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St. Gallen March 11-14, 2009
Roma 11 Giugno 2009
Teresa Gamucci
Oncologia Medica
Sora (FR)
St. Gallen: Overview
• 11th international conference“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
CHEMOTHERAPY VS HORMONAL THERAPY
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
Chemo vs Hormones in Node+ ESBC: Top 5 EU
Country Specific Chemo vs. Hormones in Node+ ESBC
Oxford Overview SABCS 2007
Paradigm of Endocrine Responsiveness
Consider chemo
Absent Uncertain Sure
Endocrine Responsiveness
ER and PR absent ER and PR low/intermediate and/or any of these:
•PgR absent•UPA / PAI-1 high•HER2 overexpressed•Increased proliferation•High grade
May not differ if N0 vs N+
Chemo only option Chemo adds to hormonal
Both receptors high levels
NoNoNoNoNo
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.
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
ANTHRACYCLINE VS NON-ANTHRACYCLINE REGIMENS
Anthracycline vs Non-Anthracycline Regimens
• Are anthracyclines a necessary component for effective chemo regimens?– NO 61% (but useful in some situations)
• USON 06090 (TC vs. TAC) trial will answer the question (for HER2- population)
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%
Stima dell’effetto epidemiologico di trastuzumab a 10 anni in 5 paesi europei
St Gallen guidelines: HER2 positivity alone confers either intermediate- or high-risk status
• HER2 is recognisedin guidelines as an independent risk factor
• Even in T1N0 disease, HER2-positive status is associated with a significant risk of relapse
Joensuu, et al. Clin Cancer Res 2003; Norris, et al. SABCS 2006 Goldhirsch, et al. Ann Oncol 2007
Breast cancer-specific survivalin T1pN0 cohort (Norris, et al)
Bre
ast
can
cer-
spec
ific
su
rviv
al
1.0
0.8
0.6
0.4
0.2
00 2 4 6 8 10 12
Time (years)
HER2 negative
HER2 positive
p=0.031
Patients untreated with trastuzumab
Più di 13.000 pazienti arruolate in 4 studi clinici multicentrici in adiuvante
Piccart-Gebhart et al 2005 Romond et al 2005; Slamon et al 2006
NCCTG N9831 (USA)
HERA (ex-USA) BCIRG 006 (global)
NSABP B-31 (USA)
IHC / FISH (n=5,090)
Observation
1 year
2 years
IHC / FISH (n=3,505)
1 year
1 year
FISH(n=3,222)
1 year
1 year
IHC / FISH (n=2,030)
1 year
DocetaxelDocetaxel + carboplatin
Doxorubicin + cyclophosphamide Trastuzum
abStandard CTx Paclitaxel
IHC, immunohistochemistry FISH, fluorescence in situ hybridisation CTx, chemotherapy
1,703 1,591 1,434 1,127 742 383 1401,698 1,535 1,330 984 639 334 127
1 year trastuzumab
Observation
No. at risk
HERA: trastuzumab significantly improves DFS
Events HR 95% CI p value
0.64 0.54–0.76 <0.0001
3-yearDFS
80.6
74.3
218
321
100
80
60
40
20
0
Pat
ien
ts(%
)
Months from randomisation0 6 12 18 24 30 36
6.3%
Smith, et al. Lancet 2007DFS = disease-free survival
Trastuzumab ha determinato una riduzione di un terzo del rischio di morte
0 1 2
B-31 / N9831 ACPH 3
HERA CTxH 1 year 2
Median follow-up, yearsOverall survival benefit
BCIRG 006 ACDH 3
BCIRG 006 DCarboH 3
FavoursTrastuzumab
Favours noTrastuzumab
HR
Slamon et al 2006 Perez et al 2007; Smith et al 2007
H, Trastuzumab; AC, doxorubicin, cyclophosphamide P, paclitaxel; D, docetaxel; Carbo, carboplatin HR, hazard ratio
Size of square represents sample size; horizontal bars indicate 95% confidence intervals
Trastuzumab migliora DFS indipendentemente dalla dimensione del tumore
Slamon et al 2006 Perez et al 2007; Smith et al 2007
>2-5 cm
BCIRG 006
>2-5 cm
>5 cm
0.0 0.5 2.51.0 1.5 2.0
0-2 cm
N9831 / B-31 0-2 cm
>5 cm
ACDH <2 cm
DCarboH <2 cm≥2 cm
≥2 cm
Favours Trastuzumab
Favours no TrastuzumabHR
HERA
DFS, disease-free survival
Trastuzumab migliora la DFS indipendentemente dallo stato linfonodale
N, node
1-3+ nodes
Favours Trastuzumab
Favours no Trastuzumab
0.0 0.5 2.51.0 1.5 2.0
1-3+ nodes≥4+ nodesNot assessed
N9831 / B-31 N-
4-9+ nodes>10+ nodes
DCarboHN-N+
N+
BCIRG 006 N-ACDH
N-HERA
HRSlamon et al 2006
Perez et al 2007; Smith et al 2007
Trastuzumab migliora la DFS indipendentemente dall’età del paziente
35-49 years
0.0 0.5 2.51.0 1.5 2.0
HERA <35 years
50-59 years
≥60 years
N9831 / B-31 <40 years
≥60 years
40-49 years
50-59 years
Favours Trastuzumab
Favours no TrastuzumabHR
Perez et al 2007; Smith et al 2007
Qual è la durata ottimale del trattamento con Trastuzumab?
HERA0.180.160.140.120.100.080.060.040.020.00
1-6 7-12 13-18 19-24 25-30 31-36
Months since randomisation
HRObservation1 year H
PACS-040.012
6
Months
HR
0 12 18 24 30 36 42 48
0.010
0.008
0.006
0.004
0.002 1 year HObservation
HR=0.5795% CI (0.30-1.09) HR=1.04
NSABP B-31 / NCCTG N9831120
0Years since randomisation
Rate per1,000 women/year
1 2 3 4
100
80
60
40
20
0
AC→TH
AC→T
Romond et al 2005Smith 2006
Spielmann et al 2007
Pazienti HER2+ con tumore < 1 cm
Quesiti aperti
HER2 POS Small Tumours (< 1 cm)
• 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
Key-messages
• 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%)
Key-messages (2)
USON 9735: 7-Year Update
DFS OS
Jones et al. J Clin Oncol. 2009
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
What’s New
• FinHER update• HERA landmark analysis• Consensus panel discussion
FinHer: Study Design
R
Docetaxel 100 mg/m2 q3w x 3 → FE60C q3w x 3
Vinorelbine 25 mg/m2 D1, 8, 15 q3w x 3 → FE60C q3w x 3
If HER2+
RTrastuzumab q wk x 9
No trastuzumab
Trastuzumab administered concomitant with docetaxel
or vinorelbine treatmentPatient population:•Node-positive or•Node-negative with T > 2 cm and PgR-•Age ≤ 65 years
Stratification factors:•HER2 status•Institution
N=1010
FinHER 5-year Update
62 months final analysis
Distant Disease-Free Survival (5-y)
FinHER 5-year Update
Treatment DDFS, % HR (95% CI) P-ValueAll patientsDoce/FECVinor/FEC
86.881.6
0.66 (0.49, 0.91) 0.010
HER2+ patientsChemo + TrastuzumabChemo
83.373.0
0.57 (0.33, 0.99) 0.047
Doce/FEC + TrastuzumabDoce/FEC
92.574.1
0.32 (0.12, 0.89) 0.029
Vinor/FEC + TrastuzumabVinor/FEC
75.272.0
0.92 (0.47, 1.83) 0.82
Overall Survival (5-y)
FinHER 5-year Update
Treatment OS, % HR (95% CI) P-ValueAll patients
Doce/FECVinor/FEC
92.689.3
0.70 (0.46, 1.05) 0.086
HER2+ patientsChemo + TrastuzumabChemo
91.382.3
0.55 (0.27, 1.11) 0.094
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.
Option to cross over to Herceptin
(after IA 2005)
HERA Study Design
HER2-positive early breast cancer(IHC 3+ and / or FISH+)
n=5102
Surgery + (neo)adjuvant chemotherapy + radiotherapy
Herceptin q3w x 1 yearObservation Herceptin
q3w x 2 years
HERA Update
100
80
60
40
20
00 6 12 18 24 30 4836 42
Months from randomisation
16981703
15641619
14401552
13631485
12971414
12401352
712854
11801280
9921020
No. at risk
Events
458369
4-yearDFS
72.278.6
HR
0.76
95% CI
0.66, 0.87
p value
<0.0001
1-year Herceptin
Observation 6.4%
Patients (%)
HERA Update
DFS (ITT): 4-year Median Follow-up
OS (ITT): 4-year Median Follow-up
0 6 12 18 24 30 4836 42
Months from randomisation
16981703
16421660
16011640
15561615
15191577
14711524
828953
13981447
11751149
Events
213182
4-yearDFS
87.789.3
HR
0.85
95% CI
0.70, 1.04
p value
0.1087
1.6%
1-year Herceptin
Observation
100
80
60
40
20
0
Patients (%)
No. at risk
HERA Update
DFS and OS Over Time
No. of deathsH 1 year vs observation
0 1 2FavoursHerceptin
Favours noHerceptin
HR
OS benefit
29 vs 37p=0.26
20051
1 year(0%)
59 vs 90p=0.0115
182 vs 213p=0.1087
Median follow-up (% follow-up time
after selective crossover)
20062
2 years(4.1%)
20084 years(30.9%)
20051
1 year (0%)
Median follow-up (% follow-up time
after selective crossover)
20062
2 years (4.3%)
20084 years (33.8%)
No. of DFS eventsH 1 year vs observation
127 vs 220p<0.0001
218 vs 321p<0.0001
369 vs 458p<0.0001
0 1 2FavoursHerceptin
Favours noHerceptin
HR
DFS benefit
1Piccart-Gebhart et al 2005; 2Smith et al 2007
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?
HERA Update
100
80
60
40
20
00
Patients alive and disease free (%)
6 12 18 24 30 36 42 48
Observation: Alive and disease free on 16 May 2005
Months from randomisation
1354 1353 1339 1316 1278 1239 1180 992 712885 885 884 878 870 851 822 690 480
Selective crossover
469 468 455 438 408 388 358 302 232
No crossover
No. at risk
HERA Update
DFS: Observation (alive, no DFS event)Selective Crossover and No Crossover
Observation: Alive and disease free on 16 May 2005
0Months from randomisation
6 12 18 24 30 36 42 48
885 885 885 883 881 875 852 718 499
Selective crossover
100
80
60
40
20
0
No. at risk
Patients alive (%)
1354 1354 1350 1344 1332 1316 1270 1065 759
No crossover
469 469 465 461 451 441 418 347 260
HERA Update
OS: Crossover vs No-crossover
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?
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
HERA Update
CARDIOTOXICITY DISCUSSIONHERA / FINHER
Cardiac Safety Update in Adjuvant Trastuzumab Trials
No. patients (%)
HERA FINHER
Observation a
N=17191-year
trastuzamabN=1682
Chemo-trastuzumab
Chemo
Cardiac death 1 (0.1) 0 (0.0) -- --
Severe CHF (NYHA III + IV)
0 (0.0) 13 (0.8) 1 (0.9) 2 (1.7)
Symptomatic CHF (II, III,+IV)
3 (0.2) 33 (2.0) -- --
Confirmed significant LVEF drop
13 (0.8) 62 (3.7) -- --
Myocardial infarction
-- -- 0 0
a Patients who crossed over are censored from the data of starting trastuzumab treatment
HERA Trial: Cardiac Safety in Observation Group
No crossover after 16 May 2005
N=469Crossover
N=885
Cardiac death 0 (0) 0 (0)
Severe CHF (NYHA III and IV) 0 (0) 0 (0)
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
Concomitant vs. Sequential
Panel Vote 2009• No formal voting• Panel considered both approaches as reasonable• Increasing body of clinical evidence for concomitant
use
Adjuvant Trastuzumab Trials: Concurrent and Sequential DFS
Trial No. of Patients
HR Absolute gain (4 years)
Median follow-up, y
Concurrent
Combined US 3968 0.48 12.8% 3
BCIRG ACTH 2147 0.61 6% 3
BCIRG TCbH 2148 0.67 5% 3
FinHER 232 0.65 10% 5
Sequential
HERA 3501 0.76 6.4% 4
PACS 04 540 0.86 -0.5% 3
NCCTG N9831 (Coming ASCO 2009)
RANDOMIZATION
Patient Population• N+ or high-risk
N- breast cancer • HER2+ (IHC 3+ or
FISH)
N=3595
AC q3w x 4 Paclitaxel qw x 12
Trastuzumab qw x 52
AC q3w x 4 Paclitaxel qw x 12
AC q3w x 4 Paclitaxel qw x 12
Trastuzumab qw x 52
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
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
TRIPLE-NEGATIVE BREAST CANCER
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 2004-01– GEICAM
NEOADJVUANT SETTING
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%
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)
