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TAC versus FAC as Adjuvant<br />
Chemotherapy for High-risk<br />
Node-negative Breast Cancer:<br />
Results from the GEICAM 9805 Trial<br />
Martín M, Lluch A, Seguí MA, Ruiz A, Ramos M,<br />
Adrover E, Rodríguez-Lescure Á, Grosse R, Calvo L,<br />
Anton A, on behalf of the Spanish Breast Cancer<br />
Research Group (GEICAM)
Background (1)<br />
• Taxanes improve disease-free survival (DFS)<br />
and overall survival (OS) in node-positive breast<br />
cancer<br />
• However, most patients have node-negative<br />
breast cancer at diagnosis, and about 30% of<br />
them are at high-risk of relapse<br />
• The role of taxanes in this setting is not fully<br />
established<br />
• GEICAM 9805 began in 1998
Background (2)<br />
Database from GEICAM (1990-1993)<br />
Colomer R et al, JCO 22: 961, 2004<br />
Probability of DFS<br />
1.0<br />
0.75<br />
0.50<br />
0.25<br />
0.0<br />
Log-rank P = 0.046<br />
Disease Free Survival<br />
N0<br />
CMF Md=NR n=211<br />
0 20 40 60 80 100 120 140 160<br />
Months<br />
FAC Md=NR n=204<br />
FAC vs CMF as adjuvant chemotherapy<br />
for early breast cancer (GEICAM 8701)<br />
Martin M, et al. Ann Oncol 14:833, 2003
Study design<br />
N=1059<br />
R<br />
Stratification<br />
• Menopausal status<br />
• Center<br />
6 x TAC<br />
6 x FAC<br />
Docetaxel 75 mg/m 2<br />
Doxorubicin 50 mg/m 2<br />
Cyclophosphamide 500 mg/m 2<br />
Day 1, every 3 weeks<br />
Fluorouracil 500 mg/m 2<br />
Doxorubicin 50 mg/m 2<br />
Cyclophosphamide 500 mg/m 2
Additional treatment<br />
• Radiotherapy<br />
– Mandatory after conservative surgery and<br />
recommended for patients with tumors >5 cm<br />
• Tamoxifen<br />
– For 5 years to all patients with hormone<br />
receptor-positive tumors<br />
• Primary prophylactic G-CSF mandatory in TAC arm<br />
– Protocol amendment after first 237 patients<br />
randomized
Main inclusion criteria<br />
• Age 18–75 years<br />
• Curative surgery for unilateral T1–T3 breast<br />
carcinoma<br />
• No axillary lymph node involvement<br />
– At least 10 lymph nodes examined<br />
• At least one St Gallen 1998 high-risk criterion<br />
– Tumor grade 2 to 3<br />
– Tumors >2 cm<br />
– Age
Main exclusion criteria<br />
• Previous history of cancer<br />
• Abnormal renal, liver, or hematologic function<br />
• Other serious illness or medical conditions<br />
• Abnormal cardiac function (normal LVEF required)<br />
LVEF, left ventricular ejection fraction
Objectives<br />
• Primary<br />
– DFS after a minimum follow-up of 5 years<br />
• Secondary<br />
– OS<br />
– Safety<br />
– Prognostic and predictive value of molecular markers<br />
– Quality of life
Statistical considerations<br />
• DFS was defined as the interval from randomization<br />
to the date of breast cancer relapse, contralateral<br />
breast cancer, other primary malignancy or death<br />
from any cause, whichever occurred first<br />
• With 511 evaluable patients in each arm, the trial<br />
has a 90% power to detect an absolute 7.5% DFS<br />
increase (87.5% vs 80.0%) with TAC at 5-year<br />
follow-up
Patient characteristics<br />
TAC FAC<br />
Randomized patients, n 539 520<br />
Median age, years (range)<br />
Age 2 cm<br />
Tumor grade, %*<br />
1<br />
2<br />
3<br />
Menopausal status, %<br />
Pre-menopausal<br />
Post-menopausal<br />
Hormone receptor status, %*<br />
ER+ and/or PR+<br />
ER– /PR –<br />
50 (23–74)<br />
42 (7.8)<br />
52.9<br />
47.1<br />
7.1<br />
40.1<br />
48.1<br />
54.4<br />
45.6<br />
63.8<br />
35.6<br />
*Data unknown in a few cases<br />
49 (23–73)<br />
33 (6.4)<br />
47.9<br />
51.9<br />
6.5<br />
44.2<br />
44.2<br />
55.0<br />
45.0<br />
67.1<br />
32.5
Safety
Treatment Exposure<br />
TAC-pre<br />
n=114<br />
TAC-post<br />
n=414<br />
FAC<br />
n=519<br />
Completed 6 cycles, n (%) 103 (90.4%) 396 (95.7%) 505 (97.3%)<br />
Relative dose intensity<br />
Median 0.99 0.99 0.98<br />
Median cumulative dose, mg<br />
Docetaxel 445 448 –<br />
Doxorubicin 298 299 300<br />
Cyclophosphamide 2998 2995 2998<br />
5-FU – – 2998
Grade 2 or greater hematologic and<br />
nonhematologic toxicities<br />
Hematologic toxicity, %<br />
Grade 2–4 anemia<br />
Febrile neutropenia (protocol) *<br />
Febrile neutropenia (NCI-CTC)<br />
Non-hematologic toxicity, %<br />
Asthenia<br />
Anorexia<br />
Myalgia<br />
Dysgeusia<br />
Nail disorder<br />
Stomatitis<br />
TAC-pre<br />
(n=114)<br />
47.4<br />
24.6<br />
27.2<br />
64.0<br />
11.4<br />
14.9<br />
7.9<br />
7.9<br />
35.1<br />
TAC-post<br />
(n=414)<br />
27.5<br />
6.5<br />
7.5<br />
48.1<br />
3.6<br />
7.7<br />
3.1<br />
1.4<br />
23.2<br />
FAC<br />
(n=519)<br />
7.5<br />
2.3<br />
3.1<br />
33.3<br />
2.9<br />
1.2<br />
2.3<br />
1.3<br />
24.5<br />
P value<br />
(TAC-pre vs<br />
TAC-post)<br />
Safety<br />
• There were no toxic deaths<br />
TAC FAC<br />
n % n %<br />
P value<br />
Cardiac toxicity 6 1.1 5 1.0 0.81<br />
Hematologic<br />
neoplasm<br />
1 0.2 1 0.2 1
Efficacy
DFS events<br />
• 142 DFS events as of the cut-off (18 April 2008)<br />
– 58 in the TAC arm<br />
– 84 in the FAC arm<br />
First DFS event TAC (n) FAC (n)<br />
Breast cancer recurrence 44 58<br />
Second breast malignancy 3 11<br />
Other second malignancy 8 12<br />
Deaths without event 3 3
DFS<br />
Survival distribution function<br />
Median follow up: 67 months<br />
1.0<br />
0.9<br />
0.8<br />
0.7<br />
0.6<br />
0.5<br />
0.4<br />
0.3<br />
0.2<br />
0.1<br />
Number of patients<br />
Events<br />
HR=0.67 [95% CI, 0.48–0.94]<br />
Stratified log-rank p=0.0181<br />
91%<br />
86%<br />
0.0 0 12 24 36 48 60 72 84 96<br />
Disease-free survival (months)<br />
TAC FAC<br />
539 520<br />
58 (11%) 84 (16%)
DFS<br />
Median follow up: 67 months<br />
Survival distribution function<br />
1.0<br />
0.9<br />
0.8<br />
0.7<br />
0.6<br />
0.5<br />
0.4<br />
0.3<br />
0.2<br />
0.1<br />
HR=0.67 [95% CI, 0.48–0.94]<br />
Stratified log-rank p=0.0181<br />
86%<br />
FAC<br />
0.0 0 12 24 36 48 60 72 84 96<br />
Disease-free survival (months)<br />
80%
DFS<br />
Survival distribution function<br />
Median follow up: 67 months<br />
1.0<br />
0.9<br />
0.8<br />
0.7<br />
0.6<br />
0.5<br />
0.4<br />
0.3<br />
0.2<br />
0.1<br />
HR=0.67 [95% CI, 0.48–0.94]<br />
Stratified log-rank p=0.0181<br />
91%<br />
TAC<br />
0.0 0 12 24 36 48 60 72 84 96<br />
Disease-free survival (months)<br />
89%
Risk reductions<br />
• 33% reduction in risk of relapse with TAC<br />
(HR for DFS: 0.67; 95% CI, 0.48–0.94; P=0.0181)<br />
• 30% reduction in risk of death with TAC (HR<br />
for OS: 0.70; 95% CI, 0.41–1.22; P=0.21),<br />
however data not yet mature<br />
– 53 deaths; TAC 22, FAC 31
DFS subgroup analysis<br />
Menopausal status<br />
Hazard ratio (95%, CI)<br />
Overall DFS 0.67 (0.48, 0.94)<br />
Hormone-receptor (HR) status<br />
HR + 0.59 (0.36, 0.95)<br />
HR – 0.73 (0.45, 1.16)<br />
Post-menopausal 0.73 (0.44, 1.20)<br />
Pre-menopausal 0.63 (0.40, 0.99)<br />
Number of high-risk features<br />
1 0.64 (0.30, 1.39)<br />
2 0.69 (0.47, 0.99) ≥<br />
0.2<br />
0.4 0.6<br />
Favors<br />
TAC<br />
0.8<br />
1.0 1.2 1.4 1.6<br />
Favors<br />
FAC
Conclusions<br />
• First trial of purely high-risk, node-negative breast<br />
cancer patients to show an efficacy benefit with taxane<br />
treatment<br />
• TAC is superior to FAC, resulting in a 33% reduction in<br />
risk of relapse at 5 years<br />
• TAC side effects are mainly hematological and are<br />
manageable with primary G-CSF<br />
• GEICAM 9805 confirms BCIRG001 that TAC is proven<br />
effective both in node positive and in high risk node<br />
negative early stage breast cancer
Acknowledgments<br />
• We thank the 1059 patients who participated in<br />
this trial<br />
• All participating centers and investigators<br />
• This trial was co-sponsored by GEICAM and<br />
sanofi-aventis
Participating centers<br />
SPAIN<br />
Arnau de Vilanova (Lérida)<br />
Arnau de Vilanova (Val.)<br />
Arquitecto Marcide<br />
Barbastro<br />
Basurto<br />
C.O. de Galicia<br />
C.S. de Terrasa<br />
Ciudad de Jaén<br />
Clinic<br />
Clínica Corachán<br />
Clínico de Valencia<br />
Clínico San Carlos<br />
Clínico San Cecilio<br />
F.H. de Alcorcón<br />
General de Albacete<br />
General de Elche<br />
General de Elda<br />
GERMANY<br />
Klinik und Poliklinik<br />
Klinikum Quedlinburg<br />
GmbH<br />
Kreiskrankenhaus<br />
Donaueschingen<br />
POLAND<br />
Serafín Morales<br />
Vicente Alberola<br />
Laura de Paz Arias<br />
Jesús Florian Gericó<br />
Purificación Mtez del Prado<br />
Manuel Ramos Vázquez<br />
Angels Arcusa Lanza<br />
Margarita Fdez Morales<br />
Montserrat Muñoz<br />
Alfonso Modollel<br />
Ana Lluch<br />
Miguel Martín<br />
José Luis García Puche<br />
Carlos Jara Sánchez<br />
Antonio Fdez Aramburo<br />
Alvaro Rguez Lescure<br />
Cristina Llorca<br />
R. Grosse<br />
O. Boldt<br />
M. Eberl<br />
General de Vic<br />
General Univ. de<br />
Alicante<br />
Germans Trias i Pujol<br />
H. de la Ribera<br />
Insular Las Palmas<br />
IVO<br />
Juan Canalejo<br />
La Fe de Valencia<br />
La Princesa<br />
Lozano Blesa<br />
Marqués de Valdecilla<br />
Miguel Servet<br />
Montecelo<br />
Ntra. Sra. de Aránzazu<br />
Parc Taulí<br />
Puerta del Mar<br />
Puerto Real<br />
St. Marien-<br />
Kankenhaus<br />
Städtisches Klinikum<br />
Universitätsfrauenkli<br />
nik<br />
Rosa Mª Franquesa<br />
Encarna Adrover<br />
Agustín Barnadas<br />
José Miguel Cuevas Sanz<br />
Adolfo Murias Rosales<br />
Amparo Ruiz<br />
Lourdes Calvo<br />
Blanca Munárriz<br />
Amalia Velasco<br />
Dolores Isla Casado<br />
José Manuel López Vega<br />
Antonio Antón Torres<br />
Manuel Constenla<br />
Isabel Alvarez López<br />
Miguel Angel Seguí<br />
José Manuel Baena<br />
Antonio Lorenzo Peñuelas<br />
Matthias Losch<br />
Med. Melchert<br />
Carsten Oberhoff<br />
Poznan (Wielkopolskie) Jerzy Zaluski Wojewodzki Szpital Piotr Koralewski<br />
Ramón y Cajal<br />
Reina Sofía<br />
Río Carrión<br />
Rodríguez<br />
Chamorro<br />
Ruber Internacional<br />
Sant Joan Reus<br />
Santa María Nai<br />
Universitario de<br />
Salamanca<br />
Virgen Blanca<br />
Virgen de la Luz<br />
Virgen de la Victoria<br />
Virgen de los Lirios<br />
Virgen del Rocío<br />
Xeral Calde de<br />
Lugo<br />
Xeral Cíes de Vigo<br />
Universitätskliniken<br />
Homburg<br />
Carmen Crespo<br />
Enrique Aranda<br />
Alberto Arizcun<br />
Marta Navalón<br />
Pedro Aramburo<br />
Amadeu Pelegrí<br />
Manuel Rubén Rodríguez<br />
Amalia Gómez Bernal<br />
Andrés García Palomo<br />
Eduardo Martínez de Dueñas<br />
Emilio Alba Conejo<br />
Amparo Oltra<br />
Luis Iglesias Pérez<br />
José Ramón Mel Lorenzo<br />
Javier Castellanos<br />
Prof. Schmidt
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