Li Siming, Kong Yan, Si Lu, Chi Zhihong, Cui Chuanliang, Sheng Xinan, Guo Jun
Department of Renal Cancer and Melanoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing 100142, China.
BMC Cancer. 2014 May 28;14:376. doi: 10.1186/1471-2407-14-376.
The incidence of renal cell cancer (RCC) has been increasing for the past decade, and the 5-year survival for patients with metastatic RCC (mRCC) is rather low. Everolimus (RAD001), a new inhibitor for mammalian target of rapamycin (mTOR), is generally well tolerated, and demonstrates clinical benefit to patients with anti-VEGF-refractory mRCC. However, factors for selection of patients who may benefit from everolimus remain largely unknown. Here we aimed to explore potential molecular indicators for mRCC patients who may benefit from everolimus treatment.
Paraffin-embedded tumor tissue specimens derived from 18 mRCC patients before everolimus treatment, who participated the phase 1b trial of everolimus in VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI)-refractory Chinese patients with mRCC (clinicaltrials.gov, NCT01152801), were examined for the expression levels of phosphorylated AKT, mTOR, eukaryotic initiation factor 4E (eIF4E) binding protein-1 (4EBP1) and 40S ribosomal protein S6 (S6RP) by immunohistochemistry. Clinical benefit rate (complete response [CR], partial response [PR], plus stable disease [SD] ≥ 6 months) and progression-free survival time (PFS) were correlated with expression levels of these mTOR-associated molecules.
In these 18 patients, there were 1 PR, 15 SDs (including 9 SDs ≥ 6 months), and 2 progressive diseases (PD). The clinical benefit rate (CBR) was 55.6% (10/18), and the median PFS time was 8.4 months. Patients with positive expression of phospho-mTOR showed a better CBR (71.4% versus 0%, P = 0.023) and PFS time (11.3 versus 3.7 months, P = 0.001) than those patients with negative expression. The median PFS of patients with positive phospho-S6RP expression was longer (11.3 versus 3.7 months, P = 0.002) than that of patients negative for phospho-S6RP expression. However, expression levels of phospho-4EBP1 and phospho-AKT were unassociated to efficacy of everolimus treatment with respect to CBR and PFS. Co-expression of phosphorylated mTOR, S6RP and/or 4EBP1 may improve the predictive value of the biomarkers for patients treated with everolimus.
The expression levels of phospho-mTOR and phospho-S6RP may be potential predictive biomarkers for efficacy of everolimus in patients with mRCC. Combining examinations of phosphorylated mTOR, S6RP and/or 4EBP1 may be a potential strategy to select mRCC patients sensitive to mTOR inhibitor treatment.
在过去十年中，肾细胞癌（RCC）的发病率一直在上升，转移性肾细胞癌（mRCC）患者的5年生存率相当低。依维莫司（RAD001）是一种新型的哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂，耐受性一般良好，对接受抗血管内皮生长因子（VEGF）治疗无效的mRCC患者显示出临床益处。然而，对于可能从依维莫司治疗中获益的患者的选择因素仍知之甚少。在此，我们旨在探索可能从依维莫司治疗中获益的mRCC患者的潜在分子指标。
对参与依维莫司在中国VEGF受体（VEGFR）-酪氨酸激酶抑制剂（TKI）治疗无效的mRCC患者中进行的1b期试验（clinicaltrials.gov，NCT01152801）的18例mRCC患者在接受依维莫司治疗前的石蜡包埋肿瘤组织标本进行免疫组织化学检查，以检测磷酸化AKT、mTOR、真核起始因子4E（eIF4E）结合蛋白-1（4EBP1）和40S核糖体蛋白S6（S6RP）的表达水平。临床获益率（完全缓解[CR]、部分缓解[PR]，加疾病稳定[SD]≥6个月）和无进展生存时间（PFS）与这些mTOR相关分子的表达水平相关。
在这18例患者中，有1例PR、15例SD（包括9例SD≥6个月）和2例疾病进展（PD）。临床获益率（CBR）为55.6%（10/18），中位PFS时间为8.4个月。磷酸化mTOR表达阳性的患者比磷酸化mTOR表达阴性的患者显示出更好的CBR（71.4%对0%，P = 0.023）和PFS时间（11.3个月对3.7个月，P = 0.001）。磷酸化S6RP表达阳性的患者的中位PFS长于磷酸化S6RP表达阴性的患者（11.3个月对3.7个月，P = 0.002）。然而，磷酸化4EBP1和磷酸化AKT的表达水平与依维莫司治疗的CBR和PFS疗效无关。磷酸化mTOR、S6RP和/或4EBP1的共表达可能提高生物标志物对接受依维莫司治疗患者的预测价值。
磷酸化mTOR和磷酸化S6RP的表达水平可能是依维莫司治疗mRCC患者疗效的潜在预测生物标志物。联合检测磷酸化mTOR、S6RP和/或4EBP1可能是选择对mTOR抑制剂治疗敏感的mRCC患者的潜在策略。
