Akkoc Mustafayev Fatma Nihan, Liu Diane D, Gutierrez Angelica M, Lewis John E, Ibrahim Nuhad K, Valero Vicente, Booser Daniel J, Litton Jennifer K, Koenig Kimberly, Yu Dihua, Sneige Nour, Arun Banu K
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Texas, USA.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Texas, USA.
Eur J Breast Health. 2023 Oct 1;19(4):267-273. doi: 10.4274/ejbh.galenos.2023.2023-7-3. eCollection 2023 Oct.
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.
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.
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.
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.
使用选择性雌激素受体（ER）调节剂和芳香化酶抑制剂进行降低风险的治疗可降低乳腺癌风险。然而，这些作用仅限于ER阳性乳腺癌。因此，迫切需要毒性特征改善且能降低ER阴性乳腺癌风险的新型药物。这项前瞻性短期预防研究的目的是评估酪氨酸激酶Src抑制剂达沙替尼对有对侧原发性乳腺癌高风险的女性正常（但风险增加）乳腺组织和血清中的生物标志物的影响。
有单侧I期、II期或III期ER阴性乳腺癌病史、无活动性疾病且已完成所有辅助治疗的女性符合条件。患者接受对侧乳房基线细针穿刺活检（FNA）并采集血清用于生物标志物分析，然后随机分为不治疗（对照组）或接受40或80毫克/天的达沙替尼治疗三个月。三个月后，再次采集血清并进行乳房FNA。计划的生物标志物分析包括乳房FNA中细胞学和Ki-67的变化，以及血清中胰岛素样生长因子1（IGF-1）、IGF结合蛋白1和IGF结合蛋白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变化和IGF相关血清生物标志物变化。还评估了毒性。
23名患者开始了他们分配的治疗。研究期间依从性高，86.9%（20/23）的患者完成了分配剂量。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。三组之间血清生物标志物未观察到显著变化。
达沙替尼耐受性良好，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，该研究未能实现其主要目标。此外，需要进一步开展更大规模的研究来评估Src抑制剂在预防乳腺癌方面的有效性。
