Comparative impact of trastuzumab and cyclophosphamide on HER-2-positive human breast cancer xenografts.
OBJECTIVE
Metronomic chemotherapy is a minimally toxic and frequently effective new treatment strategy that is beginning to show promising phase II clinical trial results, particularly for metastatic breast cancer when combined with various molecularly targeted antitumor agents. Here, we assessed a treatment strategy that uses trastuzumab plus daily oral metronomic cyclophosphamide on metastatic Her-2-positive human breast cancer models.


METHODS
Treatments were initiated on orthotopic transplanted primary tumors as well as established visceral metastatic disease of two independent Her-2-positive breast cancer models, both independently derived from the human MDA-MB-231 breast cancer cell line. Outcome was assessed by noninvasive measurements of tumor cell-secreted human choriogonadotropin in the urine as a surrogate marker of relative tumor burden, or by whole body bioluminescent imaging, in addition to prolongation of survival.


RESULTS
Orthotopic primary tumors responded to trastuzumab monotherapy with significant growth delays, whereas minimal antitumor effect was observed when mice with metastatic disease were treated. Nevertheless, trastuzumab showed a benefit in this latter setting when combined with metronomic low-dose cyclophosphamide as assessed by prolongation of survival. This benefit was similar to trastuzumab plus maximum tolerated dose cyclophosphamide, but was associated with lesser toxicity.


CONCLUSIONS
Trastuzumab combined with metronomic cyclophosphamide may be an effective long-term maintenance strategy for the treatment of Her-2-positive metastatic breast cancer.
Francia
Giulio
G
Molecular and Cellular Biology Research, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada. robert.kerbel@sri.utoronto.ca
Man
Shan
S
Lee
Chyan-Jang
CJ
Lee
Christina R
CR
Xu
Ping
P
Mossoba
Miriam E
ME
Emmenegger
Urban
U
Medin
Jeffrey A
JA
Kerbel
Robert S
RS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003520:Cyclophosphamide; D066246:ErbB Receptors; D000068878:Trastuzumab