In groundbreaking research published in the November issue of The Journal of Nuclear Medicine, scientists report a new radioimmunotherapy strategy that may cure human epidermal growth factor receptor 2 (HER2)-positive breast cancer one of the most aggressive forms of the disease. The pretargeted alpha-radioimmunotherapy (PRIT) regimen achieved durable, complete, and histologic cures in preclinical models, with minimal toxicity, marking a major advance toward safer, more effective treatment options for patients.
HER2-positive breast cancers, which account for 15–20% of all breast cancer cases, are known for their rapid progression and poor outcomes once metastatic. Despite the success of HER2-targeted therapies such as trastuzumab and pertuzumab, many patients develop resistance or experience treatment-related toxicities.To overcome these barriers, researchers at Weill Cornell Medicine and Memorial Sloan Kettering Cancer Centre explored a pretargeted radioimmunotherapy (PRIT) approach using the alpha-particle emitting radionuclide actinium-225 (²²⁵Ac). Unlike traditional HER2-directed radioimmunotherapy, which risks radiation damage to healthy organs, PRIT separates the targeting and radiolabelling steps, allowing precise tumor delivery while minimizing systemic exposure.
Actinium-225 Pretargeted Radioimmunotherapy (²²⁵Ac-PRIT) involves a multi-step strategy that precisely delivers powerful alpha radiation to tumor cells. This approach combines a targeting vector that specifically binds to cancer-associated antigens with the alpha-emitting radionuclide Actinium-225 (²²⁵Ac). Once localized, the emitted alpha particles induce DNA double-strand breaks, resulting in selective and irreversible cancer cell death while sparing surrounding healthy tissues.
The therapy involved a three-step intravenous sequence: first, administration of a bispecific anti-HER2/anti-DOTA antibody; second, a clearing agent to remove unbound antibodies; and finally, the injection of ²²⁵Ac-Pr radioimmunotherapy.
In BT-474 HER2-positive breast cancer xenograft models, 100% of mice achieved complete tumor responses, and 85% achieved histologic cure, with no chronic radiation toxicity observed. Even a single treatment cycle induced long-term remission. In patient-derived xenograft models, 60% of animals achieved complete responses and significantly extended survival compared to controls. A dose-escalation study also established thresholds for nephrotoxicity, paving the way for safe clinical translation.
Despite the recent advances in managing HER2-positive breast cancer, several limitations persist. Resistance to HER2-targeted therapy remains a major challenge, leading to disease progression in the metastatic setting. CNS metastases occur frequently in HER2-positive disease, and limited drug penetration across the blood-brain barrier reduces treatment efficacy. Cardiotoxicity associated with trastuzumab and anthracyclines can restrict therapeutic options, especially in older or comorbid patients. Tumor heterogeneity and the absence of precise predictive biomarkers complicate patient selection and treatment optimization. Moreover, the high cost of biologics, limited availability of advanced therapies, and inconsistent access to cardiac monitoring in low- and middle-income countries, including India, hinder widespread implementation of guideline-based management.
The present study illustrates the curative potential of ²²⁵Ac-PRIT as a treatment for aggressive HER2-positive breast cancer. If successfully adapted for patients, HER2-directed alpha therapy could transform care for breast cancer and other HER2-expressing solid tumors.
The findings highlight how precision-engineered radioimmunotherapy could combine the tumor specificity of antibodies with the lethal power of alpha radiation, without the systemic toxicity that has limited previous approaches. As researchers move toward human trials, the work signals a new frontier in targeted radionuclide therapy one that could redefine outcomes for patients with resistant or recurrent HER2-positive disease.
Reference
- Rinne SS, Vargas DB, Seo S, Veach D, McDevitt MR, Vaughn BA, Xu H, Guo HF, Fung EK, de Stanchina E, Miranda IC, Larson SM, Cheung NKV, Cheal SM. Pretargeted α-Radioimmunotherapy Achieves Histologic Cure in HER2-Positive Breast Cancer Models. J Nucl Med. 2025 Nov;66(11):1714–1721.
- Jalloul W, Ghizdovat V, Saviuc A, Jalloul D, Grierosu IC, Stefanescu C. Targeted Alpha Therapy: Exploring the Clinical Insights into [225Ac]Ac-PSMA and Its Relevance Compared with [177Lu]Lu-PSMA in Advanced Prostate Cancer Management. Pharmaceuticals (Basel). 2025 Aug 18;18(8):1215.