Targeting FGFR with Dovitinib (TKI258): Preclinical and Clinical Data in Breast Cancer
Targeting FGFR with Dovitinib (TKI258): Preclinical and Clinical Data in Breast Cancer
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DOI：
10.1158/1078-0432.ccr-13-0190
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发表时间：
2013-07-01
影响因子：
11.5
通讯作者：
Baselga, Jose
中科院分区：
文献类型：
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作者：
Andre, Fabrice;Bachelot, Thomas;Baselga, Jose
目的：在大约10%的乳腺癌中观察到成纤维细胞生长因子受体1（FGFR 1）和FGFR 2扩增，并且与不良结局相关。我们评估了是否dovitinib（TKI 258），FGFR 1，FGFR 2和FGFR 3的抑制剂，在FGFR-amplified breast cancer.Experimental Design中呈现抗肿瘤活性：dovitinib的临床前活性在乳腺癌细胞系和FGFR 1-amplified异种移植模型（HBCx 2）中进行了评估。然后在一项II期试验中评估了Dovitinib，该试验包括4组基于FGFR 1扩增和激素受体（HR）状态的人EGF受体2阴性转移性乳腺癌患者。通过银原位杂交评估FGFR 1扩增。预先计划的回顾性分析通过定量PCR（qPCR）评估FGFR 1、FGFR 2和FGF 3扩增的预测价值。结果：Dovitinib单药治疗抑制FGFR 1和FGFR 2扩增的乳腺癌细胞系的增殖，但不抑制FGFR正常的乳腺癌细胞系的增殖。Dovitinib还抑制FGFR 1扩增的乳腺癌异种移植物中的肿瘤生长。81例患者入组试验。在5例（25%）和1例（3%）FGFR 1扩增/HR阳性和FGFR 1非扩增/HR阳性乳腺癌患者中观察到未经证实的缓解或疾病稳定超过6个月。当qPCR鉴定的FGFR 1、FGFR 2或FGF 3扩增被分组以定义HR阳性患者中FGF途径扩增的乳腺癌时，靶病变的平均减少为21.1%，而不存在FGF途径扩增的乳腺癌的患者增加12.0%。Dovitinib在FGF扩增的乳腺癌细胞系中显示出抗肿瘤活性，并且可能在FGF途径扩增的乳腺癌中具有活性。临床癌症研究; 19（13）; 3693-702。（C）2013年AACR。
Purpose: Fibroblast growth factor receptor 1 (FGFR1) and FGFR2 amplifications are observed in approximately 10% of breast cancers and are related to poor outcomes. We evaluated whether dovitinib (TKI258), an inhibitor of FGFR1, FGFR2, and FGFR3, presented antitumor activity in FGFR-amplified breast cancers.Experimental Design: Preclinical activity of dovitinib was evaluated in both breast cancer cell lines and an FGFR1-amplified xenograft model (HBCx2). Dovitinib was then evaluated in a phase II trial that included 4 groups of patients with human EGF receptor 2-negative metastatic breast cancer on the basis of FGFR1 amplification and hormone receptor (HR) status. FGFR1 amplification was assessed by silver in situ hybridization. Preplanned retrospective analyses assessed predictive value of FGFR1, FGFR2, and FGF3 amplifications by quantitative PCR (qPCR).Results: Dovitinib monotherapy inhibits proliferation in FGFR1- and FGFR2-amplified, but not FGFR-normal, breast cancer cell lines. Dovitinib also inhibits tumor growth in FGFR1-amplified breast cancer xenografts. Eighty-one patients were enrolled in the trial. Unconfirmed response or stable disease for more than 6 months was observed in 5 (25%) and 1 (3%) patient(s) with FGFR1-amplified/HR-positive and FGFR1-nonamplified/HR-positive breast cancer. When qPCR-identified amplifications in FGFR1, FGFR2, or FGF3 were grouped to define an FGF pathway-amplified breast cancer in HR-positive patients, the mean reduction in target lesions was 21.1% compared with a 12.0% increase in patients who did not present with FGF pathway-amplified breast cancer.Conclusion: Dovitinib showed antitumor activity in FGFR-amplified breast cancer cell lines and may have activity in breast cancers with FGF pathway amplification. Clin Cancer Res; 19(13); 3693-702. (C)2013 AACR.