Cardiac safety, efficacy, and correlation of serial serum HER2-extracellular domain shed antigen measurement with the outcome of the combined trastuzumab plus CMF in women with HER2-positive metastatic breast cancer: results from the EORTC 10995 phase II study.
Cardiotoxicity is a side effect of trastuzumab. We assessed efficacy and cardiac safety of CMF with trastuzumab (CMF+T) in HER2-positive metastatic breast cancer patients (MBC).



In this phase II study, centrally confirmed, previously treated HER2-positive MBC patients with measurable disease (per RECIST v 1.0) were enrolled. Initially, patients were randomized between 8 CMF cycles alone or combined with trastuzumab during chemotherapy, followed by 3-weekly trastuzumab maintenance till progression. A protocol amendment dropped the CMF arm and thereafter all patients received CMF+T. Translational research for prediction of treatment benefit was performed through serial serum HER2-shed antigen assessments.



Ninety patients (CMF: 19; CMF+T: 71) were enrolled between 2002 and 2006. Median age was 54 years. 42 patients had prior chemotherapy (33 with anthracyclines) and 41/71 patients who received CMF+T continued trastuzumab monotherapy for a median duration of 40 weeks. Overall response rate was 50% for CMF+T (35/70) and 32% for CMF (6/19). Median duration of response was 10.3 months and 5.4 months, respectively. Median progression-free survival was 9.4 months (95% CI 8.1-11.6) and 4.8 months (95% CI 2.8-7.9), respectively. In the CMF+T arm, 13(18%) patients had an absolute LVEF decline, including 3 patients developing any grade of New York Heart Association cardiac dysfunction. Patients with an increase of 30% over baseline shed antigen had a higher progression risk (95% CI 7.6, 3.9-14.8).



CMF+T is effective, with an acceptable cardiotoxicity profile. LVEF declines were mostly asymptomatic and occurred irrespective of previous anthracycline exposure. CMF+T can be considered for these patients, if other cytotoxics are contraindicated.
EORTC Headquarters, Brussels, Belgium. konstantinos.tryfonidis@eortc.be.
Konstantinos
K
Tryfonidis
EORTC Headquarters, Brussels, Belgium.
S
S
Marreaud
Department of Medical Oncology, National Cancer Institute- Cairo University, Cairo, Egypt.
H
H
Khaled
Department of Medical Oncology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.
B
B
De Valk
Department of Medical Oncology, Antwerp University Hospital, Edegem, Belgium.
J
J
Vermorken
Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland.
M
M
Welnicka-Jaskiewicz
EORTC Headquarters, Brussels, Belgium.
K
K
Aalders
Ontario Institute for Cancer Research, Toronto, Ontario, Canada.|University of Edinburgh Cancer Research Center, Western General Hospital, Edinburgh, UK.
J M S
JMS
Bartlett
Department of Medical Oncology, New Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.
L
L
Biganzoli
EORTC Headquarters, Brussels, Belgium.
J
J
Bogaerts
University of Edinburgh Cancer Research Center, Western General Hospital, Edinburgh, UK. D.Cameron@ed.ac.uk.
David
D
Cameron
D018943:Anthracyclines / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D066126:Cardiotoxicity / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D009362:Neoplasm Metastasis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000097:blood / Q000235:genetics*; D000068878:Trastuzumab / Q000008:administration & dosage* / Q000009:adverse effects
D018943:Anthracyclines; D061067:Antibodies, Monoclonal, Humanized; D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
CMF; Cardiac toxicity; HER2-positive; Metastatic breast cancer; Serum-shed antigen; Trastuzumab