First-line trastuzumab plus epirubicin and cyclophosphamide therapy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: cardiac safety and efficacy data from the Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) trial.
OBJECTIVE
A high incidence of congestive heart failure (CHF) has been observed in patients with metastatic breast cancer (MBC) receiving doxorubicin-based chemotherapy and trastuzumab. The Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) trial evaluated trastuzumab plus cyclophosphamide and the less cardiotoxic anthracycline epirubicin.


METHODS
This prospective trial combined a phase I dose-finding stage with a phase II randomized stage. In total, 120 patients with human epidermal growth factor receptor 2 (HER2) -positive MBC and adequate cardiac function received first-line trastuzumab (4 mg/kg intravenous loading dose, then 2 mg/kg every week) plus cyclophosphamide (600 mg/m(2)) and either epirubicin 60 mg/m(2) (HEC-60) or 90 mg/m(2) (HEC-90) for six cycles, followed by trastuzumab monotherapy until progression. Sixty patients with HER2-negative disease received epirubicin (90 mg/m(2)) and cyclophosphamide (EC-90) alone. The primary end point was dose-limiting cardiotoxicity (DLC).


RESULTS
Incidence of DLC was 5.0%, 1.7%, and 0% in the HEC-90, HEC-60, and EC-90 arms, respectively. All DLC events were manageable. There were no cardiac-related deaths. Other adverse-event profiles were comparable across the three arms, except febrile neutropenia, which was reported in 10% of the HEC-90 arm compared with 3% of the other arms. Tumor response rates were 57%, 60%, and 25% in the HEC-60, HEC-90, and EC-90 arms, respectively; median time to progression was 12.5, 10.1, and 7.6 months, respectively.


CONCLUSIONS
The HEC regimen is a promising treatment option for patients with HER2-positive MBC. The lower incidence of DLC with HEC, compared with the historic incidence associated with trastuzumab plus doxorubicin, supports further evaluation of the regimen, especially in adjuvant or neoadjuvant settings.
Untch
Michael
M
HELIOS Klinikum Berlin-Buch, Frauenheilkunde mit Geburtshilfe, Berlin, Germany. michael.untch@helios-kliniken.de
Muscholl
Michael
M
Tjulandin
Sergei
S
Jonat
Walter
W
Meerpohl
Hans-Gerd
HG
Lichinitser
Mikhail
M
Manikhas
Alexey G
AG
Coumbos
Alexandra
A
Kreienberg
Rolf
R
du Bois
Andreas
A
Harbeck
Nadia
N
Jackisch
Christian
C
Müller
Volkmar
V
Pauschinger
Matthias
M
Thomssen
Christoph
C
Lehle
Michaela
M
Catalani
Olivier
O
Lück
Hans-Joachim
HJ
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D015331:Cohort Studies; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D015251:Epirubicin / Q000008:administration & dosage / Q000009:adverse effects; D005240:Feasibility Studies; D005260:Female; D006331:Heart Diseases / Q000139:chemically induced; D006801:Humans; D008875:Middle Aged; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D000068878:Trastuzumab; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003520:Cyclophosphamide; D015251:Epirubicin; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human