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)

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

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 7

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

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 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 28.000 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

References Joensuu H et al. Clin Cancer Res 2003; 9: 923-930 Norris B et al. Poster 2031 presented at the 29th SABCS, San Antonio, Texas, USA, 14-17 December 2006. Goldhirsch A et al. Ann Oncol 2007; 18:1133-1144 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 0 2 4 6 8 10 12 Time (years) Joensuu, et al. Clin Cancer Res 2003; Norris, et al. SABCS 2006 Goldhirsch, et al. Ann Oncol 2007

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 13.000 pazienti References Piccart-Gebhart MJ et al. N Engl J Med 2005; 353: 1659-1672. Romond EH et al. N Engl J Med 2005; 353: 1673-1684. Slamon D et al. Abstract 52 presented at the 29th SABCS, San Antonio, Texas, USA, 14-17 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 2005 Romond et al 2005; Slamon et al 2006

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 0 6 12 18 24 30 36 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

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, 14-17 December 2006. Smith IE et al. Lancet 2007; 369: 29-36. 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 2006 Perez et al 2007; Smith et al 2007

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, 14-17 December 2006. Smith IE et al. Lancet 2007; 369: 29-36. ≥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 2006 Perez et al 2007; Smith et al 2007 DFS, disease-free survival 19

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, 14-17 December 2006. Smith IE et al. Lancet 2007; 369: 29-36. 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 2006 Perez et al 2007; Smith et al 2007 N, node 20

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: 29-36. 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

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=0.57 95% CI (0.30-1.09) 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, 13-17 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 2006 Spielmann et al 2007 3 4 Years since randomisation

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

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

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

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%)

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

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

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

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

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.

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

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 72.2 78.6 Events 458 369 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 1698 1703 1564 1619 1440 1552 1363 1485 1297 1414 1240 1352 1180 1280 992 1020 712 854 35

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 87.7 89.3 Events 213 182 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 1698 1703 1642 1660 1601 1640 1556 1615 1519 1577 1471 1524 1398 1447 1175 1149 828 953 36

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 20051 1 year (0%) 20051 1 year (0%) 127 vs 220 p<0.0001 29 vs 37 p=0.26 20062 2 years (4.3%) 20062 2 years (4.1%) 218 vs 321 p<0.0001 59 vs 90 p=0.0115 2008 4 years (33.8%) Piccart-Gebhart et al. NEJM 2005; 353: 1659-1672. Smith IE et al. Lancet 2007; 369: 29-36. 2008 4 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

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?

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

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

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?

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

Cardiotoxicity discussion HERA / FINHER

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

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

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 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, 10-14 December 2008. Joensuu H et al. N Engl J Med 2006; 354: 809-820. 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, 14-17 December 2006. Smith IE et al. Lancet 2007; 369: 29-36. Spielmann M et al. Breast Cancer Res Treat 2007; 106 (Suppl 1): S19, abs 72.

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

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)