Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients
Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients
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DOI：
10.1073/pnas.1518808112
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发表时间：
2015-11-17
影响因子：
11.1
通讯作者：
Jain, Rakesh K.
中科院分区：
文献类型：
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作者：
Tolaney, Sara M.;Boucher, Yves;Jain, Rakesh K.
术前贝伐单抗和化疗可能使乳腺癌(BC)患者的一部分受益。为了探索这种益处的潜在机制，我们在HER2阴性的BC中进行了新辅助剂贝伐单抗(单剂)的II期研究，然后贝伐单抗和阿霉素/环磷酰胺/紫杉醇联合化疗。该方案耐受性良好，三阴性(TN)BC的病理完全应答(PCR)率(11/21例，52%，95%可信区间：30，74)高于激素受体阳性(HR)BC[5/78例，6%(95%CI：2，14)]。在HRBC中，基底样亚型与聚合酶链式反应显著相关(P=0.007；Fisher精确检验)。我们评估了贝伐单抗治疗前后的间质液体压(IFP)和组织活检，以及基线和联合治疗前后的循环血浆生物标记物。单用贝伐单抗可降低IFP，但幅度小于之前在其他肿瘤类型中观察到的程度。所有患者治疗前的微血管密度(Spearman相关系数0.465，P=0.0005)和治疗前的微血管密度(Spearman相关系数0.465，P=0.0005)与单独应用贝伐单抗治疗后的病理反应呈正相关。此外，贝伐单抗治疗后，周细胞覆盖的微血管密度(血管正常化程度的标志)的增加与治疗后病理反应的改善有关，特别是在治疗前微血管密度较高的患者。这些数据表明，贝伐单抗在修剪血管的同时使剩下的血管正常化，因此只有在最初有足够数量的血管时才是有益的。这项研究表明，预处理微血管密度是BC对贝伐单抗反应的潜在预测生物标志物，并提示需要新的治疗方法来使血管正常化而不进行修剪。
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, amarker 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.