Page 16 - ARNM-3-2

Advances in Radiotherapy
& Nuclear Medicine Role of PET/CT in exploring tumor heterogeneity

cancers, demonstrated that 68 Ga-FAPI PET/CT had varying receptor expressions, providing a clearer picture
higher sensitivity in detecting lymph node and peritoneal of tumor heterogeneity and enabling more effective patient
metastases, while F-FDG PET/CT had higher sensitivity management strategies. Several studies have suggested
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in detecting bone metastases; therefore, they proposed that combining two PET tracers (including metabolic
a combination of two tracers for PET/CT imaging for tracer and HER2-targeting agent) provides a clear benefit
better patient management. Patients with tumor lesions in evaluating heterogeneity in breast cancer patients and
positive on Ga-FAPI PET/CT scans can be considered for planning treatment strategies. 44,45
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177 Lu-FAPI therapy; however, clear indications and benefits
are still under research. 37 6.5. Various evolving tracers
6.5.1. Ga-RGD PET/CT
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6.4.2. F- FES PET/CT for breast cancer
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Tumor cells and angiogenic blood vessels express
18 F-FDG PET/CT scans are routinely conducted for staging integrins on their surface. These integrins, along with
and restaging of all types of breast cancer, including its vascular endothelial growth factor receptors (VEGFRs),
various molecular subtypes. A large number of patients are regulate the process of angiogenesis. As the peptide Arg-
hormone-positive, that is, estrogen receptor (ER)-positive Gly-Asp (RGD) binds with αvβ3 integrins, RGD labeled
and progesterone receptor (PR)-positive. Hormone- with Ga or F has been used for the diagnosis and
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positive patients can be treated with targeted therapies. The staging of a wide range of cancers, including breast cancer,
diagnosis of hormone receptor status is performed using glioma, lung cancer, head-and-neck cancer, melanoma,
immunohistochemical straining of biopsy samples, but this renal cell cancer, etc. The sensitivity of F-galacto-
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approach has certain challenges and does not fully reflect RGD or F-fluciclatide was found to be 88–94% for all
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hormone status and heterogeneity of the entire tumor burden. lesions, with a lower sensitivity of 71–88% for metastatic
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PET radiopharmaceutical F-fluoroestradiol (FES) provides lymph nodes and distant metastases. In addition, other
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a noninvasive alternative by measuring ER expression integrins (e.g., αvβ6), which are expressed in epithelial
in tumors. FES is a lipophilic molecule that is similar to cells, have been targeted using Ga-trivehexin PET. This
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estradiol and binds to ERs in the nucleus of ER-expressing imaging modality is particularly useful for diagnosing
cells. F-FES PET scans can detect more lesions with mild pancreatic cancer and head-and-neck squamous cell
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or no uptake on FDG PET scans in receptor-positive breast carcinoma. 47
cancer. Studies have demonstrated the superiority of FES
PET over other modalities, such as bone scans or F-FDG 6.5.2. Other evolving tracers
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PET scans, in the staging and restaging of hormone-positive Other PET tracers, such as 18 F-fluorothymidine
breast cancer. 40,41 Matushita et al. demonstrated that FES (FLT), target cell proliferation, 11 C-methionine, and
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PET has a pooled sensitivity of 82% and a pooled specificity 18 F-fluoroethyltyrosine (FET), are amino acid analogs
of 94%, highlighting good diagnostic accuracy, with a that exhibit uptake in enhanced protein synthesis. Tumor
pooled area under the curve (AUC) of 0.8899 for ER-positive hypoxia can be imaged using F-fluoromesonidazole
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lesions in breast cancer patients. Another study by Liu et (FMISO) and PET with C-acetate as the marker for cell
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al. studied a total of 238 lesions in newly diagnosed ER‐ membrane lipid synthesis. These tracers have limited global
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positive breast cancer. They reported a higher number of availability and are used in only a few centers, primarily for
lesions detected with FES compared to FDG, with a higher research purposes. New tracers, such as Ga-pentixafor
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sensitivity of 90.8% for F-FES compared to 82.8% for F- for multiple myeloma and labeled antibodies, have
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FDG PET. Recent advancements in PET imaging have also demonstrated promising results and are currently
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enabled the use of Zr-labeled trastuzumab, a monoclonal undergoing various research and clinical trials. Chemokine
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antibody that binds to human epidermal growth factor receptor CXCR4 is overexpressed in certain tumors,
receptor 2 (HER2), to visualize HER2-positive breast cancer especially lymphoproliferative diseases (e.g., lymphoma
sites in vivo. These developments underscore the growing and multiple myeloma), and various agents, including
role of PET radiopharmaceuticals in personalizing breast 68 Ga-pentixafor, are used to target them. Exendin-4 is
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cancer treatment. 42,43
similar to glucagon-like peptide-1 (GLP-1), which binds
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Tumor cells and their metastases may contain subclones to pancreatic β-cells, and Ga-DOTA-exendin-4 PET is
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of cells with variations in molecular subtypes; therefore, utilized for imaging insulinoma. Glypican 3 (GPC3) is
single tracers targeting a particular hormone subtype may a glycoprotein labeled with Ga, displaying a high uptake
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be inadequate to identify all the tumor lesions. Combining in hepatocellular carcinoma on PET scans, with very low
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18 F-FES with F-FDG and other PET tracers allows expression in normal tissue and hepatitis. These tracers
clinicians to better differentiate between tumors with have proven to be beneficial in various tumors as described
Volume 3 Issue 2 (2025) 8 doi: 10.36922/ARNM025040005