABCS, San Antonio, Texas, USA, December 2006.
1 year
1 year
1 year
Doxorubicin + cyclophosphamide
Docetaxel + carboplatin
Standard CTx
Docetaxel
Trastuzumab
Paclitaxel
IHC, immunohistochemistry FISH, fluorescence in situ hybridisation CTx, chemotherapy
Piccart-Gebhart et al Romond et al 2005; Slamon et al 2006

17. HERA: trastuzumab significantly improves DFS
100 80 60 40 20
1 year trastuzumab
Observation
6.3%
Patients(%)
3-year DFS
Events HR
95% CI
p value
218
80.6
0.64
0.54–0.76
<0.0001
321
74.3
Months from randomisation
No. at risk
1,703
1,591
1,434
1,127
742
383
140
1,698
1,535
1,330
984
639
334
127
DFS = disease-free survival
Smith, et al. Lancet 2007 17

18. Trastuzumab ha determinato una riduzione di un terzo del rischio di morte
Overall survival benefit
Median follow-up, years
HERA CTxH 1 year 2
B-31 / N9831 ACPH 3
BCIRG 006 ACDH 3
BCIRG 006 DCarboH 3
Dall’insieme degli studi risulta evidente il vantaggio clinicamente significativo di Trastuzumab in termini di sopravvivenza libera da malattia e globale, indipendentemente dalla variabili prese in considerazione. L’Hazard Ratio nei vari studi che confronta il gruppo di trattamento con Trastuzumab vs l’osservazione risulta nettamente a favore del braccio di trattamento con l’anticorpo monoclonale.
References
Perez EA et al. J Clin Oncol (Meeting Abstracts) 2007; 25: 6s, abs 512.
Slamon D et al. Abstract 52 presented at the 29th SABCS, San Antonio, Texas, USA, December 2006.
Smith IE et al. Lancet 2007; 369:
Favours Trastuzumab 1
Favours no Trastuzumab 2 HR
Size of square represents sample size; horizontal bars indicate 95% confidence intervals
H, Trastuzumab; AC, doxorubicin, cyclophosphamide P, paclitaxel; D, docetaxel; Carbo, carboplatin HR, hazard ratio
Slamon et al Perez et al 2007; Smith et al 2007

19. Trastuzumab migliora DFS indipendentemente dalla dimensione del tumore
HERA
0-2 cm
>2-5 cm
>5 cm
N9831 / B-31
0-2 cm
>2-5 cm
>5 cm
BCIRG 006
ACDH
<2 cm
References
Perez EA et al. J Clin Oncol (Meeting Abstracts) 2007; 25: 6s, abs 512.
Slamon D et al. Abstract 52 presented at the 29th SABCS, San Antonio, Texas, USA, December 2006.
Smith IE et al. Lancet 2007; 369:
≥2 cm
DCarboH
<2 cm
≥2 cm
0.0
0.5
1.0
1.5
2.0
2.5
Favours Trastuzumab
Favours no Trastuzumab HR
Slamon et al Perez et al 2007; Smith et al 2007
DFS, disease-free survival 19

20. Trastuzumab migliora la DFS indipendentemente dallo stato linfonodale
HERA N-
1-3+ nodes
≥4+ nodes
Not assessed
N9831 / B-31 N-
1-3+ nodes
4-9+ nodes
>10+ nodes
BCIRG 006 N-
ACDH
References
Perez EA et al. J Clin Oncol (Meeting Abstracts) 2007; 25: 6s, abs 512.
Slamon D et al. Abstract 52 presented at the 29th SABCS, San Antonio, Texas, USA, December 2006.
Smith IE et al. Lancet 2007; 369: N+ N-
DCarboH N+
0.0
0.5
1.0
1.5
2.0
2.5
Favours Trastuzumab
Favours no Trastuzumab HR
Slamon et al Perez et al 2007; Smith et al 2007
N, node 20

21. Trastuzumab migliora la DFS indipendentemente dall’età del paziente
HERA
<35 years
35-49 years
50-59 years
≥60 years
N9831 / B-31
<40 years
40-49 years
References
Perez EA et al. J Clin Oncol (Meeting Abstracts) 2007; 25: 6s, abs 512.
Smith IE et al. Lancet 2007; 369:
50-59 years
≥60 years
0.0
0.5
1.0
1.5
2.0
2.5
Favours Trastuzumab
Favours no Trastuzumab HR
Perez et al 2007; Smith et al 2007 21

22. Qual è la durata ottimale del trattamento con Trastuzumab?
HERA
Observation
1 year H
PACS-04 HR
0.18 HR
0.012
0.16
HR= % CI ( )
0.010
0.14
HR=1.04
0.12
0.008
0.10
0.08
0.006
0.06
0.004
0.04
Observation
0.02
0.002
1 year H
0.00 6 12 18 24 30 36 42 48
1-6
7-12
13-18
19-24
25-30
31-36
Months since randomisation
Months
NSABP B-31 / NCCTG N9831
La somministrazione di un anno di Trastuzumab rappresenta attualmente lo standard convenzionale
References
Romond EH et al. Slide presentation at the 41st ASCO Annual Meeting, Orlando, Florida, USA, May 2005.
Smith IE. Slide presentation in the 'Scientific Special Session: Lapatinib in Trastuzumab Resistant Breast Cancer' held at the 42nd ASCO Annual Meeting, Atlanta, Georgia, USA, 2-6 June 2006.
Spielmann M et al. Breast Cancer Res Treat 2007; 106 (Suppl 1): S19, abs 72.
Rate per 1,000 women/ year
120
100
AC→T 80 60 40 20
AC→TH 1 2
Romond et al 2005 Smith Spielmann et al 2007 3 4
Years since randomisation

23. Pazienti HER2+ con tumore < 1 cm
Quesiti aperti
Pazienti HER2+ con tumore < 1 cm

24. HER2 POS Small Tumours (< 1 cm)
I tumori piccoli hanno una buona prognosi, generalmente 24

25. Key-messages
Trastuzumab è indicato dalla linee guida come cardine per il trattamento delle pazienti HER2+
Trastuzumab permette elevate percentuali di guarigione nei pazienti con carcinoma mammario HER-positivo operabile
Il vantaggio della terapia con Trastuzumab è stato osservato in tutti i pazienti, indipendentemente dalle variabili prese in considerazione (età, stadio, tipo di chemioterapia)
Il netto beneficio del trattamento con Trastuzumab compensa di gran lunga il rischio di eventi cardiaci, nella maggior parte dei casi reversibili e facilmente trattabili
Attualmente 52 settimane di trattamento con Trastuzumab rappresentano la durata standard della terapia

26. Key-messages (2)
L’analisi più dettagliata dello studio HERA sulla popolazione anziana evidenzia che l’efficacia di Trastuzumab è simile rispetto alla popolazione generale (DFS 85.7% vs 87%)

27. USON 9735: 7-Year Update
DFS OS
Jones et al. J Clin Oncol. 2009

28. Medico-Marketing Comments
Non-anthracycline regimens are gaining ground both in Her2 positive and Her2 normal segments
Even if TCx4 is not recognized as the standard, it is highly (43%) accepted as a viable option
For which patients are doctors ready to spare anthracyclines in everyday clinical practice?
The question remains open

29. What’s New FinHER update HERA landmark analysis
Consensus panel discussion

30. R R FinHer: Study Design FinHER 5-year Update If HER2+
Docetaxel 100 mg/m2 q3w x 3 → FE60C q3w x 3
Trastuzumab q wk x 9 R R
No trastuzumab
Vinorelbine 25 mg/m2 D1, 8, 15 q3w x 3 → FE60C q3w x 3
N=1010
Trastuzumab administered concomitant with docetaxel or vinorelbine treatment
Patient population:
Node-positive or
Node-negative with T > 2 cm and PgR-
Age ≤ 65 years
Stratification factors:
HER2 status
Institution
62 months final analysis

31. Distant Disease-Free Survival (5-y)
FinHER 5-year Update
Distant Disease-Free Survival (5-y)
Treatment
DDFS, %
HR (95% CI)
P-Value
All patients
Doce/FEC
Vinor/FEC
86.8
81.6
0.66 (0.49, 0.91)
0.010
HER2+ patients
Chemo + Trastuzumab
Chemo
83.3
73.0
0.57 (0.33, 0.99)
0.047
Doce/FEC + Trastuzumab
92.5
74.1
0.32 (0.12, 0.89)
0.029
Vinor/FEC + Trastuzumab
75.2
72.0
0.92 (0.47, 1.83)
0.82

32. Overall Survival (5-y) Treatment OS, % HR (95% CI) P-Value
FinHER 5-year Update
Overall Survival (5-y)
Treatment
OS, %
HR (95% CI)
P-Value
All patients
Doce/FEC
Vinor/FEC
92.6
89.3
0.70 (0.46, 1.05)
0.086
HER2+ patients
Chemo + Trastuzumab
Chemo
91.3
82.3
0.55 (0.27, 1.11)
0.094

33. FinHer Authors’ Conclusions
Adjuvant treatment with docetaxel improves DDFS compared to vinorelbine.
A brief course of trastuzumab administered concomitantly with docetaxel is safe and effective, and warrants further evaluation.

34. HERA Study Design HERA Update
HER2-positive early breast cancer (IHC 3+ and / or FISH+) n=5102
Surgery + (neo)adjuvant chemotherapy + radiotherapy
Herceptin
q3w x 1 year
Herceptin
q3w x 2 years
Observation
Option to cross over to Herceptin
(after IA 2005) 34

35. DFS (ITT): 4-year Median Follow-up
HERA Update
DFS (ITT): 4-year Median Follow-up
Patients (%)
100
1-year Herceptin 80
Observation
6.4% 60 40
4-year DFS
Events HR
0.76
95% CI
0.66, 0.87
p value
<0.0001 20 6 12 18 24 30 36 42 48
Months from randomisation
No. at risk 35

36. OS (ITT): 4-year Median Follow-up
HERA Update
OS (ITT): 4-year Median Follow-up
Patients (%)
1-year Herceptin
100
1.6%
Observation 80 60 40
4-year DFS
Events HR
0.85
95% CI
0.70, 1.04
p value
0.1087 20 6 12 18 24 30 36 42 48
Months from randomisation
No. at risk 36

37. DFS and OS Over Time HERA Update 1Piccart-Gebhart et al 2005;
Median follow-up (% follow-up time after selective crossover)
Median follow-up (% follow-up time after selective crossover)
No. of DFS events H 1 year vs observation
No. of deaths H 1 year vs observation
DFS benefit
OS benefit
year (0%)
year (0%)
127 vs 220 p<0.0001
29 vs 37 p=0.26
years (4.3%)
years (4.1%)
218 vs 321 p<0.0001
59 vs 90 p=0.0115
years (33.8%)
Piccart-Gebhart et al. NEJM 2005; 353:
Smith IE et al. Lancet 2007; 369:
years (30.9%)
369 vs 458 p<0.0001
182 vs 213 p=0.1087
Favours Herceptin 1
Favours no Herceptin 2
Favours Herceptin 1
Favours no Herceptin 2 HR HR
1Piccart-Gebhart et al 2005;
2Smith et al 2007 37

38. HERA Update
Landmark Analysis
The landmark analysis considers only patients who were alive and disease free on 16 May 2005
N=885 patients in observation group who switched to Herceptin (randomized to 1 or 2 years)
N=469 patients in observation group who did not cross over
90% of patients who switched to Herceptin did so at ~ 9 months
Specific questions addressed:
What was the course of disease in the subgroups of observation patients who did or did not cross over to Herceptin?
Is there any effect of the late introduction of Herceptin?

39. Months from randomisation
HERA Update
DFS: Observation (alive, no DFS event) Selective Crossover and No Crossover
Patients alive and disease free (%)
100
885
884
878
870
851
822
690
480
Selective crossover
469
468
455
438
408
388
358
302
232
No crossover
Observation: Alive and disease free on 16 May 2005
Months from randomisation
1354
1353
1339
1316
1278
1239
1180
992
712 80 60 40 20 6 12 18 24 30 36 42 48
No. at risk 39

40. OS: Crossover vs No-crossover
HERA Update
OS: Crossover vs No-crossover
Patients alive (%)
100
No crossover
469
465
461
451
441
418
347
260
885
883
881
875
852
718
499
Selective crossover 80 60 40 20
Observation: Alive and disease free on 16 May 2005 6 12 18 24 30 36 42 48
Months from randomisation
No. at risk
1354
1354
1350
1344
1332
1316
1270
1065
759 40

41. HERA 4-year Follow-up Data: Summary (1)
HERA Update
HERA 4-year Follow-up Data: Summary (1)
The updated analysis at 4 years was limited to 1-year Herceptin vs observation as recommended by IDMC
Extensive selective crossover of observation patients to active therapy biased the ITT comparison
Landmark analysis of observation patients who were disease free on 16 May 2005 explored the effects of later introduction of Herceptin
Lack of randomisation limits the interpretation of the landmark analysis
different outcome due to drug effect or patient characteristics?

42. HERA 4-year Follow-up Data: Summary (2)
HERA Update
HERA 4-year Follow-up Data: Summary (2)
The DFS benefit associated with Herceptin is maintained at 4-year median follow-up
50% of patients in the observation arm crossed over to Herceptin treatment, therefore the OS benefit is no longer statistically significant
Patients crossing over at a later date appear to benefit from 1 year of Herceptin 42

43. Cardiotoxicity discussion HERA / FINHER

44. Cardiac Safety Update in Adjuvant Trastuzumab Trials
No. patients (%)
HERA
FINHER
Observation a
N=1719
1-year trastuzamab
N=1682
Chemo-trastuzumab
Chemo
Cardiac death
1 (0.1)
0 (0.0) --
Severe CHF (NYHA III + IV)
13 (0.8)
1 (0.9)
2 (1.7)
Symptomatic CHF (II, III,+IV)
3 (0.2)
33 (2.0)
Confirmed significant LVEF drop
62 (3.7)
Myocardial infarction
a Patients who crossed over are censored from the data of starting trastuzumab treatment

45. HERA Trial: Cardiac Safety in Observation Group
No crossover after 16 May 2005
N=469
Crossover
N=885
Cardiac death
0 (0)
Severe CHF (NYHA III and IV)
Symptomatic CHF (II, III, and IV)
1 (0.2)
9 (1.0)
Confirmed significant LVEF drop
5a (1.1)
26 (2.9)
Trastuzumab discontinued due to cardiac problems
43 (4.9)
a For 3 of the patients, the LVEF drop occurred after 16 May 05 and may have influenced the patient decision

46. Concomitant vs. Sequential
Panel Vote 2009
No formal voting
Panel considered both approaches as reasonable
Increasing body of clinical evidence for concomitant use

47. Adjuvant Trastuzumab Trials: Concurrent and Sequential DFS
No. of Patients HR
Absolute gain (4 years)
Median follow-up, y
Concurrent
Combined US
3968
0.48
12.8% 3
BCIRG ACTH
2147
0.61 6%
BCIRG TCbH
2148
0.67 5%
FinHER
232
0.65
10% 5
Sequential
HERA
3501
0.76
6.4% 4
PACS 04
540
0.86
-0.5%
Gianni L et al. Abstract 31 presented at the 31st SABCS, San Antonio, Texas, USA, December 2008.
Joensuu H et al. N Engl J Med 2006; 354:
Perez EA et al. J Clin Oncol (Meeting Abstracts) 2007; 25: 6s, abs 512.
Slamon D et al. Abstract 52 presented at the 29th SABCS, San Antonio, Texas, USA, December 2006.
Smith IE et al. Lancet 2007; 369:
Spielmann M et al. Breast Cancer Res Treat 2007; 106 (Suppl 1): S19, abs 72.

48. NCCTG N9831 (Coming ASCO 2009) Patient Population
AC q3w x 4
Paclitaxel qw x 12
RANDOMI ZAT ION
N=3595
AC q3w x 4
Paclitaxel qw x 12
Patient Population
N+ or high-risk N- breast cancer
HER2+ (IHC 3+ or FISH)
Trastuzumab qw x 52
AC q3w x 4
Paclitaxel qw x 12
Trastuzumab qw x 52

49. Optimum Trastuzumab Duration
St. Gallen 2007: standard duration trastuzumab accepted as 1 year
No panel vote 2009
Ongoing clinical trials to define optimal duration
SOLD: 9 weeks vs. 1 year, n=3000
ShortHER: 9 weeks vs. 1 year, n=2500
PHARE: 6 mo vs. 1 year, n=3500 (2400 enrolled to date); any adjuvant chemotherapy

50. Key Messages Trastuzumab is effective up front or after chemo
Cardiac toxicity:
Minimal with short duration (FINHER) treatment
Remains even when trastuzumab is administered long after the end of chemotherapy (HERA landmark analysis)
Concomitant use is gaining ground due to clinical evidence
BCIRG 006 to be published
NCCTG to be presented at ASCO 2009? (LBA)
Duration of trastuzumab treatment
1 year still recommended as standard
Trials ongoing to evaluate short- vs long-term duration

51. Triple-negative breast cancer

52. Triple-Negative Breast Cancer
Panel Vote 2009
Is there a standard chemotherapy regimen for triple-negative breast cancer?
NO 95%
Patients show initial sensitivity to taxanes and anthracyclines
Ongoing clinical trials to define optimal regimens
CIBOMA
GEICAM

53. Neoadjvuant setting

54. Neoadjuvant Setting 2 distinct goals of neoadjuvant therapy
Breast-conserving surgery (e.g. reduce size of tumor)
Evaluate efficacy of treatment (e.g. clinical trial)
Panel Vote 2009:
Should the criteria for choosing adjuvant and neoadjuvant chemotherapy be the same?
YES 97%
Should neoadjuvant chemotherapy include a taxane?
YES 63%

55. Overall Conclusions
Active efforts to optimize treatment while minimizing toxicity
Increased scrutiny of use of chemotherapy in highly endocrine-responsive disease
Utilization of molecular biology to identify low-risk populations (e.g. Ki67, genomic assays)
Taxanes and anthracyclines remain among most active chemotherapy agents
Non-anthracycline regimens gaining as a reasonable treatment option, including HER2-negative disease (e.g. TC, TCbH)