Predicting cetuximab accumulation in KRAS wild‐type and KRAS mutant colorectal cancer using ⁶⁴Cu‐labeled cetuximab positron emission tomography

Abstract

Overexpression of epidermal growth factor receptor (EGFR) is common in colorectal cancer. However, cetuximab as an EGFR-targeting drug is useful only for a subset of patients and currently no single predictor other than V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status has been established. In the present study, we investigated cetuximab accumulation in colorectal tumors and major organs using 111 In-DOTA-cetuximab. We also evaluated the potential of positron emission tomography (PET) imaging of 64 Cu-DOTA-cetuximab. Colorectal tumor xenografts with a different EGFR expression level and KRAS mutation status were subjected to in vivo biodistribution study and PET imaging at 48 h post-injection of radiolabeled cetuximab. The EGFR expression levels on colorectal tumors were determined by ex vivo immunoblotting and ELISA. We found that KRAS wild-type tumors had significantly higher In-DOTA-cetuximab accumulation than KRAS mutant tumors (P < 0.001). Based on KRAS mutation status, a strong correlation was found between Cu-DOTA-cetuximab allowed clear visualization of tumors. Both radiolabeled cetuximab had effectively visualized cetuximab accumulation in colorectal tumors with a wide variety of EGFR expression levels and different KRAS mutation status as commonly encountered in the clinical setting. Our findings suggest that this radioimmunoimaging therefore can be clinically translated as an in vivo tool to predict cetuximab accumulation in colorectal cancer patients prior to cetuximab therapy. (Cancer Sci 2012; 103: 600-605) I n 2008, colorectal cancer was the third most commonly diagnosed cancer worldwide, the third most common in men and the second in women. Additionally, colorectal cancer was the fourth leading cause of death from cancer with an 8% mortality rate. By 2020, the number of newly diagnosed cases of colorectal cancer is expected to grow by approximately one-third.( 1) Approximately 25% and 19% of European and American patients, respectively, present with metastases at initial diagnosis, and 89% of them die within 5 years following the diagnosis. (2,3) Therefore, to enhance the efficacy of conventional chemotherapy for advanced or metastatic colorectal carcinoma, current guidelines recommend using targeted therapy.(2,4) One of these targeted drugs is cetuximab (Erbitux), which is a chimeric monoclonal antibody (mAb) specialized in targeting the extracellular domain of epidermal growth factor receptor (EGFR) and disrupting its downstream signaling by preventing EGFR ligands binding. Since its approval in 2004, cetuximab has been widely used in clinical practice as a single agent or with other modalities for treatment of metastatic or advanced colorectal carcinoma. However, some clinical trials revealed that cetuximab can be beneficial to only approximately 31.5% of patients. (5) In the presence of EGFR ligands, EGFR has been shown to play an essential role in carcinogenesis, by initiating downstream signaling of several prosurvival cascades, such as the RAS and PI3K pathw...

PET of EGFR with 64Cu‐cetuximab‐F(ab′)2 in mice with head and neck squamous cell carcinoma xenografts

“…Tumor uptake of 64 Cu-cetuximab-F(ab′) 2 in terms of % ID/g was similar to that of the 111 In-labeled cetuximab-F(ab′) 2 tracer as described previously (13)(14)(15). Cetuximab has been radiolabeled with 64 Cu in several other studies, using DOTA as a chelator (22)(23)(24)(25)(26)(27). However, this resulted in increased radioactivity levels in the liver, which was attributed to transchelation of Cu 2+ from DOTA to superoxide dismutase and ceruloplasmin (28).…”

An Optical Probe for Noninvasive Molecular Imaging of Orthotopic Brain Tumors Overexpressing Epidermal Growth Factor Receptor

“…Imaging of differential expression of EGFR in various cancers including colorectal and head and neck squamous carcinoma, and non–small cell lung cancer has been explored extensively with positron emission tomography (PET) or PET/ computed tomographic (CT) imaging modalities radiolabeled EGF ligand (23) and EGFR-targeted antibodies (24, 25), peptides (17), and small molecules (26). The ability to noninvasively observe EGFR levels of tumors in subjects is increasingly important for the purpose of diagnosis of cancer and longitudinal monitoring of drug therapies.…”

99mTc-HYNIC-MPG: A novel SPECT probe for targeting mutated EGFR

“…Recently, associated research works have been mainly focused on dynamic imaging of the extracellular section of EGFR through imaging radiolabeled monoclonal antibodies, affibody or some substances in real time in vivo. [7][8][9][10] They can only reflect the expression level of EGFR but not EGFR mutational status, however, it remains unresolved for EGFR TKI resistance and EGFR mutation in clinical practice. On the other hand, increasing attention has been paid onto the use of radionuclides-labeled small molecule TKIs to identify EGFR mutation in vivo, such as 18 F, 11 C, and 64 Cu, etc.…”