Reappraising antiangiogenic therapy for breast cancer.
Phase III trials of antiangiogenic drugs for metastatic breast cancer have either had only limited success, e.g. the monoclonal anti-VEGF antibody bevacizumab when used with various conventional chemotherapy regimens, or have failed altogether, e.g. the small molecule oral tyrosine kinase inhibitor (TKI) sunitinib. No phase III trial has yet demonstrated an overall survival benefit and the progression free survival (PFS) benefits, when attained with bevacizumab are short, with perhaps one exception. Together, these results call for a reappraisal of using antiangiogenic drugs for breast cancer and possible strategies to improve their efficacy. Among the reasons to help explain the limited benefits observed thus far include the possibility that angiogenesis may not be a major driver of breast cancer growth, compared to some other types of cancer; that acquired resistance may develop rapidly to VEGF-pathway targeting antiangiogenic drugs, in part due to angiogenic growth factor redundancy; that optimal chemotherapy regimens have not been used in conjunction with an antiangiogenic drug; and that antiangiogenic drugs may secondarily aggravate biologic aggressiveness of the tumors, thereby reducing their overall efficacy after inducing an initial benefit. Several possible strategies are discussed for improving the efficacy of antiangiogenic drugs, including combination with different chemotherapy regimens, e.g. long term and less toxic metronomic chemotherapy protocols; validation of predictive biomarkers to individualize patient therapy; development of improved preclinical therapy models, e.g. involving advanced metastatic breast cancer, and combination with other types of anti-cancer agents especially biologies such as trastuzumab for Her2-positive breast cancer. Reasons for the current concern regarding use of antiangiogenic drug treatments for early stage cancers, including breast cancer, are also discussed.
Sunnyhrook Research Institute, Dept of Molecular & Cellular Biology Research, Professor, Dept of Medical Biophysics, University of Toronto, Toronto, ON M4N 3M5, USA.
Robert S
RS
Kerbel
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008408:Mastectomy / Q000379:methods; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D000077210:Sunitinib; D016019:Survival Analysis; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000077210:Sunitinib