-
乳腺癌的发病率在我国女性肿瘤中居首位,且近年来呈迅速上升趋势,近5年患病率高达156/10万[1]。5%~10%的乳腺癌在诊断时即为转移性乳腺癌,约有30%~40%的乳腺癌患者在完成系统治疗后,仍会出现局部复发或远处转移,这部分患者的5年生存率仅为20%[2]。尽管筛查和治疗的技术手段都在进步,转移性乳腺癌仍是无法治愈的,大多数患者因原发或获得性药物抵抗而预后不良。因此,复发转移乳腺癌的诊断和治疗仍面临巨大挑战,探索新的诊疗途径尤为重要。
放射性核素靶向治疗是以肿瘤细胞或细胞外基质中高表达的特异性受体或相应抗原为靶点,通过放射性核素在肿瘤内大量浓聚产生的生物学效应抑制或毁损病变的靶向治疗方法。对同一种生物学靶点分别进行显像核素和治疗性核素的标记,利用显像结果指导治疗给药策略,从而达到放射性核素诊疗一体化的目的。诊疗一体化是现代医学的发展趋势,我们对目前乳腺癌核素显像与治疗的相关靶点以及受体、抗体和基因介导的乳腺癌核素诊疗一体化的研究进展和改进策略进行综述。
乳腺癌核素靶向诊疗一体化的研究进展
Research progress in integrated radionuclide targeted diagnosis and treatment of breast cancer
-
摘要: 近年来,核医学仪器设备的发展以及新型特异性显像剂的出现和深入研究使乳腺癌特异性分子显像技术得以快速发展,这有利于乳腺癌的特异性诊断。同时,利用特定靶点进行的放射性核素靶向治疗还能逐步推进乳腺癌个体化治疗的发展。随着靶向分子探针的不断出现和分子靶向技术的不断完善,乳腺癌核素特异性显像和放射性核素靶向治疗将成为乳腺癌个体化诊疗的重要手段。笔者对受体、抗体和基因介导的乳腺癌核素靶向诊疗的研究进展进行综述,并介绍其诊疗一体化的改进策略和发展前景。Abstract: Great progress has been achieved in breast cancer molecular imaging thanks to the rapid development of nuclear medicine equipment and novel imaging agents. The exploration of specific molecular targets is not only helpful in the diagnostic evaluation of breast cancer, but also promotes the blossom of radionuclide targeted therapy. Along with the continuous emergence of molecular targeted probes and improvement of molecular targeted technologies, radionuclide targeted imaging and therapy may eventually become promising approaches in the personalized therapy of breast cancer. This review summarizes the research progress of radionuclide targeted therapy of breast cancer mediated by receptor, antibody and gene, and briefly introduces the improvement strategies and development prospects in the theranostics of breast cancer.
-
Key words:
- Breast neoplasms /
- Molecular targeted therapy /
- Radionuclide imaging /
- Theranostics
-
[1] Zheng RS, Zeng HM, Zhang SW, et al. National estimates of cancer prevalence in China, 2011[J]. Cancer Lett, 2016, 370(1): 33−38. DOI: 10.1016/j.canlet.2015.10.003. [2] Peres VC, Veloso DLC, Xavier RM, et al. Breast cancer in women: recurrence and survival at five years[J]. Texto contexto-enferm, 2015, 24(3): 740−747. DOI: 10.1590/0104-07072015000600014. [3] Nahta R. Molecular mechanisms of trastuzumab-based treatment in HER2-overexpressing breast cancer[J]. ISRN Oncol, 2012, 2012: 428062. DOI: 10.5402/2012/428062. [4] Dijkers EC, Oude Munnink TH, Kosterink JG, et al. Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer[J]. Clin Pharmacol Ther, 2010, 87(5): 586−592. DOI: 10.1038/clpt.2010.12. [5] Ulaner GA, Hyman DM, Ross DS, et al. Detection of HER2-positive metastases in patients with HER2-negative primary breast cancer using 89Zr-trastuzumab PET/CT[J]. J Nucl Med, 2016, 57(10): 1523−1528. DOI: 10.2967/jnumed.115.172031. [6] Rasaneh S, Rajabi H, Akhlaghpoor S, et al. Radioimmunotherapy of mice bearing breast tumors with 177Lu-labeled trastuzumab[J]. Turk J Med Sci, 2012, 42(Suppl l): S1292−1298. DOI: 10.3906/sag-1105-29. [7] Bhusari P, Vatsa R, Singh G, et al. Development of Lu-177-trastuzumab for radioimmunotherapy of HER2 expressing breast cancer and its feasibility assessment in breast cancer patients[J]. Int J Cancer, 2017, 140(4): 938−947. DOI: 10.1002/ijc.30500. [8] 王光辉, 陈楠, 王虎霞, 等. iNOS在不同乳腺病理组织中的表达水平及其与肿瘤临床预后的相关性[J]. 现代肿瘤医学, 2018, 26(1): 52−56. DOI: 10.3969/j.issn.1672-4992.2018.01.014.
Wang GH, Chen N, Wang HX, et al. Expression and clinical significance of iNOS in breast cancer[J]. J Med Oncol, 2018, 26(1): 52−56. DOI: 10.3969/j.issn.1672-4992.2018.01.014.[9] Sadri K, Ren Q, Zhang KJ, et al. PET imaging of EGFR expression in nude mice bearing MDA-MB-468, a human breast adenocarcinoma[J]. Nucl Med Commun, 2011, 32(7): 563−569. DOI: 10.1097/MNM.0b013e3283419523. [10] Xu N, Cai GM, Ye WZ, et al. Molecular imaging application of radioiodinated anti-EGFR human Fab to EGFR-overexpressing tumor xenografts[J]. Anticancer Res, 2009, 29(10): 4005−4011. DOI: 10.1016/j.ymeth.2017.07.004. [11] Vallis KA, Reilly RM, Scollard D, et al. Phase Ⅰ trial to evaluate the tumor and normal tissue uptake, radiation dosimetry and safety of 111In-DTPA-human epidermal growth factor in patients with metastatic EGFR-positive breast cancer[J/OL]. Am J Nucl Med Mol Imaging, 2014, 4(2): 181−192[2019-09-10]. http://europepmc.org/article/PMC/3992211. [12] Sun XL, Li SW, Shen BZ. Identification of disease states and response to therapy in humans by utilizing the biomarker EGFR for targeted molecular imaging[J]. Curr Protein Pept Sci, 2016, 17(6): 534−542. DOI: 10.2174/1389203717666160101123610. [13] Wang H, Yu JM, Yang GR, et al. Assessment of 11C-labeled-4-N-(3-bromoanilino)-6,7-dimethoxyquinazoline as a positron emission tomography agent to monitor epidermal growth factor receptor expression[J]. Cancer Sci, 2007, 98(9): 1413−1416. DOI: 10.1111/j.1349-7006.2007.00562.x. [14] Reilly RM, Kiarash R, Cameron RG, et al. 111In-labeled EGF is selectively radiotoxic to human breast cancer cells overexpressing EGFR[J]. J Nucl Med, 2000, 41(3): 429−438. [15] Zhang XZ, Chen XY. Preparation and characterization of 99mTc(CO)3-BPy-RGD complex as αvβ3 integrin receptor-targeted imaging agent[J]. Appl Radiat Isot, 2007, 65(1): 70−78. DOI: 10.1016/j.apradiso.2006.07.013. [16] Chen ZY, Fu FM, Li F, et al. Comparison of [99mTc]3PRGD2 imaging and [18F] FDG PET/CT in breast cancer and expression of integrin αvβ3 in breast cancer vascular endothelial cells[J]. Mol Imaging Biol, 2018, 20(5): 846−856. DOI: 10.1007/s11307-018-1178-y. [17] 邓胜明. 放射性核素标记cRGD-USPIO实现乳腺癌的双模态显像及治疗的实验研究[D]. 苏州: 苏州大学, 2015.
Deng SM. Experimental study of radionuclide labeling cRGD-USPIO for dual-modal imaging and treatment of breast cancer[D]. Suzhou: Soochow University, 2015.[18] Fowler AM, Clark AS, Katzenellenbogen JA, et al. Imaging diagnostic and therapeutic targets: steroid receptors in breast cancer[J]. J Nucl Med, 2016, 57(Suppl 1): S75−80. DOI: 10.2967/jnumed.115.157933. [19] van Kruchten M, de Vries EGE, Brown M, et al. PET imaging of oestrogen receptors in patients with breast cancer[J]. Lancet Oncol, 2013, 14(11): e465−e475. DOI: 10.1016/S1470-2045(13)70292-4. [20] Kurland BF, Peterson LM, Lee JH, et al. Estrogen receptor binding (18F-FES PET) and glycolytic activity (18F-FDG PET) predict progression-free survival on endocrine therapy in patients with ER+ breast cancer[J]. Clin Cancer Res, 2017, 23(2): 407−415. DOI: 10.1158/1078-0432.CCR-16-0362. [21] Yazaki P, Lwin T, Minnix M, et al. Improved antibody-guided surgery with a near-infrared dye on a pegylated linker for CEA-positive tumors[J]. J Biomed Opt, 2019, 24(6): 1−9. DOI: 10.1117/1.JBO.24.6.066012. [22] Berche C, Mach JP, Lumbroso JD, et al. Tomoscintigraphy for detecting gastrointestinal and medullary-thyroid cancers: first clinical results using radiolabelled monoclonal antibodies against carcinoembryonic antigen[J]. Br Med J, 1982, 285(6353): 1447−1451. DOI: 10.1136/bmj.285.6353.1447. [23] Goldenberg DM, Nabi HA. Breast cancer imaging with radiolabeled antibodies[J]. Semin Nucl Med, 1999, 29(1): 41−48. DOI: 10.1016/s0001-2998(99)80028-2. [24] van Brummelen EMJ, Huisman MC, de Wit-van der Veen LJ, et al. 89Zr-labeled CEA-targeted IL-2 variant immunocytokine in patients with solid tumors: CEA-mediated tumor accumulation and role of IL-2 receptor-binding[J/OL]. Oncotarget, 2018, 9(37): 24737−24749[2019-09-10]. https://pubmed.ncbi.nlm.nih.gov/29872502. DOI: 10.18632/oncotarget.25343. [25] Wong JYC, Chu DZ, Williams LE, et al. A phase I trial of 90Y-DOTA-anti-CEA chimeric T84.66 (cT84.66) radioimmunotherapy in patients with metastatic CEA-producing malignancies[J]. Cancer Biother Radiopharm, 2006, 21(2): 88−100. DOI: 10.1089/cbr.2006.21.88. [26] Heskamp S, Hernandez R, Molkenboer-Kuenen JDM, et al. α-versus β-emitting radionuclides for pretargeted radioimmunotherapy of carcinoembryonic antigen-expressing human colon cancer xenografts[J]. J Nuclr Med, 2017, 58(6): 926−933. DOI: 10.2967/jnumed.116.187021. [27] Alirezapour B, Rasaee MJ, Jalilian AR, et al. Development of 64Cu-DOTA-PR81 radioimmunoconjugate for MUC-1 positive PET imaging[J]. Nucl Med Biol, 2016, 43(1): 73−80. DOI: 10.1016/j.nucmedbio.2015.07.012. [28] Salouti M, Babaei MH, Rajabi H, et al. Preparation and biological evaluation of 177Lu conjugated PR81 for radioimmunotherapy of breast cancer[J]. Nucl Med Biol, 2011, 38(6): 849−855. DOI: 10.1016/j.nucmedbio.2011.02.009. [29] DeNardo SJ, Kramer EL, O'Donnell RT, et al. Radioimmunotherapy for breast cancer using indium-111/yttrium-90 BrE-3: results of a phase I clinical trial[J]. J Nucl Med, 1997, 38(8): 1180−1185. DOI: 10.1097/00004424-199708000-00009. [30] Rousseau C, Ruellan AL, Bernardeau K, et al. Syndecan-1 antigen, a promising new target for triple-negative breast cancer immuno-PET and radioimmunotherapy. A preclinical study on MDA-MB-468 xenograft tumors[J/OL]. EJNMMI Res, 2011, 1(1): 20[2019-09-10]. https://ejnmmires.springeropen.com/articles/10.1186/2191-219X-1-20. DOI: 10.1186/2191-219x-1-20. [31] 康磊, 霍焱, 王荣福, 等. MicroRNA-155靶向的放射性标记探针对乳腺癌小鼠模型的活体显像[J]. 北京大学学报: 医学版, 2018, 50(2): 326−330. DOI: 10.3969/j.issn.1671-167X.2018.02.020.
Kang L, Huo Y, Wang RF, et al. In vivo imaging of breast tumors by a 99mTc radiolabeled probe targeting microRNA-155 in mice models[J]. J Peking Univ (Health Sci), 2018, 50(2): 326−330. DOI: 10.3969/j.issn.1671-167X.2018.02.020.[32] Rao PS, Tian X, Qin W, et al. 99mTc-peptide-peptide nucleic acid probes for imaging oncogene mRNAs in tumours[J]. Nucl Med Commun, 2003, 24(8): 857−863. DOI: 10.1097/01.mnm.0000084583.29433.df. [33] Boland A, Ricard M, Opolon P, et al. Adenovirus-mediated transfer of the thyroid sodium/iodide symporter gene into tumors for a targeted radiotherapy[J]. Cancer Res, 2000, 60(13): 3484−3492. DOI: 10.1038/sj.cgt.0242. [34] Paquette M, Phoenix S, Lawson C, et al. A preclinical PET dual-tracer imaging protocol for ER and HER2 phenotyping in breast cancer xenografts[J/OL]. EJNMMI Res, 2020, 10(1): 69[2020-08-01]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334319. DOI: 10.1186/s13550-020-00656-8. [35] Zang J, Liu QX, Sui HM, et al. Combined 68Ga-NOTA-evans blue lymphoscintigraphy and 68Ga-NOTA-RM26 PET/CT evaluation of sentinel lymph node metastasis in breast cancer patients[J]. Bioconjug Chem, 2020, 31(2): 396−403. DOI: 10.1021/acs.bioconjchem.9b00789. [36] Kwon LY, Scollard DA, Reilly RM. 64Cu-labeled trastuzumab Fab-PEG24-EGF radioimmunoconjugates bispecific for HER2 and EGFR: pharmacokinetics, biodistribution, and tumor imaging by PET in comparison to monospecific agents[J]. Mol Pharm, 2017, 14(2): 492−501. DOI: 10.1021/acs.molpharmaceut.6b00963. [37] Razumienko EJ, Chen JC, Cai ZL, et al. Dual-receptor-targeted radioimmunotherapy of human breast cancer xenografts in athymic mice coexpressing HER2 and EGFR using 177Lu- or 111In-labeled bispecific radioimmunoconjugates[J]. J Nucl Med, 2016, 57(3): 444−452. DOI: 10.2967/jnumed.115.162339. [38] Kraeber-Bodéré F, Rousseau C, Bodet-Milin C, et al. A pretargeting system for tumor PET imaging and radioimmunotherapy[J/OL]. Front Pharmacol, 2015, 6: 54[2019-09-10]. https://www.frontiersin.org/articles/10.3389/fphar.2015.00054/full. DOI: 10.3389/fphar.2015.00054. [39] Cheal SM, Xu H, Guo HF, et al. Theranostic pretargeted radioimmunotherapy of internalizing solid tumor antigens in human tumor xenografts in mice: curative treatment of HER2-positive breast carcinoma[J/OL]. Theranostics, 2018, 8(18): 5106−5125[2019-09-10]. https://www.thno.org/v08p5106.htm. DOI: 10.7150/thno.26585. [40] Keyaerts M, Xavier C, Heemskerk J, et al. Phase I study of 68Ga-HER2-nanobody for PET/CT assessment of HER2 expression in breast carcinoma[J]. J Nucl Med, 2016, 57(1): 27−33. DOI: 10.2967/jnumed.115.162024. [41] Tang L, Yang XJ, Dobrucki LW, et al. Aptamer-functionalized, ultra-small, monodisperse silica nanoconjugates for targeted dual-modal imaging of lymph nodes with metastatic tumors[J]. Angew Chem Int Ed Engl, 2012, 51(51): 12721−12726. DOI: 10.1002/anie.201205271.
计量
- 文章访问数: 4050
- HTML全文浏览量: 3409
- PDF下载量: 37