REFERENCES1. Bonneterre J, Roche H, Kerbrat P, et al. Long-term cardiac follow-up in relapse-free patients after six courses

of fl uorouracil, epirubicin, and cyclophosphamide, with either 50 or 100 mg of epirubicin, as adjuvant therapy for node-positive breast cancer: French adjuvant study group. J Clin Oncol 2004;22:3070-9

2. 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 Mar 15;344(11):783-92.

3. Thürlimann B, Keshaviah A, Coates AS, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005 Dec 29;353(26):2747-57.

4. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after fi ve years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003 Nov 6;349(19):1793-802.

5. Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004 Mar 11;350(11):1081-92.

6. Spielmann M, Roché H, Delozier T, et al. Trastuzumab for Patients With Axillary-Node-Positive Breast Cancer: Results of the FNCLCC-PACS 04 Trial. J Clin Oncol. 2009 Nov 16; [Epub ahead of print]

Five year Analysis of the FNCLCC-PACS04 Trial: FEC 100 vs ED75 for Adjuvant Treatment of Node-Positive Breast CancerHenri Roché(1), Djelila Allouache(2), Gilles Romieu(3), Hugues Bourgeois(4), Jean-Luc Canon(5), Daniel Serin(6), Patrice Viens(7), Louis Mauriac(8), Alain Monnier(9), Anita Vindevoghel(10), Nadine Dohollou(11),

Elisabeth Luporsi(12), Jean-Marc Ferrero(13), Bruno Audhuy(14), Catherine Dopchie(15), Laurent Cany(16), Etienne Brain(17), Marta Jimenez(18), Lise Roca(3) and Marc Spielmann(19) for the FNCLCC Breast Group(1) Institut Claudius Regaud, Toulouse, France, (2) Centre François Baclesse, Caen, France, (3) Centre Val d'Aurelle, Montpellier, France, (4) CHU Poitiers, France, (5) Grand Hôpital de Charleroi, Charleroi, Belgium, (6) Institut Sainte Catherine, Avignon, France, (7) Institut Paoli-Calmettes, Marseille, France, (8) Institut Bergonié, Bordeaux, France, (9) CH Montbelliard, France, (10) Clinique Sainte Elisabeth, Namur, Belgium, (11) Polyclinique Bordeaux Nord-Aquitaine, Bordeaux, France, (12) Centre Alexis Vautrin, Nancy, France, (13) Centre Antoine Lacassagne, Nice, France, (14) CH, Colmar, France, (15) Clinique Notre-Dame, Tournai,

Belgium, (16) Polyclinique Francheville, Perigueux, France, (17) Centre René Huguenin, Saint-Cloud, France, (18) FNCLCC, Paris, France, (19) Institut Gustave Roussy, Villejuif, France

SABCS 2009 - Poster Discussion Session 6 – Poster 602

BACKGROUND IN 2001 Chemotherapy regimens FEC100 regimen • 6 cycles of FEC100 (Epirubicin 100 mg/m²) were considered the reference adjuvant treatment in France according to

FASG-05 trial (6FEC 50 vs 6 FEC 100) (1)

ED75 regimen At time of PACS 04 initiation, the best use of docetaxel (D) was still under investigation

• PACS 01 trial tested a sequential regimen of anthracyclines and docetaxel (3 FEC100 followed by 3 D 100 mg/m²) but results were not available in 2001

• Combination treatment of anthracyclines and docetaxel was experimented in the PACS 04 trial (6 cycles of Epirubicin 75 mg/m² + Docetaxel 75mg/m²)

Trastuzumab (T) Trastuzumab has been shown to improve outcome of erbB2 overexpressed tumors in patients with metastatic disease (2). The challenge was to introduce this drug in the adjuvant setting. Additive cardiac toxicity has been observed in metastatic disease (2). So, as epirubicin was given along chemotherapy, Trastuzumab should be proposed alone sequentially after chemotherapy.

INCLUSION CRITERIA-CT RANDOMIZATION

Main Inclusion Criteria – First randomization Histologically proven unilateral breast cancer with complete resection (T1-

T2-T3, M0) N+ (at least 5 axillary lymph nodes resected) Age ≥ 18 years and ≤ 65 years Adequate cardiac, hepatic, hematologic, and renal functions No prior treatments for breast cancer

Initial screening Bilateral mammography Chest X-ray, liver ultrasonography, bone scan Left ventricular ejection fraction (LVEF) ≥ 50% as measured by MUGA scan

or echocardiography

RADIOTHERAPY AND HORMONOTHERAPY

Radiotherapy mandarory for patients with breast conservation started within 4 weeks after the last chemotherapy cycle

Hormonal treatment Tamoxifen was prescribed for 5 years in HR-positive patients after

chemotherapy Protocol amendments allowed sequential use of aromatase inhibitors led to

modify hormonal treatment of postmenopausal patients (3) (4) (5)

TARGETED THERAPY Trastuzumab randomisation Second Randomization was performed as soon as results of HER2 assessment. HER2-positive status was defi ned by the following : • HER2 3+ (IHC) i.e. > 10% stained cells • HER2 2+ and FISH positive HER2-positive randomized patients were treated if: • they received at least 4 cycles of chemotherapy • cardiac function was adequate at completion of radiotherapy - No clinical signs of CHF - LVEF ≥55% or between 50% and 55% according to the cardiologist’s decision • With no clinical evidence of metastases

HYPOTHESIS The number of patients has been calculated on the basis of those required for the randomization with trastuzumab. Hypothesis for R2 Primary endpoint = 3-year DFS with α = 5% and 1 - β = 80%; one-sided log-rank test; 33% reduction in the risk of relapse Number of patients required = 520

Hypothesis for R1 Primary endpoint = 5-year DFS Considering that about 20% of patients over-expressed HER2, 2,600 patients were required allowing a power of 95% for

the comparison between chemotherapy regimens. Due to a lower than expected proportion of patients over-expressing HER2, the total sample size was increased to 3,000.

STATISTICAL ANALYSIS Endpoints Primary endpoint = 5-year DFS Secondary endpoint = 5-year Overall survival

Statistical analysis Intent to treat analysis DFS estimated using Kaplan-Meier method and the log-rank test, stratifi ed for the number of axillary lymph nodes (1 to

3 vs 4 or more) Multivariate analysis using Cox regression model adjusted for age, menopausal status, clinical tumor size, lymph node,

SBR grade, hormone receptors and C-erB2 typing.

MAIN OBJECTIVE To evaluate the concomitant administration of Docetaxel and Epirubicin in term of effi cacy and safety versus

standard FEC100 regimen in node positive non metastatic patients.

CONCLUSION : EFFICACY RESULTS In women with node positive early stage breast cancer the combination of epirubicin and docetaxel

does not confer superior DFS compared to FEC 100 FEC 100 remains a very active regimen in this setting 5-year DFS was improved in the 2 arms compared to PACS01, but OS was in the same range A positive interaction test was found and favored ED for the HER2 positive sub group Trastuzumab given sequentially offers little value in the C-erbB2 population6

CONCLUSION : SAFETY RESULTS Compliance to the 2 regimens was comparable and 98% of patients completed the chemotherapy

program Febrile neutropenia, use of G-CSF was higher in the ED arm Nausea, vomiting, secondary leukemias were more frequent in the FEC arm Despite a 25% higher cumulative dose of epirubicin in the FEC arm, severe cardiac events were

rare

PERSPECTIVES Due to a higher rate of hematologic toxicities and higher use of G-CSF with ED, we recommend

a sequential FEC-D (PACS01) when docetaxel needs to be included in an adjuvant program Moreover, for c-erbB2 over-expressed tumors, sequential regimens permits the integration of

concomitant trastuzumab with D More active therapy is still needed for some subgroups as triple negative population (PACS08)

ObjectiveTo evaluate the combined administration of Docetaxel (D) and Epirubicin (E) versus FEC 100 on 5-year disease-free survival (DFS) among non metastatic lymph node-positive breast cancer patients (pts).

Patients and MethodsMain inclusion criteria were: localized unilateral breast cancer, age < 65 years, at least one positive node, no metastasis, normal cardiac, hepatic, haematological and renal functions. Pts were randomized to receive on day 1 every 3 weeks either Arm A: 6 cycles of FEC100 (F and C, each at 500 mg/m², E 100 mg/m²); or Arm B, 6 cycles of ED (E and D, each at 75 mg/m²). G-CSF was mandatory for all subsequent cycles after either febrile neutropenia or treatment delay for neutropenia. Radiotherapy was given after conservative surgery. Hormone therapy was prescribed to pts with positive hormone receptors (HRs). Pts overexpressing HER2 were secondly randomized to sequential one year of trastuzumab or observation. Sample size calculation was based on an expected 10% absolute difference in 3–year DFS for HER2+ pts. Assuming a 20% prevalence of HER2 positivity, a total of 3,000 pts were to be randomised, allowing to detect an absolute difference of 6% in 5-year DFS in favour of one of the two chemotherapy regimens.

ResultsBetween February 2001 and August 2004, 3,010 pts were randomized in France and Belgium. Pts characteristics were well balanced between the 2 arms: median age 50 years, post-menopausal status 48%, breast-conserving surgery 70%, tumor size >2cm 49%, SBR grade III 40%, both HRs negative 20%, both HRs positive 62%, 1-3 involved nodes 67%, HER2+ 19%. Treatment was completed for 96% of pts in both arms. Febrile neutropenia was reported for 2.0% and 6.4% of cycles respectively in Arms A and B. Grade 3-4 NCI-CTC neutropenia were reported for 34% and 9% of pts on day 21(Arms A and B). Other grade 3-4 toxicities were: leucopenia (35 vs 47%), thrombopenia (1.7 vs 0.3%), nausea/vomiting (14 vs 8%) and mucositis (3.2 vs 3.3%). No toxic death was reported.As of April 2009, the median follow-up was 59.3 months. Overall, 576 pts experienced at least one event: 103 loco-regional relapses, 398 metastasis, 46 contralateral breast cancer, and 29 deaths as fi rst event. A total number of 35 second cancers and 288 deaths are registered. The 5-year DFS rates were 79.7% (95%CI: 77.4-81.7) and 81.7% (95%CI: 79.6-83.7) in arms A and B respectively (HR=0.89, 95%CI: 0.76-1.05, p=0.18). Multivariate Cox regression analysis, adjusted for age, tumor size, SBR grade, HRs and stratifi ed for lymph node status, revealed a signifi cant interaction term between treatment and HER2 (p=0.01).Five-year overall survival rates (OS) were 90.3% (95%CI: 88.5-91.8) with FEC and 90.1% (95%CI: 88.3-91.6) with ED (HR=1.07, 95%CI: 0.85-1.35, p=0.54).

ConclusionNo advantage in DFS or OS was observed by combination of D to E when compared to standard FEC100. The best use of D in the adjuvant setting is still uncertain.

ABSTRACT

PATIENT CHARACTERISTICS6FEC100(N=1,515)

6ED75(N=1,495) p

Age, median (range) 50 (23-65) 50 (22-66) 0.70< 50 years, % 46.5 47.1 0.740.74Conservative surgery, % 71.2 68.1 0.07Postmenopausal status, % 47.7 48.0 0.85pT > 2 cm, % 48.2 48.9 0.76N 1-3, % 67.7 67.3 0.82SBR, % grade I-II 58.6 60.1 0.43 grade III 41.4 39.9ER positive, % 77.3 77.1 0.88HR both negative, % 20.1 20.0 0.31HER2 status,% 19.7 17.7 0.17 IHC 3+ 16.9 15.8 IHC 2+/FISH+ 2.8 1.9Triple negative,% 12.1 12.5 0.79

TREATMENT CHARACTERISTICS

6FEC100(N=1,515)

6ED75(N=1,495)

Chemotherapy Received cycles, % 1-3 cycles 1.9 2.4

≥ 4 cycles 98.1 97.6Dose intensity (mg/m²/wk), median FU 162.7

Epirubicin 32.5 24.7Cyclophosphamide 163.0

Docetaxel 24.7Chemotherapy, % Mean RDI, % F 97.6

E 97.6 98.8C 97.8D 98.8

RDI > 90%, % F 87.2E 85.9 92.3C 87.3D 92.4

Hormonotherapy, % 80.2 80.2Radiotherapy, % 98.3 98.4

STUDY POPULATION

HEMATOLOGICAL TOXICITIESPer Patient 6FEC100

(N=1,509)6ED75

(N=1,481) p

Anemia gr 3-4, % 2.9 1.5 0.010.01Platelets gr 3-4, % 1.7 0.3 < 0.001Febrile Neutropenia, % 10.7 31.5 < 0.001G-CSF, % 31.0 43.2 < 0.001G-CSF/cycle*, % 20.1 31.9 < 0.001

* G-CSF was administered as secondary prophylaxis

EXTRA HEMATOLOGICAL TOXICITIES

Per Patient 6FEC100(N=1,509)

6ED75(N=1,481) p

Nausea-vomiting gr 3-4, % 13.6 7.6 < 0.001

Mucositis gr 3-4, % 3.2 3.3 0.850.85

Diarrhea gr 3-4, % 0.5 2.8 < 0.001

Neurotoxicity ≥ gr 2, % 1.0 4.0 < 0.001

Acute leukemia, n 4 1

Myeloma, n 1 0

Toxic death (non cardiac) 1* 2**

* 1 pulmonary infection ** 1 septic choc; 1 mesenteric infarct

CARDIAC TOXICITIES DURING CT REGIMENS*6FEC100(N=1,509)

6ED75(N=1,481)

LVEF< 50%, n 35 34Arrhythmia gr 3-4, n 2 11Left ventricular toxicity (clinic) gr 3, n gr 4, n

40

11

Cardiac death, n - 3*** During CT administration and the next 2 months after last cycle** 1 pulmonary embolism; 1 CHF; 1 sudden death

EVENTS, ITT

Patients, n (%) 6FEC100(N=1,515)

6ED75(N=1,496)

First event 304 272

Distant metastasis 213 (14.1) 192 (12.9)192 (12.9)

Loco-regional recurrence 56 (3.7) 41 (2.7)41 (2.7)

Controlateral breast cancer 23 (1.5) 23 (1.5)23 (1.5)

Death 12 (0.8) 16 (1.1)16 (1.1)

Distant metastasis 239 211

Contralateral breast cancer 30 33

Second cancer 21 14

Any Death 140 147

TRIAL DESIGN 5-YEAR EFFICACY RESULTS

SAFETY RESULTS

DFS AT 5 YEARS, ITT

0

6ED75 : 81.8 %

6FEC100 : 79.6 %

First Events = 576 FEC: 304 (20.0%)ED : 272 (18.2%)

0.00

0.25

0.50

0.75

1.00

12 24 36 48 60 72

HR (Cox model) = 0.89 [0.75-1.05], P-value = 0.175

Time (Months)

DFS BY NODAL STATUS, ITT

0

6ED75

6FEC100

0.00

0.25

0.50

0.75

1.00

12 24 36 48 60 72

Log-rank P-value = 0.386HR (Cox model) = 0.90 [0.71-1.14]

N 1-3

Time (Months)0

6ED75

6FEC100

0.00

0.25

0.50

0.75

1.00

12 24 36 48 60 72

Log-rank P-value = 0.294HR (Cox model) = 0.88 [0.71-1.11]

N 4+

Time (Months)

DFS BY CERB2 STATUS, ITT

0

6ED75

6FEC100

0.00

0.25

0.50

0.75

1.00

12 24 36 48 60 72

Log-rank P-value = 0.015HR (Cox model) = 0.67 [0.49-0.93]

HER2 positive

Time (Months)

OS AT 5 YEARS, ITT

0

6ED75 : 90.1 %

6FEC100 : 90.3 %

First Events = 287FEC: 140 (9.2%)ED : 147 (9.8%)

0.00

0.25

0.50

0.75

1.00

12 24 36 48 60 72

HR (Cox model) = 1.06 [0.85-1.34], P-value = 0.588

Time (Months)

FOREST PLOT ANALYSIS, DFS

0,5 1,51

ED75 FEC100 Events/pts Events/ptsAge Age<50 143/703 147/704 Age>=50 129/791 157/811

Tumor size <=20 98/756 115/774 >20 171/724 188/725

SBR I-II 108/872 113/869 III 154/580 184/613

Involved nodes 1-3 130/1006 147/1026 4+ 142/488 157/489

CerBb2 Negative 211/1229 208/1217 Positive no trastuzumab 38/149 62/180 Positive with trastuzumab 23/116 34/118

Estrogen receptors Negative 105/342 108/343 Positive 167/1152 195/1170

Progesterone receptors Negative 129/465 148/508 Positive 131/946 136/926

Hormonal status ER-PR- 96/282 97/288 ER-PR+ 8/58 11/54 ER+PR+ 123/888 125/871 ER+PR- 33/183 51/220

Triple negative No 207/1318 252/1341 Yes 65/176 52/174

TOTAL 272/1494 304/1515

HAZARD RATE(95% Cl)0.98 [0.78-1.24]0.82 [0.65-1.03]

0.85 [0.65-1.12]0.91 [0.74-1.12]

0.95 [0.73-1.23]0.88 [0.71-1.09]

0.90 [0.71-1.14]0.88 [0.70-1.11]

1.01 [0.83-1.22]0.69 [0.46-1.03]0.66 [0.38-1.12]

0.97 [0.74-1.27]0.86 [0.70-1.06]

0.95 [0.75-1.20]0.94 [0.73-1.19]

1.02 [0.77-1.36]0.62 [0.25-1.55]0.97 [0.75-1.24]10.75 [0.48-1.17]

0.82 [0.68-1.98]1.30 [0.90-1.87]

0.89 [0.75-1.05]

ED Better FEC Better

ACKNOWLEDGEMENTS The 3,010 patients who participated in the study The investigators of the 82 investigational sites The Independent Data Monitoring Committee The Ligue Nationale Contre Le Cancer Roche, Sanofi -Aventis France, Pfi zer, Amgen

PARTICIPATING CENTERSIN FRANCE : Institut Claudius REGAUD, Toulouse – Centre François BACLESSE, Caen – Centre Val d’Aurelle – Paul LAMARQUE, Montpellier – Institut Gustave ROUSSY, Villejuif – Institut CURIE, Paris – Centre Eugène MARQUIS, Rennes – Centre Paul PAPIN, Angers – Centre René GAUDUCHEAU, Nantes – Centre Georges-François LECLERC, Dijon – Institut Paoli-Calmettes, Marseille – CHU, Poitiers – Institut BERGONIÉ, Bordeaux – Centre Alexis VAUTRIN, Vandoeuvre-Les-Nancy – Institut Sainte-Catherine, Avignon - Centre Antoine LACASSAGNE, Nice – Clinique Armoricaine de Radiologie, Saint-Brieuc – CMC Les Ormeaux, Le Havre – Centre René HUGUENIN, Saint-Cloud – Polyclinique Bordeaux Nord Aquitaine, Bordeaux – Centre Henri BECQUEREL, Rouen – CH Fleyriat, Bourg en Bresse – Centre Jean PERRIN, Clermont-Ferrand – CH A. BOULLOCHE, Montbéliard – CH L. PASTEUR, Colmar – CHU Paule de VIGUIER, Toulouse – Institut Jean GODINOT, Reims - Polyclinique de Francheville, Périgueux – Institut Privé de Cancérologie, Grenoble – CHI, Créteil – APHP Tenon, Paris – CH, Rodez – Polyclinique du Parc, Toulouse – Clinique Claude BERNARD, Albi – CHU A. MICHALLON, Grenoble – CH Émile MÜLLER, Mulhouse - Polyclinique de l’Ormeau, Tarbes – CHU, Strasbourg – Clinique Tivoli, Bordeaux - Centre Léon BERARD, Lyon – CHR Notre Dame du Bon Secours, Metz – CHU A. MORVAN, Brest – CH Bretagne-Sud, Lorient - Centre Paul STRAUSS, Strasbourg – CH, Compiègne – CH de la Côte Basque, Bayonne – Clinique Plein Ciel, Mougins - Clinique PASTEUR, Evreux – CH, Le Havre – CH, Auxerre – CH de la Région Annecienne, Annecy – CH A. GAYRAUD, Carcassonne – Clinique Saint-Pierre, Perpignan – CH, Roanne – Clinique Saint-Grégoire, Tours.IN BELGIUM : Clinique Universitaire Saint-Luc, Bruxelles – Clinique Notre-Dame Reine FABIOLA, Charleroi – Clinique Saint-Pierre, Ottignies - Clinique Sainte-Elisabeth, Namur – Clinique Notre-Dame, Tournay - Hôpital de Jolimont, Haine Saint-Paul – CH Peltzer-La Tourelle, Verviers - Clinique Notre-Dame Grace, Gosselies – CH de l’Ardenne, Libramont – CHR La Citadelle, Liège – Hôpital Saint-Joseph, Mons - Clinique Saint-Joseph, Arlon – CH Hornu, Boussu – Clinique Saint-Joseph, Gilly - UCL Mont-Godinne, Yvoir – Centre de Santé des Fagnes, Chimay – Hôpital Saint-Nicolas, Epen - CH du Bois de l’Abbaye, Seraing.

SURGERY

In HER2-positive patients

Trastuzumab (T)

Observation (O)

RT HT

RT HT6 ED75 q3w Epirubicin 75 mg/m² d1Docetaxel 75 mg/m² d1

6 FEC100 q3w Fluorouracil 500 mg/m² d1Epirubicin 100 mg/m² d1Cyclophosphamide 500 mg/m² d1

R1 R2

Stratifi ed on: Center N (1-3 vs 4 or more)

ITT

HER2+

SAFETY6FEC100 6ED75

Untreated = 9Switch ED = + 4 FEC = - 1

1,515

1,509

O*=144

T*=135

1,495

1,480

O*=124

T*=125

Between February 2001 and August 2004, 3,010 patients from 82 French (n= 2,641) and Belgian (n=369) institutions were randomized

Median follow-up: 59.3 months

No data = 1Untreated = 12Switch FEC = + 1 ED = - 3

*O = observation, T = trastuzumab

0

6ED75

6FEC100

0.00

0.25

0.50

0.75

1.00

12 24 36 48 60 72

Log-rank P-value = 0.904HR (Cox model) = 1.01 [0.83-1.22]

HER2 negative

Time (Months) Interaction Test, p=0.008