title: Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02114;
authors.forename: Sara M
authors.initials: SM
authors.lastname: Tolaney
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Yves
authors.initials: Y
authors.lastname: Boucher
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: John D
authors.identifier: http://orcid.org/0000-0002-9828-8203
authors.initials: JD
authors.lastname: Martin
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Giorgio
authors.initials: G
authors.lastname: Seano
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Marek
authors.initials: M
authors.lastname: Ancukiewicz
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02114;
authors.forename: William T
authors.initials: WT
authors.lastname: Barry
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02114; Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Shom
authors.initials: S
authors.lastname: Goel
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Johanna
authors.initials: J
authors.lastname: Lahdenrata
authors.affiliation: Department of Hematology/Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Isakoff
authors.affiliation: Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Eren D
authors.initials: ED
authors.lastname: Yeh
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139;
authors.forename: Saloni R
authors.initials: SR
authors.lastname: Jain
authors.affiliation: Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Mehra
authors.initials: M
authors.lastname: Golshan
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Jane
authors.initials: J
authors.lastname: Brock
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors.forename: Matija
authors.initials: M
authors.lastname: Snuderl
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02114;
authors.forename: Eric P
authors.initials: EP
authors.lastname: Winer
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02114; ikrop@partners.org jain@steele.mgh.harvard.edu.
authors.forename: Ian E
authors.initials: IE
authors.lastname: Krop
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; ikrop@partners.org jain@steele.mgh.harvard.edu.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D000068258:Bevacizumab / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D000068258:Bevacizumab
keywords: PAM50 gene signature; antiangiogenic therapy; cellular proliferation; circulating and tissue biomarkers