Treatment of Triple-Negative Breast Cancer Using Anti-EGFR–Directed Radioimmunotherapy Combined with Radiosensitizing Chemotherapy and PARP Inhibitor

Journal of Nuclear Medicine

Alex Swarbrick¹  Wei Shi¹  Georgia Chenevix-Trench¹  Sunil R. Lakhani¹  Sarah Song¹  Michael P. Brown¹  Adrian P. Wiegmans¹  Ana Cristina Vargas¹  Alana L. Welm¹  Fares Al-Ejeh¹  Kum Kum Khanna¹  Peter T. Simpson¹  Mariska Miranda¹ 

关键词: triple-negative breast cancer;    EGFR;    PARP inhibitor;    radioimmunotherapy;    combination therapy;   

DOI  :  10.2967/jnumed.112.111534

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

Triple-negative breast cancer (TNBC) is associated with poor survival. Chemotherapy is the only standard treatment for TNBC. The prevalence of BRCA1 inactivation in TNBC has rationalized clinical trials of poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors. Similarly, the overexpression of epidermal growth factor receptor (EGFR) rationalized anti-EGFR therapies in this disease. However, clinical trials using these 2 strategies have not reached their promise. In this study, we used EGFR as a target for radioimmunotherapy and hypothesized that EGFR-directed radioimmunotherapy can deliver a continuous lethal radiation dose to residual tumors that are radiosensitized by PARP inhibitors and chemotherapy. Methods: We analyzed EGFR messenger RNA in published gene expression array studies and investigated EGFR protein expression by immunohistochemistry in a cohort of breast cancer patients to confirm EGFR as a target in TNBC. Preclinically, using orthotopic and metastatic xenograft models of EGFR-positive TNBC, we investigated the effect of the novel combination of 177Lu-labeled anti-EGFR monoclonal antibody, chemotherapy, and PARP inhibitors on cell death and the survival of breast cancer stem cells. Results: In this first preclinical study of anti-EGFR radioimmunotherapy in breast cancer, we found that anti-EGFR radioimmunotherapy is safe and that TNBC orthotopic tumors and established metastases were eradicated in mice treated with anti-EGFR radioimmunotherapy combined with chemotherapy and PARP inhibitors. We showed that the superior response to this triple-agent combination therapy was associated with apoptosis and eradication of putative breast cancer stem cells. Conclusion: Our data support further preclinical investigations toward the development of combination therapies using systemic anti-EGFR radioimmunotherapy for the treatment of recurrent and metastatic TNBC.

【 授权许可】

Unknown