Milani Manuela, Venturini Sergio, Bonardi Simone, Allevi Giovanni, Strina Carla, Cappelletti Maria Rosa, Corona Silvia Paola, Aguggini Sergio, Bottini Alberto, Berruti Alfredo, Jubb Adrian, Campo Leticia, Harris Adrian L, Gatter Kevin, Fox Stephen B, Generali Daniele, Roviello Giandomenico
U.O. Multidisciplinare di Patologia Mammaria, U.S Terapia Molecolare e Farmacogenomica, ASST Cremona, Viale Concordia 1, Cremona, Italy.
CE.R.G.A.S., Università Bocconi, Milano, Italy.
Oncotarget. 2017 Aug 14;8(45):78870-78881. doi: 10.18632/oncotarget.20239. eCollection 2017 Oct 3.
To identify hypoxia-related biomarkers indicative of response and resistance to epirubicin treatment in patients with locally advanced breast cancer.
One hundred seventy-six women with T2-4 N0-1 breast tumours were randomly assigned to receive epirubicin 120 mg/m2/1-21 (EPI ARM), epirubicin 120 mg/m2/1-21 + erythropoietin 10.000 IU sc three times weekly (EPI-EPO ARM) and epirubicin 40 mg/m2/w-q21 (EPI-W ARM). Sixteen tumour proteins involved in cell survival, hypoxia, angiogenesis and growth factor, were assessed by immunohistochemistry in pre-treatment samples. A multivariate generalized linear regression approach was applied using a penalized least-square minimization to perform variable selection and regularization.
VEGF and GLUT-1 expression were significantly positively associated with complete response (CR) to treatment in all leave-one-out iterations. Bcl-2 expression was inversely correlated with pCR, whilst EPO expression was positively correlated with pathological complete response (pCR). Haemaglobin and HIF-1a nuclear expression were inversely correlated with pCR. HB and HIF-1a expression were associated with a higher risk of relapse and overall survival.
Hypoxic biomarkers determines the epirubicin resistance in breast cancer. Assessment of such biomarkers, may be useful for predicting chemosensitivity and also anthracycline-based treatment outcome.
鉴定与局部晚期乳腺癌患者对表柔比星治疗的反应和耐药性相关的缺氧相关生物标志物。
176例患有T2-4 N0-1乳腺肿瘤的女性被随机分配接受表柔比星120 mg/m²/1-21（表柔比星组）、表柔比星120 mg/m²/1-21 + 促红细胞生成素10000 IU皮下注射，每周三次（表柔比星-促红细胞生成素组）以及表柔比星40 mg/m²/周，每21周一次（表柔比星-周疗组）。通过免疫组织化学在治疗前样本中评估16种参与细胞存活、缺氧、血管生成和生长因子的肿瘤蛋白。应用多元广义线性回归方法，采用惩罚最小二乘最小化进行变量选择和正则化。
在所有留一法迭代中，VEGF和GLUT-1表达与治疗的完全缓解（CR）显著正相关。Bcl-2表达与pCR呈负相关，而EPO表达与病理完全缓解（pCR）呈正相关。血红蛋白和HIF-1a核表达与pCR呈负相关。HB和HIF-1a表达与更高的复发风险和总生存期相关。
缺氧生物标志物决定了乳腺癌对表柔比星的耐药性。评估此类生物标志物可能有助于预测化疗敏感性以及基于蒽环类药物的治疗结果。
