Abstract
Phase III clinical trials evaluating bevacizumab (an antibody to the angiogenic ligand, VEGF-A) in breast cancer have found improved responses in the presurgical neoadjuvant setting but no benefits in the postsurgical adjuvant setting. The objective of this study was to evaluate alternative antiangiogenic therapies, which target multiple VEGF family members or differentially modulate the Angiopoietin/Tie2 pathway, in a mouse model of resectable triple-negative breast cancer (TNBC). Neoadjuvant therapy experiments involved treating established orthotopic xenografts of an aggressive metastatic variant of the MDA-MB-231 human TNBC cell line, LM2-4. Adjuvant therapies were given after primary tumor resections to treat postsurgical regrowths and distant metastases. Aflibercept (‘VEGF Trap’, which neutralizes VEGF-A, VEGF-B and PlGF) showed greater efficacy than nesvacumab (an anti-Ang2 antibody) as an add-on to neoadjuvant/adjuvant chemotherapy. Concurrent inhibition of Ang1 and Ang2 signaling (through an antagonistic anti-Tie2 antibody) was not more efficacious than selective Ang2 inhibition. In contrast, short-term perioperative BowAng1 (a recombinant Ang1 variant) improved the efficacy of adjuvant chemotherapy. In conclusion, concurrent VEGF pathway inhibition is more likely than Ang/Tie2 pathway inhibition (e.g., anti-Ang2, anti-Ang2/Ang1, anti-Tie2) to improve neoadjuvant/adjuvant chemotherapies for TNBC. Short-term perioperative Ang1 supplementation may also have therapeutic potential in conjunction with adjuvant chemotherapy for TNBC.
Highlights
The clinical utility of VEGF pathway-targeted antiangiogenic therapies is well-established in some cancer types
On the contrary, Ang[1] supplementation during a short perioperative window improved the efficacy of adjuvant paclitaxel chemotherapy, with or without aflibercept
In a recent preclinical study by Paez-Ribes et al, we had shown in the resected orthotopic LM2-4 breast cancer model that DC101 (VEGFR2-specific inhibition) was unable to improve Overall survival (OS) when added to adjuvant paclitaxel chemotherapy[23]
Summary
The clinical utility of VEGF pathway-targeted antiangiogenic therapies is well-established in some cancer types. For early-stage non-metastatic HER2− breast cancer in the preoperative (neoadjuvant) setting, bevacizumab consistently improved overall pathological complete response (pCR) rates when added to various cytotoxic chemotherapies in phase III clinical trials (GBG-4410, NSABP B-4011 and ARTemis[12]). GBG-44 used the most stringent definition of pCR (see Supplemental Table S2), defined as the complete eradication of invasive disease in the breast and axillary lymph nodes plus non-invasive (intraductal) disease in the breast[10] Using this definition, an improved pCR rate due to neoadjuvant bevacizumab therapy was observed only in the “triple-negative breast cancer (TNBC)” subgroup (i.e., HER2− as well as negative for the estrogen receptor (ER) and progesterone receptor (PgR))[10]. Updated results from the NSABP B-40 trial showed an OS benefit associated with adding neoadjuvant-plus-adjuvant bevacizumab to standard neoadjuvant chemotherapies[16]
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