Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases.
Brain metastases are a serious obstacle in the treatment of patients with human epidermal growth factor receptor-2 (HER2)-amplified breast cancer. Although extracranial disease is controlled with HER2 inhibitors in the majority of patients, brain metastases often develop. Because these brain metastases do not respond to therapy, they are frequently the reason for treatment failure. We developed a mouse model of HER2-amplified breast cancer brain metastasis using an orthotopic xenograft of BT474 cells. As seen in patients, the HER2 inhibitors trastuzumab and lapatinib controlled tumor progression in the breast but failed to contain tumor growth in the brain. We observed that the combination of a HER2 inhibitor with an anti-VEGF receptor-2 (VEGFR2) antibody significantly slows tumor growth in the brain, resulting in a striking survival benefit. This benefit appears largely due to an enhanced antiangiogenic effect: Combination therapy reduced both the total and functional microvascular density in the brain xenografts. In addition, the combination therapy led to a marked increase in necrosis of the brain lesions. Moreover, we observed even better antitumor activity after combining both trastuzumab and lapatinib with the anti-VEGFR2 antibody. This triple-drug combination prolonged the median overall survival fivefold compared with the control-treated group and twofold compared with either two-drug regimen. These findings support the clinical development of this three-drug regimen for the treatment of HER2-amplified breast cancer brain metastases.
Edwin L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
David P
DP
Kodack
Euiheon
E
Chung
Hiroshi
H
Yamashita
Joao
J
Incio
Annique M M J
AM
Duyverman
Youngchul
Y
Song
Christian T
CT
Farrar
Yuhui
Y
Huang
Eleanor
E
Ager
Walid
W
Kamoun
Shom
S
Goel
Matija
M
Snuderl
Alisha
A
Lussiez
Lotte
L
Hiddingh
Sidra
S
Mahmood
Bakhos A
BA
Tannous
April F
AF
Eichler
Dai
D
Fukumura
Jeffrey A
JA
Engelman
Rakesh K
RK
Jain
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D001943:Breast Neoplasms / Q000188:drug therapy*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003952:Diagnostic Imaging; D004195:Disease Models, Animal; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000473:pathology; D000077341:Lapatinib; D051379:Mice; D058990:Molecular Targeted Therapy; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016019:Survival Analysis; D000068878:Trastuzumab; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D000068878:Trastuzumab; C511761:DC101 monoclonal antibody