No Advantage of Concurrent vs Sequential Trastuzumab/Anthracycline Neoadjuvant Therapy in Patients With HER2-Positive Breast Cancer
In the phase III Z1041 trial reported in The Lancet Oncology, Aman U. Buzdar, MD, of The University of Texas MD Anderson Cancer Center, and colleagues compared neoadjuvant therapy with FEC-75 (fluorouracil [5-FU], epirubicin, and cyclophosphamide) followed by paclitaxel plus trastuzumab (Herceptin) (sequential trastuzumab/anthracycline) vs paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab (concurrent trastuzumab/anthracycline) in patients with HER2-positive breast cancer. They found that the concurrent trastuzumab/anthracycline regimen was not associated with a greater complete pathologic response rate compared with the sequential trastuzumab/anthracycline regimen.
Study Details
In this open-label trial performed in 36 centers in the United States and Puerto Rico between September 2007 and December 2011, 282 women with operable HER2-positive invasive breast cancer were randomly assigned to 5-FU at 500 mg/m2, epirubicin at 75 mg/m2, and cyclophosphamide at 500 mg/m2 (FEC-75) on day 1 of a 21-day cycle for four cycles followed by paclitaxel at 80 mg/m2 and trastuzumab at 2 mg/kg (after a 4-mg/kg loading dose) once per week for 12 weeks (sequential group, n = 140) or paclitaxel and trastuzumab once per week for 12 weeks followed by four cycles of FEC-75 (on day 1 of each 21-day cycle) plus once-weekly trastuzumab (concurrent group, n = 142). Surgery was performed within 6 weeks of completion of neoadjuvant treatment.
Patients were stratified for age, tumor size, and hormone receptor status. The primary outcome measure was pathologic complete response rate.
Two sequential group patients withdrew before treatment. The sequential and concurrent groups were well balanced for age (67% and 72% 40–59 years), race (85% and 80% white), body mass index (69% and 68% ≥ 25.0 m/kg2), Eastern Cooperative Oncology Group performance status (0 in 93% and 90%), clinical T stage (T2 in 55% in both, T3 in 30% and 29%), clinical N stage (N0 in 36% and 37%, N1 in 52% and 58%), hormone receptor status (estrogen receptor/progesterone receptor–positive in 35.5% and 41.5%, estrogen receptor–positive/progesterone receptor–negative in 22.5% and 16%, estrogen receptor–negative/progesterone receptor–positive in 3% and 1%, and estrogen receptor–negative/progesterone receptor–negative in 39% and 41%), tumor grade (2 in 42% and 33%, 3 in 56% and 64%), histology (ductal in 95% and 97%), and method of baseline left-ventricular ejection fraction measurement (multigated acquisition scan in 72% in both and echocardiography in 28% in both).
Response Rates
Pathologic complete response was observed in 56.5% of the sequential group vs 54.2% of the concurrent group (difference = 2.3%, 95% confidence interval [CI] = –9.3% to 13.9%), yielding an adjusted odds ratio (accounting for age, hormone receptor status, and clinical T stage) of 0.90 (95% CI = 0.55–1.49) for the concurrent vs sequential group. Response rates were 70.4% in the sequential group vs 77.6% (difference = –7.2%, 95% CI = –23.5% to 9.0%) among women with estrogen receptor–negative/progesterone receptor–negative disease and 47.6% vs 38.1% (difference = 9.5%, 95% CI = –5.3% to 24.4%) among women with estrogen receptor–positive or progesterone receptor–positive disease.
Adverse Events
There were no treatment-related deaths. In total, 39.9% of the sequential group and 53.5% of the concurrent group had a grade 3 or 4 adverse event considered at least possibly related to study treatment. The most common grade 3 or 4 adverse events in the concurrent group were neutropenia (32% vs 25% in the sequential group), leukocytopenia (10% vs 3%), fatigue (8.5% vs 4%), lymphopenia (5% vs 3%), and neurosensory difficulties (5% vs 4%); the most common in the sequential group were neutropenia and fatigue.
Hospital admission due to treatment-related adverse events occurred for 12.3% of the sequential group and 16.9% of the concurrent group. Left-ventricular ejection fraction dropped below the institutional lower limit of normal in 0.8% of the sequential group and 2.9% of the current group by week 12 and in 7.1% and 4.6% by week 24.
The investigators concluded, “We found that the proportion of patients who achieved a pathological complete response was similar with concurrent [vs] sequential trastuzumab and fluorouracil, epirubicin, and cyclophosphamide. Thus, concurrent administration of trastuzumab with anthracyclines offers no additional benefit and is not warranted.”
The study was funded by the National Cancer Institute.
Kelly K. Hunt, MD, of The University of Texas MD Anderson Cancer Center, is the corresponding author for the The Lancet Oncology article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
