Department of Cancer Medicine, Breast Cancer Committee, Gustave Roussy, Villejuif, France; INSERM Unit 981, Gustave Roussy, Villejuif, France.
Statistics and Epidemiology Unit, Gustave Roussy, Villejuif, France; CESP, Medical School, INSERM, Université Paris Saclay, Villejuif, France.
Ann Oncol. 2018 Aug 1;29(8):1755-1762. doi: 10.1093/annonc/mdy202.
The cyclin-dependent kinase 4 (CDK4)/6 inhibitor Palbociclib is a new standard treatment in hormone-receptor positive breast cancer patients. No predictive biomarkers have been identified and no pharmacodynamics has properly been described so far.
Patients with early-breast cancer were randomized 3 : 1 to oral palbociclib 125 mg daily for 14 days until the day before the surgery versus no treatment. Primary objective was antiproliferative response defined as a natural logarithm of Ki67 expression at day 15 below 1. Secondary end points were subgroups analyses and safety. Exploratory analyses included search for predictive biomarkers. Immunostainings (Ki67, RB, pRB, p16, pAKT, pER, pCDK2, CyclinD1), FISH (CCND1) and gene expression (GE) arrays were carried out at baseline and at surgery. In addition, activating PIK3CA and AKT1 mutations were assessed at baseline.
74 patients were allocated to palbociclib and 26 to control. Most patients (93%) were hormone-receptor (HR)-positive, whereas 8% were HER2-positive. Palbociclib led to significantly more antiproliferative responses when compared with control (58% versus 12%, P < 0.001), and to a significantly higher Ki67 decrease (P < 0.001). In the HR-positive/HER2-negative subgroup, this antiproliferative effect was even more marked in the palbociclib arm when compared with control (70% versus 9%, P < 0.001). Palbociclib treatment led also to a significantly higher decrease from baseline in phospho-Rb when compared with control (P < 0.001). Among treated patients, changes in Ki67 correlated with changes in phospho-Rb (Spearman rank r = 0.41, P < 0.0001). GE analyses confirmed a major effect on proliferation and cell cycle genes. Among treated patients, CCNE2 expression was significantly more decreased in antiproliferative responders versus nonresponders (P = 0.006).
Short-term preoperative palbociclib decreases Ki67 in early-breast cancer patients. Early decrease of Rb phosphorylation correlates with drug's effect on cell proliferation and could potentially identify patients with primary resistance.
NCT02008734.
细胞周期蛋白依赖性激酶 4（CDK4）/6 抑制剂帕博西尼（Palbociclib）是激素受体阳性乳腺癌患者的一种新的标准治疗方法。目前尚未确定预测性生物标志物，也没有对药效学进行适当描述。
早期乳腺癌患者被随机分为 3:1 组，分别接受每日口服帕博西尼 125mg 治疗 14 天，直至手术前一天或不治疗。主要目的是根据第 15 天 Ki67 表达的自然对数，将抗增殖反应定义为低于 1。次要终点是亚组分析和安全性。探索性分析包括寻找预测性生物标志物。在基线和手术时进行免疫组化（Ki67、RB、pRB、p16、pAKT、pER、pCDK2、CyclinD1）、FISH（CCND1）和基因表达（GE）阵列。此外，还在基线时评估了激活的 PIK3CA 和 AKT1 突变。
74 例患者被分配至帕博西尼组，26 例患者分配至对照组。大多数患者（93%）为激素受体（HR）阳性，而 8%为 HER2 阳性。与对照组相比，帕博西尼组的抗增殖反应显著更多（58%比 12%，P<0.001），Ki67 下降也显著更多（P<0.001）。在 HR 阳性/HER2 阴性亚组中，与对照组相比，帕博西尼组的这种抗增殖作用更为明显（70%比 9%，P<0.001）。与对照组相比，帕博西尼治疗还导致磷酸化 RB 的基线水平显著降低（P<0.001）。在接受治疗的患者中，Ki67 的变化与磷酸化 RB 的变化相关（Spearman 秩相关系数 r=0.41，P<0.0001）。GE 分析证实了对增殖和细胞周期基因的主要影响。在接受治疗的患者中，与非应答者相比，增殖应答者的 CCNE2 表达显著降低（P=0.006）。
短期术前帕博西尼可降低早期乳腺癌患者的 Ki67。Rb 磷酸化的早期下降与药物对细胞增殖的作用相关，可能潜在地识别出具有原发性耐药的患者。
NCT02008734。
