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.antiangiogenic therapy | circulating and tissue biomarkers | PAM50 gene signature | cellular proliferation

Heterogeneous perivascular cell coverage affects breast cancer metastasis and response to chemotherapy

“…Within these perivascular segments, cells that were positive for either one or both pericyte markers were distinctly defined, namely Figure 1A and Supplemental Figure 1, A and B). While TNBC patients showed significantly higher MVD when compared with patients with luminal breast cancer ( Figure 1B), which is in agreement with previous reports (36) Figure 1C), thus indicating that a higher proportion of vessels in TNBC are immature with diminished pericyte coverage. Within each patient tumor evaluated, the MPI did not reflect a bias with respect to MVD, indicating that the computed pericyte coverage adequately reflects the heterogeneous composition of perivascular cells rather than reflecting overall low MVD (Supplemental Figure 1, C-F).…”

“…Patients with triple-negative breast cancer (TNBC) may present with higher microvascular density (MVD), which possibly enhances their response to neoadjuvant anti-VEGF/bevacizumab therapy, which targets immature and newly formed blood vessels (36). However, the heterogeneous perivascular composition in subtypes of breast cancer remains undefined.…”

Stromal-Based Signatures for the Classification of Gastric Cancer

“…Conversely, Avastintreated samples had a significant decrease of the signature 1 and 2 genes with a concomitant enrichment of signature 3 genes compared with vehicle samples. This analysis reveals the selective loss of less mature stroma (represented by signatures 1 and 2) upon treatment with anti-VEGF, consistent with prior preclinical and clinical studies (18)(19)(20)(21). Avastin only blocks human VEGF-A in this murine model, so we also explored an anti-mouse-VEGFA antibody (G6) in our Ad-VEGFA flank model.…”

“…Interestingly, we observed differences in the frequency of stromal/vascular phenotypes between the two major histologies in gastric cancer, Lauren's "diffuse" and "intestinal" (Fig. 5A) (21). About 50% of intestinal-type gastric tumors contained predominantly immature stroma, as marked by high proportions of poorly lumenized CD34-postive vessels with little to no vWF staining (Fig.…”

18F-fluoromisonidazole PET and Activity of Neoadjuvant Nintedanib in Early HER2-Negative Breast Cancer: A Window-of-Opportunity Randomized Trial

“…This observation is complex to explain within the context of the model of vascular normalization and the positive effects of adding bevacizumab to chemotherapy in lung cancer (39). Other studies suggest that antiangiogenic agents improve the perfusion (16,40,41); one of these studies showed an improved vascular network at the microscopic level in the patients that experienced favorable outcomes; however, the low number of patients and the nonrandomized nature of the study precludes definitive conclusions (40). We expected to observe a heterogeneous response, and that the patients showing improved oxygenation or hypoxia worsening would be those with better and worse outcomes respectively, as an indirect proof of vascular normalization.…”