Radiopharmaceutical therapy, traditionally limited to refractory metastatic cancer, is being increasingly used at earlier stages, such as for treating minimal residual disease. The aim of this study was to compare the effectiveness of ⁹⁰Y, ¹⁷⁷Lu, ¹¹¹In, and ¹⁶¹Tb at irradiating micrometastases. ⁹⁰Y and ¹⁷⁷Lu are widely used β⁻-emitting radionuclides. ¹⁶¹Tb is a medium-energy β⁻ radionuclide that is similar to ¹⁷⁷Lu but emits a higher percentage of conversion and Auger electrons. ¹¹¹In emits γ-photons and conversion and Auger electrons. Methods: We used the Monte Carlo code CELLDOSE to assess electron doses from a uniform distribution of ⁹⁰Y, ¹⁷⁷Lu, ¹¹¹In, or ¹⁶¹Tb in spheres with diameters ranging from 10 mm to 10 μm. Because these isotopes differ in electron energy per decay, the doses were compared assuming that 1 MeV was released per μm³, which would result in 160 Gy if totally absorbed. Results: In a 10-mm sphere, the doses delivered by ⁹⁰Y, ¹⁷⁷Lu, ¹¹¹In, and ¹⁶¹Tb were 96.5, 152, 153, and 152 Gy, respectively. The doses decreased along with the decrease in sphere size, and more abruptly so for ⁹⁰Y. In a 100-μm metastasis, the dose delivered by ⁹⁰Y was only 1.36 Gy, compared with 24.5 Gy for ¹⁷⁷Lu, 38.9 Gy for ¹¹¹In, and 44.5 Gy for ¹⁶¹Tb. In cell-sized spheres, the dose delivered by ¹¹¹In and ¹⁶¹Tb was higher than that of ¹⁷⁷Lu. For instance, in a 10-μm cell, ¹⁷⁷Lu delivered 3.92 Gy, compared with 22.8 Gy for ¹¹¹In and 14.1 Gy for ¹⁶¹Tb. Conclusion: ¹⁷⁷Lu, ¹¹¹In, and ¹⁶¹Tb might be more appropriate than ⁹⁰Y for treating minimal residual disease. ¹⁶¹Tb is a promising radionuclide because it combines the advantages of a medium-energy β⁻ emission with those of Auger electrons and emits fewer photons than ¹¹¹In.

Background: Targeted radionuclide therapy (TRT) is gaining importance. For TRT to be also used as adjuvant therapy or for treating minimal residual disease, there is a need to increase the radiation dose to small tumours. The aim of this in silico study was to compare the performances of ¹⁶¹Tb (a medium-energy β⁻ emitter with additional Auger and conversion electron emissions) and ¹⁷⁷Lu for irradiating single tumour cells and micrometastases, with various distributions of the radionuclide. Methods: We used the Monte Carlo track-structure (MCTS) code CELLDOSE to compute the radiation doses delivered by ¹⁶¹Tb and ¹⁷⁷Lu to single cells (14 μm cell diameter with 10 μm nucleus diameter) and to a tumour cluster consisting of a central cell surrounded by two layers of cells (18 neighbours). We focused the analysis on the absorbed dose to the nucleus of the single tumoral cell and to the nuclei of the cells in the cluster. For both radionuclides, the simulations were run assuming that 1 MeV was released per μm³ (1436 MeV/cell). We considered various distributions of the radionuclides: either at the cell surface, intracytoplasmic or intranuclear. Results: For the single cell, the dose to the nucleus was substantially higher with ¹⁶¹Tb compared to ¹⁷⁷Lu, regardless of the radionuclide distribution: 5.0 Gy vs. 1.9 Gy in the case of cell surface distribution; 8.3 Gy vs. 3.0 Gy for intracytoplasmic distribution; and 38.6 Gy vs. 10.7 Gy for intranuclear location. With the addition of the neighbouring cells, the radiation doses increased, but remained consistently higher for ¹⁶¹Tb compared to ¹⁷⁷Lu. For example, the dose to the nucleus of the central cell of the cluster was 15.1 Gy for ¹⁶¹Tb and 7.2 Gy for ¹⁷⁷Lu in the case of cell surface distribution of the radionuclide, 17.9 Gy for ¹⁶¹Tb and 8.3 Gy for ¹⁷⁷Lu for intracytoplasmic distribution and 47.8 Gy for ¹⁶¹Tb and 15.7 Gy for ¹⁷⁷Lu in the case of intranuclear location. Conclusion: ¹⁶¹Tb should be a better candidate than ¹⁷⁷Lu for irradiating single tumour cells and micrometastases, regardless of the radionuclide distribution.

A growing body of evidence suggests that gastrin-releasing peptide receptor (GRPR) might be a valuable target in breast cancer. To understand which patients can be potential candidates for GRPR-based imaging or targeted therapy, we screened invasive breast cancers by immunohistochemistry for the presence and intensity of GRPR expression. Methods: We explored a tissue microarray of 1,432 primary breast tumors from patients who underwent surgery between 2000 and 2005 at Institut Bergonié, without prior neoadjuvant treatment. We studied associations between GRPR expression and clinical, pathologic, and biologic parameters. The association between GRPR expression and distant metastasis-free interval was also examined. Results: GRPR overexpression was found in 75.8% of the 1,432 tumors and was most strongly associated with estrogen receptor (ER) positivity (GRPR was high in 83.2% of ER-positive and 12% of ER-negative tumors; P < 0.00001). When molecular subtypes of breast cancer were considered, GRPR was overexpressed in 86.2% of luminal A–like tumors, 70.5% of luminal B–like human epidermal growth factor receptor 2 (HER2)–negative tumors, 82.8% of luminal B–like HER2-positive tumors, 21.3% of HER2-enriched tumors, and 7.8% of triple-negative tumors. Importantly, when breast tumors overexpressed GRPR, high GRPR expression was also found in metastatic lymph nodes in 94.6% of cases. Primary tumors with high GRPR expression were associated with lower risk of distant metastases at follow-up in univariate analysis (Log-rank P = 0.0084) but not in multivariate analysis. Hence, the prognostic impact of GRPR was lost when examined within specific molecular subtypes. Conclusion: Because GRPR is overexpressed in a high percentage of ER-positive tumors, GRPR targeting offers wide perspectives for imaging and treatment in patients with ER-positive breast cancer, using recently developed radiolabeled GRPR ligands.

Receptors for some regulatory peptides are highly expressed in tumors. Selective radiolabeled peptides can bind with high affinity and specificity to these receptors and exhibit favorable pharmacologic and pharmacokinetic properties, making them suitable agents for imaging or targeted therapy. The success encountered with radiolabeled somatostatin analogs is probably the first of a long list, as multiple peptide receptors are now recognized as potential targets. This review focuses on 3 neuropeptide receptor systems (bombesin, neurotensin, and neuropeptide-Y) that offer high potential in the field of nuclear oncology. The underlying biology of these peptide/receptor systems, their physiologic and pathologic roles, and their differential distribution in normal and tumoral tissues are described with emphasis on breast, prostate, and lung cancers. Radiolabeled analogs that selectively target these receptors are highlighted.

PURPOSE: Radionuclide therapy is increasingly seen as a promising option to target minimal residual disease. Copper-67, scandium-47 and terbium-161 have a medium-energy β^- emission which is similar to that of lutetium-177, but offer the advantage of having diagnostic partner isotopes suitable for pretreatment imaging. The aim of this study was to compare the efficacy of ⁶⁷Cu, ⁴⁷Sc and ¹⁶¹Tb to irradiate small tumors.

Considering the wide range of therapeutic options for localized prostate cancer (e.g., active surveillance, radiation-beam therapy, focal therapy, and radical prostatectomy), accurate assessment of the aggressiveness and localization of primary prostate cancer lesions is essential for treatment decision making. National Comprehensive Cancer Network guidelines recognize prostate-specific membrane antigen (PSMA) PET/CT for use in initial staging of high-risk primary prostate cancer. The gastrin-releasing peptide receptor (GRP-R) is a neuropeptide receptor overexpressed by low-risk prostate cancer cells. We aimed to perform the first (to our knowledge) prospective head-to-head comparison of PSMA- and GRP-R–targeted imaging at initial staging to understand how PSMA PET and GRP-R PET can be used or combined in clinical practice. Methods: This was a prospective, single-center, diagnostic cross-sectional imaging study using anonymized, masked, and independent interpretations of paired PET/CT studies in 22 patients with ⁶⁸Ga-PSMA-617 (a radiolabeled PSMA inhibitor) and ⁶⁸Ga-RM2 (⁶⁸Ga-DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, a radiolabeled GRP-R antagonist). We enrolled patients with newly diagnosed, biopsy-proven prostate cancer. None had received neoadjuvant hormone therapy or chemotherapy, and all underwent extended pelvic lymph node dissection. Histologic findings served as a reference. Results: On a lesion-based analysis (including lesions < 0.1 cm³), ⁶⁸Ga-PSMA-617 PET/CT detected 74.3% (26/35) of all tumor lesions and ⁶⁸Ga-RM2 PET/CT detected 78.1% (25/32; 1 patient could not be offered ⁶⁸Ga-RM2 PET/CT). Paired examinations showed positive uptake of the 2 tracers in 21 of 32 lesions (65.6%), negative uptake in 5 of 32 lesions (15.6%), and discordant uptake in 6 of 32 lesions (18.8%). Uptake of ⁶⁸Ga-PSMA-617 was higher when the International Society of Urological Pathology (ISUP) score was at least 4 versus at least 1 (P < 0.0001) or 2 (P = 0.0002). There were no significant differences in uptake between ISUP scores for ⁶⁸Ga-RM2. Median ⁶⁸Ga-RM2 SUV_max was significantly higher than median ⁶⁸Ga-PSMA-617 SUV_max in the ISUP-2 subgroup (P = 0.01). Conclusion:⁶⁸Ga-PSMA-617 PET/CT is useful to depict higher, more clinically significant ISUP score lesions, and ⁶⁸Ga-RM2 PET/CT has a higher detection rate for low-ISUP tumors. Combining PSMA PET and GRP-R PET allows for better classification of intraprostatic lesions. Visual Abstract