Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial

Earl, Helena; Hiller, Louise; Dunn, Janet A.; Blenkinsop, Clare; Grybowicz, Louise; Vallier, Anne-Laure; Abraham, Jean; Thomas, Jeremy; Provenzano, Elena; Hughes-Davies, Luke; Gounaris, Ioannis; McAdam, Karen; Chan, Sy; Ahmad, Rizvana; Hickish, Tamas; Houston, Stephen; Rea, Daniel; Bartlett, John M.S.; Caldas, Carlos; Cameron, David; Hayward, Larry

doi:10.1016/s1470-2045(15)70137-3

Cited by 122 publications

(112 citation statements)

References 30 publications

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“…More patients achieved pCR in the combination-therapy arm compared to the chemotherapy alone arm, in line with reports from previous studies (6,7,10,11). A significant benefit of adding bevacizumab was observed in the ER-positive subgroup consistent with the larger NSAPB-B40 trial (11), in contradiction to the GeparQuinto trial, where the ERnegative tumors were found to benefit from bevacizumab (10), and the CALGB40603 study, including patients with a low ER expression, or triple negative tumors (6).…”

Section: Discussionsupporting

confidence: 82%

“…Blocking VEGF by bevacizumab, a monoclonal antibody, has been proposed to cause inhibition of neovascularization, regression of existing immature micro-vessels, and normalization of abnormal vasculature (4,5); this has consequences for the flux of oxygen, nutrients, metabolites and therapeutic agents, ultimately preventing tumor growth and resulting in tumor shrinkage. However, addition of bevacizumab to standard chemotherapy in unselected breast cancer patients has resulted only in a modest increase in response rate and progression free survival (6)(7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

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The Longitudinal Transcriptional Response to Neoadjuvant Chemotherapy with and without Bevacizumab in Breast Cancer

Silwal-Pandit

Nord

Gythfeldt

et al. 2017

Clinical Cancer Research

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

The Longitudinal Transcriptional Response to Neoadjuvant Chemotherapy with and without Bevacizumab in Breast Cancer

Silwal-Pandit

Nord

Gythfeldt

et al. 2017

Clinical Cancer Research

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“…Recent studies report significant increases in the percentage of patients with no detectable residual diseasereferred to as pathologic complete response (pCR)-with the addition of bevacizumab to neoadjuvant chemotherapy in human epidermal growth factor receptor 2 (HER2)-negative BC. The GeparQuinto, the CALGB 40603, and the ARTemis trials demonstrated a significant increase in pCR with the addition of bevacizumab in patients with triple-negative BC (TNBC) (6)(7)(8). However, the National Surgical Adjuvant Breast and Bowel Project Significance Emerging evidence indicates patients who benefit from antiangiogenic therapies have improved vessel function.…”

mentioning

confidence: 99%

Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients

Tolaney

Boucher

Duda

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

218

170

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Preoperative bevacizumab and chemotherapy may benefit a subset of breast cancer (BC) patients. To explore potential mechanisms of this benefit, we conducted a phase II study of neoadjuvant bevacizumab (single dose) followed by combined bevacizumab and adriamycin/cyclophosphamide/paclitaxel chemotherapy in HER2-negative BC. The regimen was well-tolerated and showed a higher rate of pathologic complete response (pCR) in triple-negative (TN)BC (11/21 patients or 52%, [95% confidence interval (CI): 30,74]) than in hormone receptor-positive (HR)BC [5/78 patients or 6% (95%CI: 2,14)]. Within the HRBCs, basal-like subtype was significantly associated with pCR (P = 0.007; Fisher exact test). We assessed interstitial fluid pressure (IFP) and tissue biopsies before and after bevacizumab monotherapy and circulating plasma biomarkers at baseline and before and after combination therapy. Bevacizumab alone lowered IFP, but to a smaller extent than previously observed in other tumor types. Pathologic response to therapy correlated with sVEGFR1 postbevacizumab alone in TNBC (Spearman correlation 0.610, P = 0.0033) and pretreatment microvascular density (MVD) in all patients (Spearman correlation 0.465, P = 0.0005). Moreover, increased pericyte-covered MVD, a marker of extent of vascular normalization, after bevacizumab monotherapy was associated with improved pathologic response to treatment, especially in patients with a high pretreatment MVD. These data suggest that bevacizumab prunes vessels while normalizing those remaining, and thus is beneficial only when sufficient numbers of vessels are initially present. This study implicates pretreatment MVD as a potential predictive biomarker of response to bevacizumab in BC and suggests that new therapies are needed to normalize vessels without pruning.antiangiogenic therapy | circulating and tissue biomarkers | PAM50 gene signature | cellular proliferation

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“…These results suggest that ARHGAP17 mediated by VEGF–NRP1 interaction partly contributed to DFS in HR(−) BCs. As shown in Supporting Information Table S10, the association between HR status and bevacizumab treatment efficacy in clinical trials has been inconsistent 9, 41, 42, 43, 44, 45, 46, 47. Our findings demonstrated that there are bevacizumab‐independent VEGF signals in HR(−) BC tumors.…”

Section: Discussionmentioning

confidence: 62%

Long isoform of VEGF stimulates cell migration of breast cancer by filopodia formation via NRP1/ARHGAP17/Cdc42 regulatory network

Kiso

Tanaka

Toi

et al. 2018

Intl Journal of Cancer

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VEGF stimulates endothelial cells as a key molecule in angiogenesis. VEGF also works as a multifunction molecule, which targets a variety of cell members in the tumor microenvironment. We aimed to reveal VEGF‐related molecular mechanisms on breast cancer cells. VEGF‐knocked‐out MDA‐MB‐231 cells (231VEGFKOex3) showed rounded morphology and shorter perimeter (1.6‐fold, p < 0.0001). The 231VEGFKOex3 cells also showed impaired cell migration (2.6‐fold, p = 0.002). Bevacizumab treatment did not induce any change in morphology and mobility. Soluble neuropilin‐1 overexpressing MDA‐MB‐231 cells (231sNRP1) exhibited rounded morphology and shorter perimeter (1.3‐fold, p < 0.0001). The 231sNRP1 cells also showed impaired cell migration (1.7‐fold, p = 0.003). These changes were similar to that of 231VEGFKOex3 cells. As MDA‐MB‐231 cells express almost no VEGFR, these results indicate that the interaction between NRP1 and long isoform of VEGF containing a NRP‐binding domain regulates the morphology and migration ability of MDA‐MB‐231 cells. Genome‐wide gene expression profiling identified ARHGAP17 as one of the target genes in the downstream of the VEGF/NRP1 signal. We also show that VEGF/NRP1 signal controls filopodia formation of the cells by modulating Cdc42 activity via ARHGAP17. Among 1,980 breast cancer cases from a public database, the ratio of VEGF and SEMA3A in primary tumors (n = 450) of hormone‐receptor‐negative breast cancer is associated with ARHGAP17 expression inversely, and with disease free survival. Altogether, the bevacizumab‐independent VEGF/NRP1/ARHGAP17/Cdc42 regulatory network plays important roles in malignant behavior of breast cancer.

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Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial

Abstract: Cancer Research UK, Roche, Sanofi-Aventis.

Cited by 122 publications

References 30 publications

The Longitudinal Transcriptional Response to Neoadjuvant Chemotherapy with and without Bevacizumab in Breast Cancer

The Longitudinal Transcriptional Response to Neoadjuvant Chemotherapy with and without Bevacizumab in Breast Cancer

Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients

Long isoform of VEGF stimulates cell migration of breast cancer by filopodia formation via NRP1/ARHGAP17/Cdc42 regulatory network

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