达沙替尼对雌激素受体阴性乳腺癌症化疗预防的短期生物标志物调节研究。

Fatma Nihan Akkoc Mustafayev, Diane D Liu, Angelica M Gutierrez, John E Lewis, Nuhad K Ibrahim, Vicente Valero, Daniel J Booser, Jennifer K Litton, Kimberly Koenig, Dihua Yu, Nour Sneige, Banu K Arun
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引用次数: 0

摘要

目的:选择性雌激素受体(ER)调节剂和芳香化酶抑制剂的风险降低治疗可降低癌症风险。然而,效果仅限于ER-阳性乳腺癌症。因此,迫切需要具有改进的毒性特征的新药物,以降低ER阴性乳腺癌的风险。这项前瞻性、短期的预防研究的目的是评估酪氨酸激酶Src抑制剂达沙替尼对第二对侧原发性癌症高危女性正常(但风险增加)乳腺组织和血清中生物标志物的影响。材料和方法:有单侧I、II或III期ER-阴性癌症病史,无活动性疾病,并完成所有辅助治疗的女性符合条件。患者接受了对侧乳房的基线细针抽吸(FNA)和血清采集以进行生物标志物分析,并被随机分组接受不治疗(对照)或40或80 mg/天的达沙替尼治疗三个月。三个月后,重复血清采集和乳腺FNA。计划的生物标志物分析包括乳腺FNA上细胞学和Ki-67的变化,以及血清胰岛素样生长因子1(IGF-1)、IGF结合蛋白1和IGF结合蛋白质3水平的变化。主要目的是评估Ki-67的变化,次要目的包括乳腺组织细胞学和IGF相关血清生物标志物的变化。还对毒性进行了评估。结果:23名患者开始了他们指定的治疗。研究期间的依从性很高,86.9%(20/23)的患者完成了指定剂量。达沙替尼耐受性良好,未观察到与药物相关的3级和4级不良事件。由于只有一名患者符合配对FNA样本的充分性标准,我们无法评估Ki-67水平或细胞学变化。在这三组中,没有观察到血清生物标志物的显著变化。结论:达沙替尼具有良好的耐受性,但未引起血清生物标志物的任何显著变化。由于配对FNA样本数量不足,该研究无法实现其主要目标。此外,还需要更大规模的研究来评估Src抑制剂在预防癌症方面的有效性。
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Short-Term Biomarker Modulation Study of Dasatinib for Estrogen Receptor-Negative Breast Cancer Chemoprevention.

Objective: Risk-reducing therapy with selective estrogen receptor (ER) modulators and aromatase inhibitors reduce breast cancer risk. However, the effects are limited to ER-positive breast cancer. Therefore, new agents with improved toxicity profiles that reduce the risk in ER-negative breast cancers are urgently needed. The aim of this prospective, short-term, prevention study was to evaluate the effect of dasatinib, an inhibitor of the tyrosine kinase Src, on biomarkers in normal (but increased risk) breast tissue and serum of women at high risk for a second, contralateral primary breast cancer.

Materials and methods: Women with a history of unilateral stage I, II, or III ER-negative breast cancer, having no active disease, and who completed all adjuvant therapies were eligible. Patients underwent baseline fine-needle aspiration (FNA) of the contralateral breast and serum collection for biomarker analysis and were randomized to receive either no treatment (control) or dasatinib at 40 or 80 mg/day for three months. After three months, serum collection and breast FNA were repeated. Planned biomarker analysis consisted of changes in cytology and Ki-67 on breast FNA, and changes in serum levels of insulin-like growth factor 1 (IGF-1), IGF-binding protein 1, and IGF-binding protein 3. The primary objective was to evaluate changes in Ki-67 and secondary objective included changes in cytology in breast tissue and IGF-related serum biomarkers. Toxicity was also evaluated.

Results: Twenty-three patients started their assigned treatments. Compliance during the study was high, with 86.9% (20/23) of patients completing their assigned doses. Dasatinib was well tolerated and no drug-related grade 3 and 4 adverse events were observed. Since only one patient met the adequacy criteria for the paired FNA sample, we could not evaluate Ki-67 level or cytological changes. No significant change in serum biomarkers was observed among the three groups.

Conclusion: Dasatinib was well tolerated but did not induce any significant changes in serum biomarkers. The study could not fulfill its primary objective due to an inadequate number of paired FNA samples. Further, larger studies are needed to evaluate the effectiveness of Src inhibitors in breast cancer prevention.

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