Department of Medical Oncology, INSERM Unit U981, Paris Sud University, Institut Gustave-Roussy, Villejuif, France.
Clin Cancer Res. 2013 Jul 1;19(13):3693-702. doi: 10.1158/1078-0432.CCR-13-0190. Epub 2013 May 8.
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.
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).
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.
Dovitinib showed antitumor activity in FGFR-amplified breast cancer cell lines and may have activity in breast cancers with FGF pathway amplification.
成纤维细胞生长因子受体 1（FGFR1）和 FGFR2 扩增约见于 10%的乳腺癌患者，且与不良预后相关。我们评估了 FGFR1、FGFR2 和 FGFR3 抑制剂多韦替尼（TKI258）在 FGFR 扩增型乳腺癌中的抗肿瘤活性。
在乳腺癌细胞系和 FGFR1 扩增型异种移植模型（HBCx2）中评估多韦替尼的临床前活性。然后，根据 FGFR1 扩增和激素受体（HR）状态，在包含 4 组人表皮生长因子受体 2 阴性转移性乳腺癌患者的 II 期试验中评估多韦替尼。FGFR1 扩增通过银原位杂交评估。基于定量 PCR（qPCR），对 FGFR1、FGFR2 和 FGF3 扩增的预测价值进行了预先计划的回顾性分析。
多韦替尼单药治疗可抑制 FGFR1 和 FGFR2 扩增但不抑制 FGFR 正常的乳腺癌细胞系的增殖。多韦替尼还可抑制 FGFR1 扩增的乳腺癌异种移植瘤的生长。该试验共纳入 81 例患者。FGFR1 扩增/HR 阳性和 FGFR1 非扩增/HR 阳性乳腺癌患者中，未确认缓解或疾病稳定超过 6 个月的分别有 5 例（25%）和 1 例（3%）。当 qPCR 鉴定的 FGFR1、FGFR2 或 FGF3 扩增被分组以定义 HR 阳性患者中 FGF 通路扩增的乳腺癌时，与未出现 FGF 通路扩增的乳腺癌患者相比，靶病变的平均缩小率为 21.1%。
多韦替尼在 FGFR 扩增型乳腺癌细胞系中显示出抗肿瘤活性，并且可能对具有 FGF 通路扩增的乳腺癌具有活性。
