三阴性乳腺癌靶向药物早期疗效监测
三阴性乳腺癌的三大受体（雌激素受体、孕激素受体、HER2）均为阴性，通常对内分泌药物和HER2靶向药物无效，但是三阴性乳腺癌还有其他靶点，可能对其他靶向药物有效，例如哌柏西利、瑞博西利、阿贝西利等周期蛋白依赖性激酶CDK4和CDK6（不是CDK46）抑制剂，可阻止细胞有丝分裂周期由脱氧核糖核酸（DNA）合成前期进入合成期，而癌细胞的基本特征之一就是有丝分裂周期失控而疯狂分裂繁殖，这主要由于CDK4和CDK6过度活跃引起。不过，CDK4和CDK6抑制剂并非对任何三阴性乳腺癌患者都有效，如何快速并有效地判断CDK4和CDK6抑制剂对三阴性乳腺癌的早期疗效仍是难题。
2021年3月10日，日本核医学会《核医学年鉴》在线发表复旦大学附属肿瘤医院马光、刘成、连尉伶、张勇平、袁慧瑜、章英剑、宋少莉、杨忠毅等学者的研究报告，探讨了利用氟-18同位素胸腺嘧啶脱氧核糖核苷（18F-FLT）正电子发射计算机断层扫描（PET/CT）监测CDK4和CDK6抑制剂对三阴性乳腺癌的早期疗效。
众所周知，氟的原子量为19，共有18个同位素，只有氟-19是稳定的，而不稳定的氟-18衰变为稳定的氟-19时，可发射出正电子，其半衰期适中，大约为2小时，对人体长期影响较少，但是仍有足够时间进行后续合成及运输，其发射的正电子动能较低，故在体内移动路径较短，造成的影像定位失真较轻微，而且很少从放射性药物中分解，故不会污染其他正常器官，与碘等其他卤素相比，离子半径较小，可模拟人体已有分子，参与生物反应，例如18F-FLT可参与癌细胞的DNA合成。作为一种无创的功能成像技术，PET/CT能够在解剖结构改变之前探测到包括增殖、凋亡、乏氧等多种生物学信息变化
该研究首先将来自美国德克萨斯大学门罗·达纳韦·安德森（MDA）癌症中心的人类三阴性乳腺癌细胞（对哌柏西利敏感的MDA-MB-231、对哌柏西利不敏感的MDA-MB-468）注入小鼠皮下建立肿瘤模型，再通过体外实验进行细胞生存能力分析、细胞周期分析和蛋白质免疫印迹测定，随后通过体内实验在哌柏西利用药之前和用药之后1～3天进行PET/CT成像测定小鼠肿瘤与肌肉的18F-FLT比值，并且每天记录肿瘤体积，连续15天。
体外实验结果表明，MDA-MB-231与MDA-MB-468相比，磷酸化视网膜母细胞瘤蛋白pRB和转录因子E2F水平显著较低，引起细胞有丝分裂周期停滞。
体内实验结果表明，MDA-MB-231治疗组与对照组相比，肿瘤与肌肉的18F-FLT比值显著并持续降低1～3天（全部P<0.05）。不过，MDA-MB-468治疗组与对照组相比，肿瘤与肌肉的18F-FLT比值相似。
治疗组与对照组相比，MDA-MB-231肿瘤体积从第11天开始显著缩小，而MDA-MB-468肿瘤体积直至第15天才开始显著缩小。
因此，该研究结果表明，18F-FLT PET/CT成像可快速并有效地监测哌柏西利对三阴性乳腺癌的早期疗效，故有必要进一步开展中国人类乳腺癌临床研究进行验证。
相关链接
Ann Nucl Med. 2021 Mar 10. Online ahead of print.
(18)F-FLT PET/CT imaging for early monitoring response to CDK4/6 inhibitor therapy in triple negative breast cancer.
Ma G, Liu C, Lian W, Zhang Y, Yuan H, Zhang Y, Song S, Yang Z.
Fudan University Shanghai Cancer Center, Shanghai, China; Shanghai Medical College, Fudan University, Shanghai, China; Center for Biomedical Imaging, Fudan University, Shanghai, China; Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, China; Shanghai Proton and Heavy Ion Center, Shanghai, China.
PURPOSE: Our study was to investigate 18F-FLT PET/CT imaging monitor the early response of CDK4/6 inhibitor therapy in triple negative breast cancer (TNBC).
METHODS: MDA-MB-231 and MDA-MB-468 cell lines and corresponding subcutaneous tumor models in CB17-SCID mice were used. Cell viability assay, cell-cycle analysis, and western blotting were performed in vitro experiments. 18F-FLT PET/CT imaging was performed and the value of tumor/muscle (T/M) of mice was measured before and 1-3 days after treatment in vivo experiments. Then, the tumor volume was recorded every day for 15 days.
RESULTS: In the presence of Palbociclib (CDK4/6 inhibitor), the results of in vitro experiments showed that protein pRB and E2F levels were significantly down-regulated in MDA-MB-231 cells leading to G0/G1 arrest with consumption in S phase compared with MDA-MB-468 cells. In PET/CT imaging, the 18F-FLT T/M ratio of treatment group was a significant and sustained reduction from 1 to 3 days (all p < 0.05) compared with control group in MDA-MB-231 section. However, there was no significant difference between treatment and control groups in MDA-MB-468 section. Compared with the control group, the tumor volume of the treatment group was significantly reduced from the 11th day in MDA-MB-231 section, but not in MDA-MB-468 section until 15 days.
CONCLUSION: 18F-FLT PET/CT imaging can immediately and effectively monitor the early treatment response of CDK4/6 inhibitors in TNBC.
KEYWORDS: 18F-FLT; CDK4/6 inhibitor; Early treatment response; Monitor; Triple negative breast cancer
PMID: 33689138
DOI: 10.1007/s12149-021-01603-w