Neoadjuvant antiangiogenic therapy reveals contrasts in primary and metastatic tumor efficacy

• Published in: EMBO molecular medicine Vol. 6; no. 12; pp. 1561 - 1576
• Main Authors: Ebos, John ML, Mastri, Michalis, Lee, Christina R, Tracz, Amanda, Hudson, John M, Attwood, Kristopher, Cruz‐Munoz, William R, Jedeszko, Christopher, Burns, Peter, Kerbel, Robert S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2014; John Wiley & Sons, Inc; EMBO Press; BlackWell Publishing Ltd; Springer Nature
• Subjects: Adjuvant treatment; Angiogenesis Inhibitors - administration & dosage; Animal models; Animals; antibodies; Antimitotic agents; Antineoplastic agents; Breast; Breast cancer; Cancer; Cancer therapies; Chemotherapy; Clinical trials; Drug dosages; Drug therapy; EMBO03; EMBO46; Humans; Hypotheses; Indoles - administration & dosage; Kidney cancer; Kidneys; Kinases; Melanoma; Metastases; Metastasis; Mice; Mice, SCID; neoadjuvant; Neoadjuvant Therapy; Neoplasm Metastasis - drug therapy; Neoplasm Metastasis - genetics; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Pyrroles - administration & dosage; Research Article; Studies; Surgery; Surgical outcomes; Survival; Treatment Outcome; Tumors; tyrosine kinase inhibitors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular endothelial growth factor receptors; VEGF; tyrosine kinase inhibitors; neoadjuvant; antibodies; VEGF; surgery
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.201403989

Thousands of cancer patients are currently in clinical trials evaluating antiangiogenic therapy in the neoadjuvant setting, which is the treatment of localized primary tumors prior to surgical intervention. The rationale is that shrinking a tumor will improve surgical outcomes and minimize growth of occult micrometastatic disease—thus delaying post‐surgical recurrence and improving survival. But approved VEGF pathway inhibitors have not been tested in clinically relevant neoadjuvant models that compare pre‐ and post‐surgical treatment effects. Using mouse models of breast, kidney, and melanoma metastasis, we demonstrate that primary tumor responses to neoadjuvant VEGFR TKI treatment do not consistently correlate with improved post‐surgical survival, with survival worsened in certain settings. Similar negative effects did not extend to protein‐based VEGF pathway inhibitors and could be reversed with altered dose, surgical timing, and treatment duration, or when VEGFR TKIs are combined with metronomic ‘anti‐metastatic’ chemotherapy regimens. These studies represent the first attempt to recapitulate the complex clinical parameters of neoadjuvant therapy in mice and identify a novel tool to compare systemic antiangiogenic treatment effects on localized and disseminated disease. Synopsis A novel preclinical methodology to examine efficacy of neoadjuvant therapy in a clinically relevant setting and a scoring system to predict drug combinations that maximize neoadjuvant VEGF RTKI treatment benefits. Antibodies blocking extracellular VEGF pathway components improve post‐surgical outcomes following neoadjuvant treatment. Neoadjuvant VEGF receptor tyrosine kinase inhibitor (RTKI) treatment benefits in primary tumor do not consistently predict for benefits after surgery, with outcomes worsened in some models. Increased doses and earlier surgery may significantly improve post‐surgical benefits of neoadjuvant VEGF RTKI treatment. Anti‐metastatic effects of neoadjuvant low‐dose metronomic chemotherapy may improve limitations of VEGF RTKI treatment. Development of a neoadjuvant efficacy score (NES) allows comparison of pre‐surgical treatment effects on post‐surgical disease recurrence to potentially guide treatment combinations to maximize benefit. Graphical Abstract A novel preclinical methodology to examine efficacy of neoadjuvant therapy in a clinically relevant setting and a scoring system to predict drug combinations that maximize neoadjuvant VEGF RTKI treatment benefits.