Theranostics with somatostatin receptor antagonists in SCLC: Correlation of 
The increasing importance of theranostics, particularly radiotheranostics, in oncology is evident . This is driven by the unmet clinical need to understand and face the heterogeneity of response of tumors to standard therapies and by growing interest in potential novel clinical applications, resulting in an increasing number of available target structures . In this context, molecular imaging holds tremendous promise to validate target structures. In comparison to conventional techniques like immunohistochemistry (IHC), non-invasive whole-body molecular imaging offers distinct advantages, particularly in capturing the temporal and spatial tumor heterogeneity with greater fidelity . In the multidisciplinary management of patients with lung cancer, molecular imaging of glucose metabolism by 18 F-FDG positron emission tomography (PET) plays a crucial role in treatment decision-making for both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) , . However, no theranostic applications have been widely established for these most frequent thoracic malignancies yet. SCLC is a highly aggressive tumor with a dismal prognosis, accounting for approximately 15% of lung cancer diagnoses . While large parts of the molecular profile of SCLC remain untargetable, neuroendocrine characteristics with notable expression of type 2 somatostatin receptors (SSTR2) in a relevant fraction of patients suggest a potential for SSTR2-directed theranostics . SSTR-directed peptide receptor radionuclide therapy (PRRT) using SSTR-agonists like 177 Lu-DOTATATE or 177 Lu-DOTATOC and their 68 Ga-labeled counterparts for PET imaging have not only been approved in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) , , but are also successfully applied in lung NETs , . In patients with SCLC, however, molecular imaging with SSTR2-agonists yielded inconsistent results with high PET tracer accumulation only in selected subgroups of patients , and SSTR2-agonist PRRT has not found its way into clinical practice. Here, SSTR2-antagonists, like the theranostic pair 68 Ga-satoreotide trizoxetan/ 177 Lu-satoreotide tetraxetan ( 68 Ga-SSO120/ 177 Lu-SSO110, previously 68 Ga-OPS-202/ 177 Lu-OPS-201 or 68 Ga-NODAGA-JR11/ 177 Lu-DOTA-JR11), offer higher tumor uptake and prolonged retention times, potentially due to their binding to SSTRs in both active and inactive states . Initial clinical applications in GEP-NETs have demonstrated improved sensitivity in PET imaging and higher tumor-absorbed doses in PRRT . Moreover, we recently found comparable detection rates of 68 Ga-SSO120 PET to the gold standard of 18 F-FDG PET in the initial staging of patients with SCLC and high uptake in up to 40% of patients . This highlights the potential of radiotheranostics using SSTR2-antagonists in this dismal disease. However, in SCLC, lesion uptake in 68 Ga-SSO120 PET as a biomarker of SSTR2-expression has not been validated against histopathological examination. Furthermore, it remains to be elucidated whether SSTR2-expression in SCLC is associated with favorable prognosis, as previously assumed, or an indicator of specific molecular subtypes and poorer prognosis, as suggested by more recent literature . Therefore, the primary objective of this study is to investigate the correlation between tracer uptake in 68 Ga-SSO120 PET and expression of SSTR2 in IHC in patients with SCLC. Additionally, the study aims to analyze the prognostic potential of SSTR2-expression assessed by 68 Ga-SSO120 PET or by IHC for time to treatment failure (TTF) and overall survival (OS) in comparison with established clinical and imaging-based parameters. Lastly, patients are stratified based on their whole-body SSTR2-expression to provide insights into patient eligibility for SSTR2-antagonist PRRT.   Patients/Ethics We conducted a retrospective review of our institutional database, identifying patients who underwent 68 Ga-SSO120 PET/CT as an institutional standard-of-care for staging of SCLC with neuroendocrine differentiation (based on IHC for CD56, synaptophysin SP11, and thyroid transcription factor TTF-1). For further analysis, we specifically selected patients who were tested with 68 Ga-SSO120 PET in primary diagnostic workup at the initiation of first-line therapy (allowing PET imaging before, within, or after a first cycle of primary chemotherapy). Clinical data were retrieved from the patients' electronic health records system encompassing demographics, clinical history, therapy lines, and blood results (serum lactate dehydrogenase (LDH)). Additionally, survival data were obtained from our institutional Center for Cancer Registry encompassing governmental registration data. Prior to undergoing clinical PET examinations, patients provided written informed consent. The study received approval from the local institutional ethics committee at the University of Duisburg-Essen, medical faculty, under the ethics protocol number 22-11013-BO. The committee waived the need for study-specific consent. PET/CT imaging PET/CT images were acquired on a Biograph Vision 600, a Biograph mCT (both Siemens Healthineers), or a Vereos (Philips Healthcare) PET/CT system 64 ± 16 min (mean ± standard deviation SD) after administration of 141.8 ± 29.0 MBq (mean ± SD) of 68 Ga-SSO120. PET/CT acquisition started with a contrast enhanced whole-body CT; the CT images were used for attenuation correction and anatomical localization of PET uptake. If a contrast enhanced whole-body CT was already clinically available within 4 weeks prior to the examination date, a low-dose CT was performed instead. PET/CT acquisition and image reconstruction was performed according to our established institutional protocols for 68 Ga-based PET tracers . Where available within a two-week interval before or after 68 Ga-SSO120 PET, additional staging 18 F-FDG PET/CT was considered for comparison under the condition that no significant morphological differences were observed in the CT images (stable disease according to RECIST 1.1 criteria). PET image analysis Analysis of PET images was independently performed by three nuclear medicine physicians with several years of experience in PET reporting (A.R., D.K., and H.H.). In case of discrepant findings, re-evaluation for consensus decision making was performed. Segmentation of PET-positive tumor was performed using the Syngo.via software solution (Siemens Medical Solutions, Erlangen, Germany) in a semi-automatic approach. First, a spherical volume-of-interest (VOI) in the right liver lobe (in analogy to Positron Emission Response Criteria in Solid Tumors (PERCIST) 1.0 criteria) was automatically determined to estimate the standardized uptake values SUV max , SUV peak , and SUV mean . Next, all foci with a SUV max value ≥ (1.5 x SUV mean + 2 x SD of SUV mean in the liver VOI) were automatically segmented, determining lesion boundaries by a 41-% local SUV max threshold derived from current recommendations of the European Association of Nuclear Medicine . Lesions with a volume <0.1 mL were not considered. Finally, all segmented foci were manually validated to exclude regions of physiological uptake, and additional lesions were added if visually detected. Here, tumor lesions were defined as regions with focal markedly increased 68 Ga-SSO120-/ 18 F-FDG-uptake compared to local background without physiological explanation. Volume, SUV max , SUV peak , and SUV mean of the individual tumor VOIs were determined. As a robust measure of lesion tracer uptake, the normalized tumor-to-liver ratios (TLR peak and TLR mean ) were defined using the liver VOI as reference : Whole-body SSTR2-expressing tumor volume (SSTR-TV) and metabolic tumor volume (MTV) were defined as the sum of the volumes of all segmented lesions in 68 Ga-SSO120 and 18 F-FDG PET, respectively. Whole-body tumor SUV mean and TLR mean were calculated from the SUV mean and TLR mean of all segmented lesions in 68 Ga-SSO120 and 18 F-FDG PET per patient, respectively. Total lesion SSTR2-expression (TL-SSTR) and total lesion glycolysis (TLG) were defined as: and in 68 Ga-SSO120 PET and 18 F-FDG PET/CT, respectively. Moreover, the lesion with the highest SUV max and TLR peak value (hottest lesion) and the number of detected lesions per patient in 68 Ga-SSO120 PET were determined. Immunohistochemistry Systematic endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is routinely performed for mediastinal and hilar lymph node staging and primary tumor diagnostics at our institution leading to a high number of available samples. For eligible patients with available biopsy specimens, histopathologic analysis was conducted. Staining of biopsy specimens was performed with standard hematoxylin and eosin and SSTR2 IHC stains. The biopsy specimens were cut into up to 2 µm thin slices of the bronchoscopic samples and stained by IHC using a polyclonal antibody for SSTR2 (dilution 1:50, incubation time at 36 °C for 40 min, Zytomed Systems, Berlin, Germany). The automated system used for staining was the Ventana Benchmark Ultra in combination with an Optiview DAB IHC detection kit for visualization (Roche, Basel, Switzerland). The staining results were visually evaluated by two experienced pathologists (D.T. and T.H.) who were blinded to the imaging findings. The scoring system used for SSTR2 staining results employed a 4-level scale (SSTR2 score 0: negative, 1: 1-29%, 2: 30-69%, 3: ≥70%), providing a systematic assessment of SSTR2 expression. The SSTR2 score of the examined IHC specimens was correlated with SUV max /TLR peak in 68 Ga-SSO120 PET on a lesion level. For this purpose, the lesion which was biopsied was specifically selected in the PET images to determine its uptake parameters (only in patients with at least one day difference between 68 Ga-SSO120 PET and 18 F-FDG PET to avoid uptake interferences when performed on the same day). Study endpoints We defined parameters indicative of tumor load (M status, number of lesions in 68 Ga-SSO120 PET, LDH), of SSTR2 expression (SSTR2 score in IHC, SUV max /TLR peak /whole-body tumor SUV mean /whole-body tumor TLR mean in 68 Ga-SSO120 PET), and combination parameters (SSTR-TV, TL-SSTR2). Moreover, two established parameters for survival prediction from 18 F-FDG PET (MTV and TLG ) were used for validation. Primary study endpoints were correlation of SSTR2 expression assessed by IHC with SUV max /TLR peak in 68 Ga-SSO120 PET on a lesion-level and correlation of SSTR2 expression (assessed by IHC and 68 Ga-SSO120 PET) with TTF and OS. Secondary endpoints included correlation of parameters of tumor load, combination parameters, and MTV/TLG with OS and TTF, comparison of whole-body tumor SUV mean and SSTR-TV in 68 Ga-SSO120 PET with SUV mean and MTV in 18 F-FDG PET/CT, as well as assessment of patient-based mean 68 Ga-SSO120 uptake (assessed by mean TLR peak per patient) as surrogate of applicability of theranostic approaches. TTF was defined as the time from 68 Ga-SSO120 PET until the initiation of a second line therapy after documented disease progression or death. For patients without documented progression, TTF was censored on the date the patient was last known to be non-progressing after first-line therapy. OS was defined as the time from 68 Ga-SSO120 PET to the date of death; patients without documented death on the cut-off date were censored on the date the patient was last known to be alive. For imaging studies, different definitions of the starting date for calculation of OS and TTF are frequently used. As in this study the time from 68 Ga-SSO120 PET aligns with the time of recruitment and differs from the initiation of chemotherapy by a maximum several days, it is a precise and accurate point of reference. Statistical analysis/software For comparison of non-normally distributed data, a non-parametric Mann-Whitney U test was employed, with measures reported as median and interquartile range (QR). Beforehand, data was assessed for parametric distribution using the Shapiro-Wilk test. The correlation of SSTR2 expression in IHC and uptake in 68 Ga-SSO120 PET was evaluated using ANOVA analysis and the Spearman rank correlation coefficient; linear regression after semi-logarithmic transformation was performed to assess for exponential relationship. To determine the association of PET data, IHC SSTR2 score, LDH, and M status with survival data, uni- and multivariate Cox regression analyses were performed; median follow up was calculated by the reverse Kaplan-Meier method. Continuous variables were binarized using cut-off values that were identified on data for optimal separation and Hazard ratios (HR) with 95%-confidence intervals were calculated. For parameters of SSTR expression (primary endpoint), additional Cox regression analyses of continuous variables were calculated. The results of survival analyses are visually presented using Kaplan-Meier curves. Stratified Cox regression analyses were performed to account for different baseline hazards between patients with M0 or M1 status. Adjusted Kaplan Meier curves were used to adapt survival for confounding parameters of tumor load and clinical characteristics. In all statistical tests, p-values (p) <0.05 were regarded significant. All statistical evaluations were performed using R statistical software in version 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria, www.R-project.org). Cut-off values for binarization in Cox regression analyses were calculated using the surv_cutpoint function from the survminer package; adjusted Kaplan Meier curves were generated using the adjustedCurves package based on the direct standardization method . The graphical abstract was created using BioRender.com (BioRender, San Francisco, USA, www.BioRender.com). Data availability statement The data generated in this study are available upon request from the corresponding author.   We conducted a retrospective review of our institutional database, identifying patients who underwent 68 Ga-SSO120 PET/CT as an institutional standard-of-care for staging of SCLC with neuroendocrine differentiation (based on IHC for CD56, synaptophysin SP11, and thyroid transcription factor TTF-1). For further analysis, we specifically selected patients who were tested with 68 Ga-SSO120 PET in primary diagnostic workup at the initiation of first-line therapy (allowing PET imaging before, within, or after a first cycle of primary chemotherapy). Clinical data were retrieved from the patients' electronic health records system encompassing demographics, clinical history, therapy lines, and blood results (serum lactate dehydrogenase (LDH)). Additionally, survival data were obtained from our institutional Center for Cancer Registry encompassing governmental registration data. Prior to undergoing clinical PET examinations, patients provided written informed consent. The study received approval from the local institutional ethics committee at the University of Duisburg-Essen, medical faculty, under the ethics protocol number 22-11013-BO. The committee waived the need for study-specific consent.   PET/CT images were acquired on a Biograph Vision 600, a Biograph mCT (both Siemens Healthineers), or a Vereos (Philips Healthcare) PET/CT system 64 ± 16 min (mean ± standard deviation SD) after administration of 141.8 ± 29.0 MBq (mean ± SD) of 68 Ga-SSO120. PET/CT acquisition started with a contrast enhanced whole-body CT; the CT images were used for attenuation correction and anatomical localization of PET uptake. If a contrast enhanced whole-body CT was already clinically available within 4 weeks prior to the examination date, a low-dose CT was performed instead. PET/CT acquisition and image reconstruction was performed according to our established institutional protocols for 68 Ga-based PET tracers . Where available within a two-week interval before or after 68 Ga-SSO120 PET, additional staging 18 F-FDG PET/CT was considered for comparison under the condition that no significant morphological differences were observed in the CT images (stable disease according to RECIST 1.1 criteria).   Analysis of PET images was independently performed by three nuclear medicine physicians with several years of experience in PET reporting (A.R., D.K., and H.H.). In case of discrepant findings, re-evaluation for consensus decision making was performed. Segmentation of PET-positive tumor was performed using the Syngo.via software solution (Siemens Medical Solutions, Erlangen, Germany) in a semi-automatic approach. First, a spherical volume-of-interest (VOI) in the right liver lobe (in analogy to Positron Emission Response Criteria in Solid Tumors (PERCIST) 1.0 criteria) was automatically determined to estimate the standardized uptake values SUV max , SUV peak , and SUV mean . Next, all foci with a SUV max value ≥ (1.5 x SUV mean + 2 x SD of SUV mean in the liver VOI) were automatically segmented, determining lesion boundaries by a 41-% local SUV max threshold derived from current recommendations of the European Association of Nuclear Medicine . Lesions with a volume <0.1 mL were not considered. Finally, all segmented foci were manually validated to exclude regions of physiological uptake, and additional lesions were added if visually detected. Here, tumor lesions were defined as regions with focal markedly increased 68 Ga-SSO120-/ 18 F-FDG-uptake compared to local background without physiological explanation. Volume, SUV max , SUV peak , and SUV mean of the individual tumor VOIs were determined. As a robust measure of lesion tracer uptake, the normalized tumor-to-liver ratios (TLR peak and TLR mean ) were defined using the liver VOI as reference : Whole-body SSTR2-expressing tumor volume (SSTR-TV) and metabolic tumor volume (MTV) were defined as the sum of the volumes of all segmented lesions in 68 Ga-SSO120 and 18 F-FDG PET, respectively. Whole-body tumor SUV mean and TLR mean were calculated from the SUV mean and TLR mean of all segmented lesions in 68 Ga-SSO120 and 18 F-FDG PET per patient, respectively. Total lesion SSTR2-expression (TL-SSTR) and total lesion glycolysis (TLG) were defined as: and in 68 Ga-SSO120 PET and 18 F-FDG PET/CT, respectively. Moreover, the lesion with the highest SUV max and TLR peak value (hottest lesion) and the number of detected lesions per patient in 68 Ga-SSO120 PET were determined.   Systematic endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is routinely performed for mediastinal and hilar lymph node staging and primary tumor diagnostics at our institution leading to a high number of available samples. For eligible patients with available biopsy specimens, histopathologic analysis was conducted. Staining of biopsy specimens was performed with standard hematoxylin and eosin and SSTR2 IHC stains. The biopsy specimens were cut into up to 2 µm thin slices of the bronchoscopic samples and stained by IHC using a polyclonal antibody for SSTR2 (dilution 1:50, incubation time at 36 °C for 40 min, Zytomed Systems, Berlin, Germany). The automated system used for staining was the Ventana Benchmark Ultra in combination with an Optiview DAB IHC detection kit for visualization (Roche, Basel, Switzerland). The staining results were visually evaluated by two experienced pathologists (D.T. and T.H.) who were blinded to the imaging findings. The scoring system used for SSTR2 staining results employed a 4-level scale (SSTR2 score 0: negative, 1: 1-29%, 2: 30-69%, 3: ≥70%), providing a systematic assessment of SSTR2 expression. The SSTR2 score of the examined IHC specimens was correlated with SUV max /TLR peak in 68 Ga-SSO120 PET on a lesion level. For this purpose, the lesion which was biopsied was specifically selected in the PET images to determine its uptake parameters (only in patients with at least one day difference between 68 Ga-SSO120 PET and 18 F-FDG PET to avoid uptake interferences when performed on the same day).   We defined parameters indicative of tumor load (M status, number of lesions in 68 Ga-SSO120 PET, LDH), of SSTR2 expression (SSTR2 score in IHC, SUV max /TLR peak /whole-body tumor SUV mean /whole-body tumor TLR mean in 68 Ga-SSO120 PET), and combination parameters (SSTR-TV, TL-SSTR2). Moreover, two established parameters for survival prediction from 18 F-FDG PET (MTV and TLG ) were used for validation. Primary study endpoints were correlation of SSTR2 expression assessed by IHC with SUV max /TLR peak in 68 Ga-SSO120 PET on a lesion-level and correlation of SSTR2 expression (assessed by IHC and 68 Ga-SSO120 PET) with TTF and OS. Secondary endpoints included correlation of parameters of tumor load, combination parameters, and MTV/TLG with OS and TTF, comparison of whole-body tumor SUV mean and SSTR-TV in 68 Ga-SSO120 PET with SUV mean and MTV in 18 F-FDG PET/CT, as well as assessment of patient-based mean 68 Ga-SSO120 uptake (assessed by mean TLR peak per patient) as surrogate of applicability of theranostic approaches. TTF was defined as the time from 68 Ga-SSO120 PET until the initiation of a second line therapy after documented disease progression or death. For patients without documented progression, TTF was censored on the date the patient was last known to be non-progressing after first-line therapy. OS was defined as the time from 68 Ga-SSO120 PET to the date of death; patients without documented death on the cut-off date were censored on the date the patient was last known to be alive. For imaging studies, different definitions of the starting date for calculation of OS and TTF are frequently used. As in this study the time from 68 Ga-SSO120 PET aligns with the time of recruitment and differs from the initiation of chemotherapy by a maximum several days, it is a precise and accurate point of reference.   For comparison of non-normally distributed data, a non-parametric Mann-Whitney U test was employed, with measures reported as median and interquartile range (QR). Beforehand, data was assessed for parametric distribution using the Shapiro-Wilk test. The correlation of SSTR2 expression in IHC and uptake in 68 Ga-SSO120 PET was evaluated using ANOVA analysis and the Spearman rank correlation coefficient; linear regression after semi-logarithmic transformation was performed to assess for exponential relationship. To determine the association of PET data, IHC SSTR2 score, LDH, and M status with survival data, uni- and multivariate Cox regression analyses were performed; median follow up was calculated by the reverse Kaplan-Meier method. Continuous variables were binarized using cut-off values that were identified on data for optimal separation and Hazard ratios (HR) with 95%-confidence intervals were calculated. For parameters of SSTR expression (primary endpoint), additional Cox regression analyses of continuous variables were calculated. The results of survival analyses are visually presented using Kaplan-Meier curves. Stratified Cox regression analyses were performed to account for different baseline hazards between patients with M0 or M1 status. Adjusted Kaplan Meier curves were used to adapt survival for confounding parameters of tumor load and clinical characteristics. In all statistical tests, p-values (p) <0.05 were regarded significant. All statistical evaluations were performed using R statistical software in version 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria, www.R-project.org). Cut-off values for binarization in Cox regression analyses were calculated using the surv_cutpoint function from the survminer package; adjusted Kaplan Meier curves were generated using the adjustedCurves package based on the direct standardization method . The graphical abstract was created using BioRender.com (BioRender, San Francisco, USA, www.BioRender.com).   The data generated in this study are available upon request from the corresponding author.   Patient Characteristics Between May 2022 and November 2023, a total of 66 patients underwent 68 Ga-SSO120 PET/CT for staging or restaging of SCLC at our institution (University Hospital Essen). Of these, 54 patients underwent 68 Ga-SSO120 PET/CT at initial staging and were included in this analysis. Database closure for survival status was end of January 2024. Evaluable additional staging 18 F-FDG PET/CT was available for 43 patients (75.4%). Figure shows a consort diagram depicting patient inclusion and study workflow. In the study cohort, both sexes were equally represented (24 men, 30 women) and median age was 65 years. According to the current TNM classification (World Health Organization WHO/International Association for the Study of Lung Cancer IALSC 8 th edition ), 7 patients were classified as stage IIIA (12.9%), 6 as IIIB (11.1%), 8 as IIIC (14.8%), and 33 as IV (61.1%); 21 patients without distant metastases (M0) showed limited disease (38.1%) and 33 with distant metastases (M1) extensive disease (61.1%) according to the Veterans Administration Lung Study Group (VALG) classification. Detailed patient characteristics are given in Supplemental . In first line, 21 patients received platinum-based chemotherapy (platinum/etoposid) and 33 patients a platinum-based chemo-immunotherapy combination (25 cisplatin/etoposid/durvalumab, 8 carboplatin/etoposid/atezolizumab) according to current guidelines . The median number of first-line therapy cycles was 4. Median TTF was 9.5 mos (interquartile range QR: 7.3-14.9 mos) and median OS was 16.1 mos (QR: 13.0 mos - not estimable). Only 2 patients progressed during the first line therapy. However, at censoring point, 29 patients had progressed and 21 patients were deceased; 4 patients were lost to follow-up for OS. Median LDH was 263 U/l (QR: 217-345). PET Imaging Results All included patients had at least one SSTR2-positive lesion in 68 Ga-SSO120 PET with a median number of 7 detected lesions per patient (QR: 2-18). Median SUV max and TLR peak of the hottest lesion per patient were 13.1 (QR: 5.9-27.6) and 2.9 (QR: 1.4-8.1), respectively. Median SSTR-TV, TL-SSTR, whole-body tumor SUV mean , and whole-body tumor TLR mean were 96.7 mL (QR: 33.6-174.8 mL), 343.1 (QR: 128.5-827.0), 3.8 (QR: 2.7-11.5), and 1.5 (1.0-4.1), respectively. Median MTV was 103.3 mL (QR: 42.6-240.2 mL) and median TLG was 800.0 (QR: 253.0-1760.0). When comparing patients with M0 versus M1 status, the number of lesions was significantly higher in patients with M1 status. Also, tumor volumes (SSTR-TV and MTV) and TLG were higher in M1, almost reaching statistical significance. Parameters of SSTR2 expression and LDH were not significantly different between both groups. Detailed results are given in Table . A comparison of SSTR2-TV versus MTV and whole-body tumor SUV mean from 68 Ga-SSO120 PET versus 18 F-FDG PET revealed no correlation (scatter plots are presented in Supplemental ). Correlation of 68 Ga-SSO120 PET with SSTR2 expression in IHC A total of 43 specimens were available for IHC analysis. 21 patients (48.8%) were negative for SSTR2 expression in IHC (SSTR2 score 0), 8 patients (18.6%) were evaluated with low (SSTR2 score 1), 5 (11.6%) with intermediate (SSTR2 score 2), and 9 (20.9%) with high expression (SSTR2 score 3). In ANOVA analysis, SUV max and TLR peak values were significantly higher in lesions with higher SSTR2 score (p < 0.001) and a strong monotonical correlation was found between SSTR2 score in IHC and corresponding lesion SUV max (Spearman's rho 0.86, p < 0.001) and TLR peak (Spearman's rho 0.81, p < 0.001) in 68 Ga-SSO120 PET. Image examples and a boxplot representation of TLR peak values in patients with different SSTR2 score in IHC are shown in Figure . In-depth analysis indicated an exponential relationship between SUV max /TLR peak and SSTR2 score in IHC (R 2 for log transformed SUV max /TLR peak in linear regression: 0.76/0.70, details in Supplemental ). Univariate survival analyses Regarding the primary study endpoint, SSTR2 expression both in PET imaging and in IHC analysis was associated with shorter TTF and OS. Statistical significance was reached for SSTR2 score in IHC as well as for SUV max and TLR peak of the hottest lesion per patient and whole-body tumor TLR mean in 68 Ga-SSO120 PET. For example, a SSTR2 score ≥1 in IHC was associated with worse TTF (HR = 0.24, 95%CI: 0.09-0.64, p = 0.004) and OS (HR = 0.26, 95%CI 0.07-0.83, p = 0.023). The same holds for a high TLR peak (TTF: HR = 0.44 for TLR peak ≤ 2.9, 95% CI: 0.19-0.96, p = 0.038; OS: HR = 0.23, 95%CI: 0.07-0.71, p = 0.011). This trend was confirmed in analyses of continuous variables ( Supplemental ). Regarding secondary endpoints (analysis of non-SSTR2 co-variables), parameters indicating higher tumor load (M1 status, higher LDH, and higher number of lesions), combination parameters (higher SSTR-TV and higher TL-SSTR), and higher MTV/TLG showed an association with poorer survival, both in terms of TTF and OS. Here, statistical significance was reached for M status, LDH, MTV, and TLG. Patients with metastasized disease showed a significantly shorter TTF (HR = 0.31, 95%CI: 0.12-0.74, p = 0.004) and OS (HR = 0.34, 95%CI: 0.12-0.95, p = 0.04), while patients with higher TLG exhibited a significantly shorter OS (HR = 0.25, 95%CI: 0.08-0.75, p = 0.01). Details showing median TTF and OS for all parameters are given in Table . Kaplan-Meier curves for M status, SSTR2 score in IHC, TLR peak of the hottest lesion, and TLG are shown in Figure A and Supplemental A . Stratified and multivariate survival analyses To account for different baseline hazards, stratified Cox regression analysis for M status was performed for all parameters that showed significant associations in univariate analyses (SSTR2 score, SUV max and TLR peak of the hottest lesion, whole-body tumor TLR mean , LDH, MTV, and TLG). In the stratified analysis, TLR peak of the hottest lesion and TLG yet showed a significant association with shorter OS (TLR peak : HR = 0.30, 95%CI: 0.09-0.97, p = 0.0431; TLG: HR = 0.29, 95%CI: 0.09-0.92, p = 0.034), while SSTR2 expression in IHC yet showed a significant association with shorter TTF (HR = 0.32, 95%CI: 0.12-0.87, p = 0.024). Detailed results are shown in Supplemental . SSTR2 score and TLR peak of the hottest lesion, the IHC- and 68 Ga-SSO120 PET-derived parameters of SSTR2-expression that showed best significant association with survival, were analyzed in separate multivariate Cox regression with demography- and tumor burden-associated co-variables (sex, age larger/smaller than median, M stage, and LDH). Higher SSTR2 score in IHC and higher TLR peak of the hottest lesion still showed a significant association with shorter survival. In detail, higher TLR peak was associated with significantly shorter OS (HR = 0.26, 95%CI: 0.08-0.84, p = 0.02), and SSTR2 expression in IHC with significantly shorter TTF (HR = 0.24, 95%CI: 0.08-0.71, p = 0.001) and OS (HR = 0.22, 95%CI: 0.06-0.84, p = 0.03). Forest plots providing detailed results are shown in Figure B and Supplemental B and S4. Adjusted Kaplan Meier plots (adjusted for the same co-variates) are shown in Supplemental A and S5B. In these visualizations, SSTR2 expression showed a correlation with poorer survival: Patients with higher TLR peak of the hottest lesion exhibited a shorter adjusted median OS (13.1 mos versus 18.1 mos, 95%CI: 8.5-16.3 mos versus 14.8 mos - not estimable) and TTF (7.9 mos versus 14.8 mos, 95%CI: 6.2-10.8 mos versus 8.1-16.5 mos). Analysis of mean tumor SSTR2 expression Clustering patients according to their whole-body tumor TLR mean as a surrogate parameter to identify possible candidates for radioligand therapy revealed 12 patients (22.2%) with low mean TLR mean (<1), 21 patients (38.9%) with intermediate mean TLR mean (≥1 but <2), 14 patients (25.9%) with high mean TLR mean (≥2 but <5), and 7 patients (13.0%) with very high mean TLR mean (≥5). In this classification 42 patients (77.8%) with intermediate, high, and very high uptake exhibited higher mean uptake than liver uptake and could, therefore, be potential candidates for PRRT. Figure shows image examples of patients with different uptake levels as assessed by 68 Ga-SSO120 PET and the distribution of different uptake groups.   Between May 2022 and November 2023, a total of 66 patients underwent 68 Ga-SSO120 PET/CT for staging or restaging of SCLC at our institution (University Hospital Essen). Of these, 54 patients underwent 68 Ga-SSO120 PET/CT at initial staging and were included in this analysis. Database closure for survival status was end of January 2024. Evaluable additional staging 18 F-FDG PET/CT was available for 43 patients (75.4%). Figure shows a consort diagram depicting patient inclusion and study workflow. In the study cohort, both sexes were equally represented (24 men, 30 women) and median age was 65 years. According to the current TNM classification (World Health Organization WHO/International Association for the Study of Lung Cancer IALSC 8 th edition ), 7 patients were classified as stage IIIA (12.9%), 6 as IIIB (11.1%), 8 as IIIC (14.8%), and 33 as IV (61.1%); 21 patients without distant metastases (M0) showed limited disease (38.1%) and 33 with distant metastases (M1) extensive disease (61.1%) according to the Veterans Administration Lung Study Group (VALG) classification. Detailed patient characteristics are given in Supplemental . In first line, 21 patients received platinum-based chemotherapy (platinum/etoposid) and 33 patients a platinum-based chemo-immunotherapy combination (25 cisplatin/etoposid/durvalumab, 8 carboplatin/etoposid/atezolizumab) according to current guidelines . The median number of first-line therapy cycles was 4. Median TTF was 9.5 mos (interquartile range QR: 7.3-14.9 mos) and median OS was 16.1 mos (QR: 13.0 mos - not estimable). Only 2 patients progressed during the first line therapy. However, at censoring point, 29 patients had progressed and 21 patients were deceased; 4 patients were lost to follow-up for OS. Median LDH was 263 U/l (QR: 217-345).   All included patients had at least one SSTR2-positive lesion in 68 Ga-SSO120 PET with a median number of 7 detected lesions per patient (QR: 2-18). Median SUV max and TLR peak of the hottest lesion per patient were 13.1 (QR: 5.9-27.6) and 2.9 (QR: 1.4-8.1), respectively. Median SSTR-TV, TL-SSTR, whole-body tumor SUV mean , and whole-body tumor TLR mean were 96.7 mL (QR: 33.6-174.8 mL), 343.1 (QR: 128.5-827.0), 3.8 (QR: 2.7-11.5), and 1.5 (1.0-4.1), respectively. Median MTV was 103.3 mL (QR: 42.6-240.2 mL) and median TLG was 800.0 (QR: 253.0-1760.0). When comparing patients with M0 versus M1 status, the number of lesions was significantly higher in patients with M1 status. Also, tumor volumes (SSTR-TV and MTV) and TLG were higher in M1, almost reaching statistical significance. Parameters of SSTR2 expression and LDH were not significantly different between both groups. Detailed results are given in Table . A comparison of SSTR2-TV versus MTV and whole-body tumor SUV mean from 68 Ga-SSO120 PET versus 18 F-FDG PET revealed no correlation (scatter plots are presented in Supplemental ).   68 Ga-SSO120 PET with SSTR2 expression in IHC A total of 43 specimens were available for IHC analysis. 21 patients (48.8%) were negative for SSTR2 expression in IHC (SSTR2 score 0), 8 patients (18.6%) were evaluated with low (SSTR2 score 1), 5 (11.6%) with intermediate (SSTR2 score 2), and 9 (20.9%) with high expression (SSTR2 score 3). In ANOVA analysis, SUV max and TLR peak values were significantly higher in lesions with higher SSTR2 score (p < 0.001) and a strong monotonical correlation was found between SSTR2 score in IHC and corresponding lesion SUV max (Spearman's rho 0.86, p < 0.001) and TLR peak (Spearman's rho 0.81, p < 0.001) in 68 Ga-SSO120 PET. Image examples and a boxplot representation of TLR peak values in patients with different SSTR2 score in IHC are shown in Figure . In-depth analysis indicated an exponential relationship between SUV max /TLR peak and SSTR2 score in IHC (R 2 for log transformed SUV max /TLR peak in linear regression: 0.76/0.70, details in Supplemental ).   Regarding the primary study endpoint, SSTR2 expression both in PET imaging and in IHC analysis was associated with shorter TTF and OS. Statistical significance was reached for SSTR2 score in IHC as well as for SUV max and TLR peak of the hottest lesion per patient and whole-body tumor TLR mean in 68 Ga-SSO120 PET. For example, a SSTR2 score ≥1 in IHC was associated with worse TTF (HR = 0.24, 95%CI: 0.09-0.64, p = 0.004) and OS (HR = 0.26, 95%CI 0.07-0.83, p = 0.023). The same holds for a high TLR peak (TTF: HR = 0.44 for TLR peak ≤ 2.9, 95% CI: 0.19-0.96, p = 0.038; OS: HR = 0.23, 95%CI: 0.07-0.71, p = 0.011). This trend was confirmed in analyses of continuous variables ( Supplemental ). Regarding secondary endpoints (analysis of non-SSTR2 co-variables), parameters indicating higher tumor load (M1 status, higher LDH, and higher number of lesions), combination parameters (higher SSTR-TV and higher TL-SSTR), and higher MTV/TLG showed an association with poorer survival, both in terms of TTF and OS. Here, statistical significance was reached for M status, LDH, MTV, and TLG. Patients with metastasized disease showed a significantly shorter TTF (HR = 0.31, 95%CI: 0.12-0.74, p = 0.004) and OS (HR = 0.34, 95%CI: 0.12-0.95, p = 0.04), while patients with higher TLG exhibited a significantly shorter OS (HR = 0.25, 95%CI: 0.08-0.75, p = 0.01). Details showing median TTF and OS for all parameters are given in Table . Kaplan-Meier curves for M status, SSTR2 score in IHC, TLR peak of the hottest lesion, and TLG are shown in Figure A and Supplemental A .   To account for different baseline hazards, stratified Cox regression analysis for M status was performed for all parameters that showed significant associations in univariate analyses (SSTR2 score, SUV max and TLR peak of the hottest lesion, whole-body tumor TLR mean , LDH, MTV, and TLG). In the stratified analysis, TLR peak of the hottest lesion and TLG yet showed a significant association with shorter OS (TLR peak : HR = 0.30, 95%CI: 0.09-0.97, p = 0.0431; TLG: HR = 0.29, 95%CI: 0.09-0.92, p = 0.034), while SSTR2 expression in IHC yet showed a significant association with shorter TTF (HR = 0.32, 95%CI: 0.12-0.87, p = 0.024). Detailed results are shown in Supplemental . SSTR2 score and TLR peak of the hottest lesion, the IHC- and 68 Ga-SSO120 PET-derived parameters of SSTR2-expression that showed best significant association with survival, were analyzed in separate multivariate Cox regression with demography- and tumor burden-associated co-variables (sex, age larger/smaller than median, M stage, and LDH). Higher SSTR2 score in IHC and higher TLR peak of the hottest lesion still showed a significant association with shorter survival. In detail, higher TLR peak was associated with significantly shorter OS (HR = 0.26, 95%CI: 0.08-0.84, p = 0.02), and SSTR2 expression in IHC with significantly shorter TTF (HR = 0.24, 95%CI: 0.08-0.71, p = 0.001) and OS (HR = 0.22, 95%CI: 0.06-0.84, p = 0.03). Forest plots providing detailed results are shown in Figure B and Supplemental B and S4. Adjusted Kaplan Meier plots (adjusted for the same co-variates) are shown in Supplemental A and S5B. In these visualizations, SSTR2 expression showed a correlation with poorer survival: Patients with higher TLR peak of the hottest lesion exhibited a shorter adjusted median OS (13.1 mos versus 18.1 mos, 95%CI: 8.5-16.3 mos versus 14.8 mos - not estimable) and TTF (7.9 mos versus 14.8 mos, 95%CI: 6.2-10.8 mos versus 8.1-16.5 mos).   Clustering patients according to their whole-body tumor TLR mean as a surrogate parameter to identify possible candidates for radioligand therapy revealed 12 patients (22.2%) with low mean TLR mean (<1), 21 patients (38.9%) with intermediate mean TLR mean (≥1 but <2), 14 patients (25.9%) with high mean TLR mean (≥2 but <5), and 7 patients (13.0%) with very high mean TLR mean (≥5). In this classification 42 patients (77.8%) with intermediate, high, and very high uptake exhibited higher mean uptake than liver uptake and could, therefore, be potential candidates for PRRT. Figure shows image examples of patients with different uptake levels as assessed by 68 Ga-SSO120 PET and the distribution of different uptake groups.   This study endeavors to comprehensively investigate the potential of 68 Ga-SSO120 PET as a biomarker in order to offer an innovative radiotheranostic approach in patients with SCLC. It is the largest study so far to describe the use of SSTR-antagonist PET in SCLC. Primary aim of the study was to enhance the understanding of SSTR2 expression in SCLC in correlation with histopathology, standard of care molecular imaging, and patient outcomes, ultimately contributing to improved personalized management strategies for SCLC patients. Regarding the first primary study endpoint, a significant correlation between SSTR2 expression in IHC and uptake values in 68 Ga-SSO120 PET was shown ( Figure and Supplemental ). This validates that 68 Ga-SSO120 PET reliably visualizes SSTR2 expression in SCLC, so that PET imaging can be used to assess whole-body target expression and select patients in a theranostic setting. PET-guided biopsy could reduce sampling errors and overcome limitations of temporal and spatial tumor heterogeneity. In addition, it could pave the way for theranostic approaches in both metastasized and non-metastasized disease stages of SCLC. Regarding the second primary study endpoint, SSTR2 expression, as detected by both 68 Ga-SSO120 PET and IHC, was significantly correlated with shorter TTF and OS ( Figure and Supplemental ), suggesting its potential as a prognostic marker in SCLC. This result could be influenced by differences in SSTR2 expression between patients with M0 and M1 status as well as different baseline hazards. To account for these factors, we conducted various analyses: Firstly, parameters of SSTR2 expression were not significantly different between these two groups ( Table ). Secondly, the effect of poorer survival in patients with high SSTR2 expression was also evident in Cox regression stratified for M status ( Supplemental ), in multivariate Cox regression ( Figure B, Supplemental B, Supplemental ), and in adjusted Kaplan Meier curves ( Supplemental ). RNA sequencing results from other recent studies, for example by Lehman et al. , also suggest that high SSTR2 expression correlates with unfavorable outcomes in non-metastasized SCLC, emphasizing a role of SSTR2 signaling in progression and survival of tumor cells. This could be a sign of SSTR2-expression in SCLC being indicative of immune evasion and increased tumor cell invasiveness , contradicting earlier assumptions derived from NETs, which assumed that SSTR2-expression could indicate less aggressive tumors and a potential for favoring apoptosis . This trend is underlined by recent literature stating that absence of SSTR2 expression could activate apoptosis through alternate pathways . These observations may hint at different roles of SSTR2-related molecular pathways in different cancer types . There is a very limited, increasing though, number of studies, which tried to explore the prognostic role of SSTR expression both in SCLC and other tumor entities. In SCLC, Sen et al. and Lapa et al. did not find any statistic significant correlation between SSTR expression and survival. On the other hand, comparable studies in nasopharyngeal carcinomas, gliomas, and thymic carcinomas suggested a negative correlation , , in alignment with our study. With regards to the secondary study endpoints (influence of non-SSTR2 co-variables), M status, LDH, as well as MTV and TLG derived from 18 F-FDG PET were also significantly associated with poorer TTF and OS ( Table , Supplemental A and Figure ). This is in line with previous results for these markers of tumor burden and metabolic activity . LDH and TLG were also significant prognosticators in multivariate or stratified analyses. About 40% of patients exhibited high or very high 68 Ga-SSO120 uptake as assessed by their whole-body tumor TLR mean ( Figure ). This validates the findings of a preliminary study in a smaller patient subcohort of this study conducted by our group , wherein we additionally showcased comparable detection rates between 68 Ga-SSO120 and 18 F-FDG PET. This underscores the effectiveness of both imaging modalities for the initial staging of SCLC. In the realm of personalized medicine and theranostic options, understanding the molecular underpinnings of SCLC tumor biology is crucial for selecting the optimal therapy. In this context, the high uptake in a relevant fraction of patients shows the potential of SSTR-targeted therapies in this patient group. Possible SSTR-targeting therapeutic options comprise (long-acting) somatostatin analogues like lanreotide which are successfully applied in GEP-NETs and pulmonary NETs and targeted radionuclide therapy . Nevertheless, in SCLC patients only few applications of somatostatin analogues - or SSTR-agonist PRRT , - were described and remained without sufficient results for wide clinical applications. For example, Sen et al. reported on a total of 67 patients with advanced SCLC who were screened with 68 Ga-DOTATATE PET/CT. About 50% showed mainly SSTR-positive lesions, however, in contrast to the evaluation at primary staging in our study, an association with survival outcome was not demonstrated. PRRT was performed in 14 patients, resulting in disease control in 5/13 (about 40%) of patients . Kim et al. enrolled 6 patients with extensive SCLC for a combination therapy of 177 Lu-DOTATATE with nivolumab; one patient showed a partial response, indicating a favorable efficacy profile and antitumor activity . These data indicate the potential of SSTR-targeted PRRT in patients with SCLC. Moreover, addition of 177 Lu-DOTATATE to first line chemoimmunotherapy in patients with extensive-disease SCLC in a multi-modal treatment concept is currently investigated in a phase 1 trial (CAAA601A42101, ClinicalTrials registration NCT05142696). Furthermore, a phase 1 trial analyzes RYZ101 ( 225 Ac-DOTATATE), an alpha-emitting radiopharmaceutical , in a comparable setting (ClinicalTrials registration NCT05595460). On the other hand, radiolabeled SSTR2-antagonists exhibit improved pharmacokinetic properties and can offer promising novel therapeutic options , bearing the potential of improved response rates because of increased tumor uptake and longer residence times . For NET patients, tumor doses for 177 Lu-SSO110 were increased by a factor of up to ten compared to 177 Lu-DOTATATE . Therefore, in SCLC patients with sufficient uptake in PET imaging, SSTR2-antagonist PRRT might be considered in a multi-modal theranostic approach. Notably, mean tumor 68 Ga-SSO120 uptake was larger than liver uptake in almost 80% of patients ( Figure ), which is a typical criterion to evaluate eligibility of patients for radionuclide therapies (Krenning score ).This indicates that SSTR-antagonist theranostics could open up a promising novel therapeutic option for maintenance or consolidation in patients with both M0 and M1 SCLC, particularly intriguing as higher expression of the target was associated with poorer OS and faster progression. Until now, no study results of SSTR-antagonist PRRT in SCLC have been described. An ongoing phase Ib study investigates addition of 177 Lu-SSO110 to maintenance therapy in extensive stage SCLC (protocol presented at European Association of Nuclear Medicine annual meeting 2023). In patients with NETs, a prospective phase I and a prospective phase I/II trial investigated 177-Lu-SSO110 and showed promising clinical efficacy , . Moreover, the PROMENADE trial compared 177 Lu-SSO110 treatment with the more established 177 Lu-DOTATOC therapy in the same patients with progressive standard-therapy refractory meningioma showing a favorable therapeutic index with high disease control rate . Collectively, these findings support that 68 Ga-SSO120 PET holds promise for the characterization and prognostication of SCLC and could possibly open novel theranostic opportunities. However, special attention might have to be taken on strategies to mitigate adverse effects. For example, in the phase I trial in NET patients, after the 2nd cycle of 177 Lu-SSO110 therapy, grade 4 hematologic toxicity occurred in four of seven (57%) patients. After adjustment of dose and treatment intervals restricting the cumulative absorbed bone marrow dose to 1 Gy possible hematologic toxicity was resolved . This indicates that SSTR-antagonist PRRT can be possible under careful surveillance and individual selection of treatment dosage. Future research might focus on the evaluation of patients in later therapy lines to validate the target expression against the background of possible clonal evolution and heterogenous uptake patterns. In future, molecular imaging with various tracers might be performed in individual patients to select the optimal theranostic targets. SSTR-antagonists belong to the substances with highest potential due to high expression levels in a large number of patients. Main limitation of the study is the yet limited number of included patients, although it is a large cohort for this tumor entity. Therefore, multivariate survival analyses in comparison to 18 F-FDG PET-derived parameters were not performed. Moreover, not all parameters of SSTR-expression were statistically significant predictors of OS and TTF in all analyses. However, the prognostic significance of established parameters like M status and TLG/MTV (the latter in univariate analysis) indicate the validity of the obtained results. Future (prospective) studies with longer follow-up are warranted to investigate SSTR2-antagonist molecular imaging and targeted therapy in patients with SCLC.   In patients with SCLC, SSTR2 expression assessed by 68 Ga-SSO120 PET and by IHC were closely correlated and associated with shorter survival. More than 75% of patients showed higher whole-body 68 Ga-SSO120 tumor uptake than liver uptake and almost 40% high or very high uptake, possibly paving the way towards theranostic applications.   Supplementary figures and tables.   