Preclinical evaluation of 64Cu-labeled cetuximab in immuno-PET for detecting sentinel lymph node metastasis in epidermal growth factor receptor-positive breast cancer

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Despite advances in breast cancer imaging, reliable detection of sentinel lymph node (SLN) metastasis remains challenging. This study aimed to determine the ability of immuno-positron emission tomography (PET) using 64 Cu-labeled cetuximab to detect SLN metastasis in a model of epidermal growth factor receptor (EGFR)-positive breast cancer. The SLN metastasis model was established using the EGFR-strongly-expressing MDA-MB-468 breast cancer cell line. In this xenograft model, [ 64 Cu]Cu-PCTA-cetuximab was administered intravenously (5.8 ± 0.9 MBq; n = 12) or both intradermally and subdermally into the parapapillary region of the tumor-containing mammary gland (4.3 ± 0.4 MBq; n = 11), after which PET was performed. 18 F-FDG PET was also performed intravenously (9.1 ± 1.4 MBq; n = 4) or intradermally/subdermally (5.4 ± 2.2 MBq; n = 3) in the same cohort before [ 64 Cu]Cu-PCTA-cetuximab PET. PET/computed tomography was performed 60 min after administration of 18 F-FDG and 24 h after administration of [ 64 Cu]Cu-PCTA-cetuximab. Delayed PET/CT scans were conducted 48 h after administration for all mice in the intradermally/subdermally administered [ 64 Cu]Cu-PCTA-cetuximab group and for four of the 12 mice in the intravenously administered [ 64 Cu]Cu-PCTA-cetuximab group. SLNs were identified using blue dye, and PET and pathological evaluations of the resected SLN were performed to confirm metastases. After intravenous administration of [ 64 Cu]Cu-PCTA-cetuximab ( n = 12), accumulation was detected in the primary tumor in all mice and in the axilla of eight mice (67%, SUV max 1.24 ± 0.51), all of which were found to have SLNs with histologically confirmed metastasis. The sensitivity, specificity, accuracy, and negative and positive predictive values for PET with intravenously administered [ 64 Cu]Cu-PCTA-cetuximab were 89%, 100%, 92%, 75%, and 100%, respectively. In contrast, all mice with intradermal/subdermal administration ( n = 11) showed high accumulation in both the primary tumor and axillary lymph nodes (SUV max 4.28 ± 1.19), with six mice (55%, SUV max 5.01 ± 1.12) having histologically confirmed metastasis. The sensitivity, specificity, accuracy, and positive predictive values for PET with intradermally/subdermally administered [ 64 Cu]Cu-PCTA-cetuximab were 100%, 0%, 55% and 55%, respectively. SLN metastasis was not detectable by intravenous or intradermal/subdermal 18 F-FDG PET. PET with intravenously administered [ 64 Cu]Cu-PCTA-cetuximab demonstrated high precision for diagnosis of SLN metastasis in a xenograft model of EGFR-positive human breast cancer. Although further evaluation is necessary, intradermal/subdermal administration could be a useful therapeutic approach owing to its high accumulation in SLNs.

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