Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial.
BACKGROUND
Neoadjuvant chemotherapy with trastuzumab for patients with HER2-positive breast cancer can produce a pathological complete response in the breast in 30-65% of patients. We investigated the effect of the timing of trastuzumab administration with anthracycline and taxane neoadjuvant chemotherapy.


METHODS
This randomised trial was done at 36 centres in the USA and Puerto Rico. Women with operable HER2-positive invasive breast cancer were randomly assigned (1:1) with a biased coin minimisation algorithm, stratified for age, tumour size, and hormone receptor status. Neither patients nor investigators (except for a cardiac safety review panel) were masked to treatment assignment. Patients randomly assigned to sequential treatment received fluorouracil 500 mg/m(2), epirubicin 75 mg/m(2), and cyclophosphamide 500 mg/m(2) (FEC-75) on day 1 of a 21-day cycle for four cycles followed by paclitaxel 80 mg/m(2) and trastuzumab 2 mg/kg (after a 4 mg/kg loading dose) once per week for 12 weeks, while those randomly assigned to the concurrent treatment group received paclitaxel and trastuzumab once per week for 12 weeks followed by four cycles of FEC-75 (on day 1 of each 21-day cycle) and once-weekly trastuzumab, in the same doses as the sequential group. Surgery, including evaluation of the axilla, was done within 6 weeks of completion of neoadjuvant treatment. The primary outcome was the percentage of patients who had a pathological complete response in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00513292.


RESULTS
From Sept 15, 2007, to Dec 15, 2011, 282 women were enrolled (140 in the sequential group, 142 in the concurrent group). Two patients in the sequential group withdrew consent before starting treatment. 78 of 138 (56·5%, 95% CI 47·8-64·9) patients who received sequential treatment had a pathological complete response in the breast versus 77 of 142 (54·2%, 95% CI 45·7-62·6) who received concurrent treatment (difference 2·3%, 95% CI -9·3 to 13·9). No treatment-related deaths occurred. The most common severe toxic effects were neutropenia (35 [25·3%] of 138 patients in the sequential group vs 45 [31·7%] of 142 patients in the concurrent group) and fatigue (six [4·3%] vs 12 [8·5%]). Left ventricular ejection fraction dropped below the institutional lower limit of normal at week 12 in one (0·8%) of 130 patients who received sequential treatment and four (2·9%) of 137 patients who received concurrent treatment; by week 24, it had dropped below this limit in nine (7·1%) of 126 patients and in six (4·6%) of 130 patients, respectively.


CONCLUSIONS
Concurrent administration of trastuzumab with anthracyclines offers no additional benefit and is not warranted.


BACKGROUND
US National Cancer Institute.
Office of Vice President for Clinical Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Aman U
AU
Buzdar
Vera J
VJ
Suman
Funda
F
Meric-Bernstam
A Marilyn
AM
Leitch
Matthew J
MJ
Ellis
Judy C
JC
Boughey
Gary
G
Unzeitig
Melanie
M
Royce
Linda M
LM
McCall
Michael S
MS
Ewer
Kelly K
KK
Hunt
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D015251:Epirubicin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008198:Lymph Nodes / Q000473:pathology / Q000601:surgery; D008207:Lymphatic Metastasis; D008408:Mastectomy / Q000379:methods; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D011647:Puerto Rico; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D013318:Stroke Volume / Q000187:drug effects; D013997:Time Factors; D000068878:Trastuzumab; D016896:Treatment Outcome; D014481:United States
D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D003520:Cyclophosphamide; D015251:Epirubicin; D005472:Fluorouracil; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human