Adjuvant Auger Electron-Emitting Radioimmunotherapy with [¹¹¹In]In-DOTA-Panitumumab in a Mouse Model of Local Recurrence and Metastatic Progression of Human Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) has a high risk for recurrence and metastasis. We studied the effectiveness of Auger electron (AE) radioimmunotherapy (RIT) with antiepidermal growth factor receptor (EGFR) panitumumab conjugated with DOTA complexed to 111 In ([ 111 In]In-DOTA-panitumumab) for preventing metastatic progression after local treatment of 231/LM2–4 Luc+ human TNBC tumors in the mammary fat pad of NRG mice. Prior to RIT, the primary tumor was resected, and tumor margins were treated with X-irradiation (XRT; 5 days × 6 Gy/d). RIT was administered 1 day post-XRT by intravenous injection of 26 MBq (15 μg) or 2 × 10 MBq (15 μg each) separated by 7 d. These treatments were compared to tumor resection with or without XRT combined with DOTA-panitumumab (15 μg) or irrelevant [ 111 In]In-DOTA-IgG 2 (24 MBq; 15 μg), and efficacy was evaluated by Kaplan–Meier survival curves. The effect of [ 111 In]In-DOTA-panitumumab (23 MBq; 15 μg) after tumor resection without local XRT was also studied. Tumor resection followed by XRT and RIT with 26 MBq [ 111 In]In-DOTA-panitumumab significantly increased the median survival to 35 d compared to tumor resection with or without XRT (23–24 d; P < 0.0001). Local treatment with tumor resection and XRT followed by 2 × 10 MBq of [ 111 In]In-DOTA-panitumumab, DOTA-panitumumab, or [ 111 In]In-DOTA-IgG 2 did not significantly improve median survival (26 days for all treatments). RIT alone with [ 111 In]In-DOTA-panitumumab postresection of the tumor without XRT increased median survival to 29 days, though this was not significant. Despite significantly improved survival in mice treated with tumor resection, XRT, and RIT with [ 111 In]In-DOTA-panitumumab, all mice eventually succumbed to advanced metastatic disease by 45 d post-tumor resection. SPECT/CT with [ 111 In]In-DOTA-panitumumab, PET/MRI with [ 64 Cu]Cu-DOTA-panitumumab F(ab′) 2, and PET/CT with [ 18 F]FDG were used to detect recurrent and metastatic disease. Uptake of [ 111 In]In-DOTA-panitumumab at 4 d p.i. in the MFP tumor was 26.8 ± 9.7% ID/g and in metastatic lymph nodes (LN), lungs, and liver was 34.2 ± 26.9% ID/g, 17.5 ± 6.0% ID/g, and 9.4 ± 2.4%ID/g, respectively, while uptake in the lungs (6.0 ± 0.9% ID/g) and liver (5.2 ± 2.9% ID/g) of non-tumor-bearing NRG was significantly lower ( P < 0.05). Radiation-absorbed doses in metastatic LN, lungs, and liver were 9.7 ± 6.1, 6.4 ± 2.1, and 10.9 ± 2.7 Gy, respectively. In conclusion, we demonstrated that RIT with [ 111 In]In-DOTA-panitumumab combined with tumor resection and XRT significantly improved the survival of mice with recurrent TNBC. However, the aggressive nature of 231/LM2–4 Luc+ tumors in NRG mice may have contributed to the tumor recurrence and progression observed.

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