Radium-223 dichloride bone-targeted alpha particle therapy for hormone-refractory breast cancer metastatic to bone

Experimental Hematology & Oncology

Vivek Subbiah¹  Scott Adams²  Amol Takalkar² 

[1] Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;PET Imaging Center, Biomedical Research Foundation of Northwest Louisiana, Shreveport, LA 71103, USA

关键词: Exceptional responder;    Outlier responder;    Unusual responder;    Alpha particle;    Bone metastases;    Breast cancer;    Xofigo;    Radium 223;   

Others  :  1135303
DOI  :  10.1186/2162-3619-3-23

 received in 2014-07-07, accepted in 2014-08-18,  发布年份 2014

【 摘 要 】

Background

Hormone-refractory breast cancer metastatic to bone is a clinically challenging disease associated with high morbidity, poor prognosis, and impaired quality of life owing to pain and skeletal-related events. In a preclinical study using a mouse model of breast cancer and bone metastases, Ra-223 dichloride was incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all P values < .001) in vitro. Ra-223 dichloride also induced double-strand DNA breaks in cancer cells in vivo.

Methods

The US Food and Drug Administration recently approved radium-223 (Ra-223) dichloride (Ra-223; Xofigo injection) alpha-particle therapy for the treatment of symptomatic bone metastases in patients with castration-resistant prostate cancer. On the basis of a strong preclinical rationale, we used Ra-223 dichloride to treat bone metastases in a patient with breast cancer.

Results

A 44-year-old white woman with metastatic breast cancer who was estrogen receptor–positive, BRCA1-negative, BRCA2-negative, PIK3CA mutation (p.His1047Arg) positive presented with diffuse bony metastases and bone pain. She had hormone refractory and chemotherapy refractory breast cancer. After Ra-223 therapy initiation her bone pain improved, with corresponding decrease in tumor markers and mixed response in ¹⁸F-FDG PET/CT and ¹⁸F-NaF bone PET/CT. The patient derived clinical benefit from therapy.

Conclusion

We have shown that Ra-223 dichloride can be safely administered in a patient with hormone-refractory bone metastasis from breast cancer at the US FDA–approved dose for prostate cancer. Furthermore, because the treatment did not cause any drop in hematologic parameters, it has the potential to be combined with other radiosensitizing therapies, which may include chemotherapy or targeted therapies. Given that Ra-223 dichloride is already commercially available, this case report may help future patients and provide a rationale for initiating clinical research in the use of Ra-223 dichloride to treat bone metastasis from breast cancer. A randomized clinical trial is needed to provide evidence of efficacy, safety, and good outcomes.

【 授权许可】

   
2014 Takalkar et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Sze WM, Shelley M, Held I, Mason M: Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy - a systematic review of the randomised trials. Cochrane Database Syst Rev 2004, 2:CD004721.
• [2]Anderson P, Salazar-Abshire M: Improving outcomes in difficult bone cancers using multimodality therapy, including radiation: physician and nursing perspectives. Curr Oncol Rep 2006, 8(6):415-422.
• [3]Kluetz PG, Pierce W, Maher VE, Zhang H, Tang S, Song P, Liu Q, Haber MT, Leutzinger EE, Al-Hakim A, Chen W, Palmby T, Alebachew E, Sridhara R, Ibrahim A, Justice R, Pazdur R: Radium ra 223 dichloride injection: u.s. Food and drug administration drug approval summary. Clin Canc Res 2014, 20(1):9-14.
• [4]Eckhardt BL, Francis PA, Parker BS, Anderson RL: Strategies for the discovery and development of therapies for metastatic breast cancer. Nat Rev Drug Discov 2012, 11(6):479-497.
• [5]Baidoo KE, Yong K, Brechbiel MW: Molecular pathways: targeted alpha-particle radiation therapy. Clin Canc Res 2013, 19(3):530-537.
• [6]Bruland OS, Jonasdottir TJ, Fisher DR, Larsen RH: Radium-223: From Radiochemical Development to Clinical Applications in Targeted Cancer Therapy. Current Radoipharmaceuticals 2008, 1(1):203-208.
• [7]Bruland OS, Nilsson S, Fisher DR, Larsen RH: High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Canc Res 2006, 12(20 Pt 2):6250s-6257s.
• [8]Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fossa SD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall'Oglio M, Franzén L, Coleman R, Vogelzang NJ, O'Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, Bruland ØS, Sartor O, et al.: Alpha emitter radium-223 and survival in metastatic prostate cancer. New Engl J Med 2013, 369(3):213-223.
• [9]Suominen MI, Rissanen JP, Kakonen R, Fagerlund KM, Alhoniemi E, Mumberg D, Ziegelbauer K, Halleen JM, Kakonen SM, Scholz A: Survival benefit with radium-223 dichloride in a mouse model of breast cancer bone metastasis. J Natl Canc Inst 2013, 105(12):908-916.
• [10]Coleman R, Aksnes AK, Naume B, Garcia C, Jerusalem G, Piccart M, Vobecky N, Thuresson M, Flamen P: A phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bone-dominant disease. Breast Canc Res Treat 2014, 145(2):411-418.