Abstract
Pancreatic neuroendocrine tumors (pNETs) are rare and heterogeneous. Well-differentiated G1/G2 pNETs typically express somatostatin receptors (SSTRs), making them responsive to somatostatin analogue (SSA) therapy. However, therapeutic options become limited once SSTR expression decreases. This case report describes a 55-year-old man with grade 2 pNET who developed multiple liver metastases after undergoing pancreaticoduodenectomy in 2015. From August 2019 to October 2020, he received long-acting octreotide and transarterial chemoembolization (TACE), achieving stable disease. However, in August 2022, MRI scans indicated disease progression, leading to discontinuation of octreotide. In September 2022, oral surufatinib was initiated but paused in September 2023 due to adverse effects. In January 2024, everolimus therapy was started, resulting in a partial response by April 2024, with a significant reduction in liver metastases. Due to small intestinal ulcers, the dose of everolimus was reduced in August 2024. Follow-up scans showed stable disease through January 2025. In February 2025, [68Ga]Ga-DOTATATE PET/CT scans revealed significant re-expression of SSTR2 in liver lesions, likely induced by everolimus, allowing reinitiation of SSA therapy with increased octreotide dosage. This case demonstrates that everolimus can induce SSTR re-expression in advanced, SSTR-negative pNETs, offering new therapeutic possibilities. The “induction plus re-evaluation” approach could guide personalized treatment strategies in late-stage pNETs, although further studies are needed to validate this approach.
1 Background
Pancreatic neuroendocrine tumors (pNETs) are rare, and highly heterogeneous solid tumors that originate from the endocrine cells of the pancreas. They are characterized by the ability to secrete various hormones or neuropeptides, and account for approximately 1%–2% of all pancreatic neoplasms (). With the ongoing advances in molecular imaging, laboratory diagnostics, and clinical awareness, the detection rates of pNETs have increased in recent years. However, their pathogenesis remains incompletely understood and involves a complex interplay of molecular events, including dysregulated gene expression, chromosomal deletions, and tumor suppressor gene methylation ().
Somatostatin receptors (SSTRs) are G-protein-coupled receptors that mediate the inhibitory effects of somatostatin on hormone secretion and cell proliferation. Among the five subtypes, SSTR2 is predominantly expressed in neuroendocrine tumors NETs and is crucial for targeted therapies (). Somatostatin analogs (SSAs), such as octreotide and lanreotide, bind to SSTR2 to control hormone-related symptoms and inhibit tumor growth. Clinical studies, including the PROMID and CLARINET trials, have demonstrated that SSAs or SSAs combined with transarterial chemoembolization (TACE) can significantly prolong progression-free survival in patients with well-differentiated NETs.
In well-differentiated G1/G2 pancreatic pNETs, SSTRs, particularly SSTR2, are highly expressed, making them ideal therapeutic targets for SSAs like long-acting octreotide. These therapies not only offer symptomatic relief but also exert antiproliferative effects. The PROMID trial demonstrated that octreotide (30 mg monthly) significantly prolonged PFS in patients with metastatic midgut NETs, from 6 months (placebo) to 14.3 months (HR 0.34) (). Similarly, the CLARINET trial showed that lanreotide (120 mg every 4 weeks) improved PFS in patients with well-differentiated enteropancreatic NETs, the median PFS was not reached in the lanreotide group, compared to 18.0 months in the placebo group (HR 0.47) (). And SSAs are generally well-tolerated, with common side effects including gastrointestinal symptoms, hyperglycemia, and injection site reactions, serious adverse effects like cholelithiasis and bradycardia are rare.
For patients with liver metastases, the combination of SSA and transarterial chemoembolization (TACE) has been demonstrated to significantly prolong progression-free survival (PFS) and improve objective response rates, particularly in those with a high hepatic tumor burden ().
Additionally, the anti-angiogenic inhibitor surufatinib or the mTOR inhibitor everolimus are firstly considered for advanced SSTR-negative pNETs and for SSTR-positive pNETs when disease progresses following SSA therapy. The SANET-p phase III trial demonstrated that surufatinib extended the median PFS from 3.7 to 10.9 months, while everolimus improved median PFS from 4.6 to 11.0 months in the RADIANT-3 study (; ). Despite their efficacy, these targeted agents are frequently associated with adverse effects—including hypertension, proteinuria, oral ulcers, and bone marrow suppression—necessitating careful dose adjustment or treatment interruption based on individual tolerance ().
Despite the progress made in treating NET with SSA, surufatinib, and everolimus, patients still face significant challenges after disease progression (). There is a lack of standardized treatment options, and for those who progress after multiple lines of therapy, the prognosis is generally poor with limited survival ().
Recent findings reveal that everolimus can enhance the expression of the SSTR2 gene and protein in NET cell lines in vitro, offering new therapeutic prospects for lesions initially lacking SSTR expression (). Building on this “induction and reassessment” strategy, advanced SSTR-negative G2 pNET patients may first receive everolimus to restore receptor expression, followed by [68Ga]Ga-DOTATATE imaging to determine renewed eligibility for peptide receptor radionuclide therapy (PRRT) or SSA treatment. This approach may expand therapeutic options and potentially improve survival outcomes.
This case report highlights the clinical significance of everolimus-induced SSTR re-expression, leading to the reintroduction of SSA. It underscores the value of multidisciplinary care and dynamic pathological monitoring in pNET management and offers a meaningful reference for personalized treatment strategies in advanced disease.
2 Case presentation
A 55-year-old man presented with scleral icterus and weight loss. In August 2015, contrast-enhanced abdominal CT revealed a 4.5 cm × 3.4 cm soft-tissue mass at the pancreaticoduodenal junction with marked enhancement. He underwent pancreaticoduodenectomy with cholecystectomy; histopathology confirmed a pNET G2, with immunohistochemistry showing PCK (+), CD56 (+), CgA (+), Syn (+), somatostatin (−) and a Ki-67 index of ∼5%.
At the follow-up on 15 July 2019, contrast CT of the chest and abdomen demonstrated multiple arterial phases enhancing nodules in the liver and enlarged lymph nodes along the superior mesenteric artery and mesentery, suggestive of metastases. Percutaneous liver biopsy confirmed metastatic neuroendocrine tumor, with tumor cells positive for PCK (+), CD56 (+), Syn (+), CgA (+), SSTR2 (+) and a Ki-67 index of ∼2%. Physical examination was negative for flushing, rash, edema, or acromegaly. Laboratory studies showed hemoglobin 68 g/L; liver and renal function, tumor markers (AFP, CEA, CA 19-9, CA 125, NSE), stool and urine tests were unremarkable. He had a 10-year history of hypertension, well controlled on medication. Multidisciplinary team (MDT) staging was pT3N1M0 (stage IIIB) pNET with multiple liver metastases (stage IV), suspected abdominal lymph-node involvement and, moderate anemia.
From August 2019, he received long-acting octreotide 30 mg every 4 weeks as first-line systemic therapy, combined with five sessions of transarterial chemoembolization (TACE) between 20 August 2019 and 30 October 2020. From December 2019 to February 2022, all response evaluations indicated stable disease (SD). No significant adverse events were observed; anemia improved to ∼110 g/L with iron supplementation. The August 2022 MRI showed an increased size of hepatic lesions; treatment response was assessed as progressive disease (PD), and octreotide microspheres were discontinued (Figure 1).
FIGURE 1
Second-line therapy began in September 2022, with surufatinib 300 mg daily. In the SANET III phase III trial, surufatinib significantly prolonged PFS in pNETs (). The MRI efficacy evaluations in January, June, and September 2023 all demonstrated SD (Figure 2). During treatment he developed mild-to-moderate proteinuria and anemia (hemoglobin 78 g/L). Considering the patient experienced intermittent melena in September 2023, after MDT discussion and temporary drug discontinuations he was screened for the “[177Lu]Lu-DOTATATE Injection versus Long-Acting Octreotide Study”. [68Ga]Ga-DOTATATE imaging demonstrated that some hepatic metastases were SSTR-negative, and he therefore failed screening (Figure 3). Surufatinib was resumed at a reduced dose of 200 mg daily. On 8 January 2024, the patient passed approximately 200 mL of dark red stool. A gastroscopy revealed multiple small-intestinal ulcers at the gastroenteric anastomosis site (A1 stage, Forrest III). After a comprehensive evaluation of efficacy and safety, surufatinib was discontinued.
FIGURE 2
FIGURE 3
In January 2024, third-line treatment with everolimus 10 mg daily was initiated. Everolimus, an oral mTOR inhibitor, has been shown in RADIANT-3 and RADIANT-4 to significantly delay progression of advanced pNETs (). In April and July 2024, CT scans demonstrated shrinkage of most hepatic lesions, with the treatment response assessed as a partial response (PR). However, owing to multiple small-intestinal ulcers at that time, the everolimus dose was reduced to 5 mg once daily in August 2024. Subsequent CT re-evaluations in October 2024 and January 2025 both showed SD (Figure 4).
FIGURE 4
The MDT recommended repeating [68Ga]Ga-DOTATATE imaging to reassess tumor burden and SSTR2 expression. On 12 February 2025, [68Ga]Ga-DOTATATE uptake in multiple hepatic metastases was markedly increased, indicating SSTR2 upregulation following everolimus therapy (Figure 3; Supplementary Tables S1, S2). The patient was then re-screened for the “[177Lu]Lu-DOTATATE Injection versus Long-Acting Octreotide Study” and was randomized to the control arm, receiving 60 mg of long-acting octreotide every 4 weeks, and a CT performed in May 2025 showed SD on response assessment (Supplementary Figures S1, S2).
3 Discussion
First-line therapy for advanced pNETs typically includes SSAs to control tumor proliferation and symptoms, with optimal efficacy in SSTR-positive grade 1/2 NETs (; ). Upon disease progression, the patient received surufatinib and everolimus. Surufatinib, a multikinase inhibitor targeting VEGFR and other receptors, suppresses angiogenesis and tumor growth (). In the SANET-p phase III trial, surufatinib significantly improved PFS in pNETs (). However, common adverse events—hypertension and proteinuria—require close monitoring; this patient’s surufatinib discontinuation underscores interpatient variability in tolerability. Following surufatinib cessation, everolimus was chosen as third-line therapy. In RADIANT-3, everolimus extended median PFS in advanced pNETs from 4.6 to 11.0 months (). Our patient achieved a PR with everolimus, demonstrating both efficacy and tolerability.
Notably, this patient exhibited dynamic changes in SSTR expression during everolimus treatment. Pre-treatment [68Ga]Ga-DOTATATE imaging showed negligible uptake, indicating low SSTR expression often seen in poorly differentiated or highly proliferative NETs (). After several months of everolimus, hepatic lesions regained high SSTR expression and “lit up” on imaging—a phenomenon of SSA receptor re-expression that has gained attention ().
Quantitatively, although SUV_max values of 10–40 are common in well-differentiated NETs, outliers with very high uptake have been reported on [^68Ga]Ga-DOTATATE PET/CT (tumor SUV_max up to 118), so the value of 83.08 observed here falls within published extremes (). Our two studies were acquired on the same system with ∼60-min uptake times and similar activities, consistent with current SNMMI/EANM procedure standards; thus, protocol differences are unlikely to explain the increase (). The marked rise is more plausibly attributed to high post-treatment SSTR2 availability and favorable background activity (with normal spleen and liver SUVs in the expected ranges), as reflected by elevated tumor-to-liver and tumor-to-spleen ratios now detailed in Supplementary Tables S1, S2.
Beyond mTOR inhibitors, case reports suggest that CAPTEM (capecitabine + temozolomide) chemotherapy may similarly induce SSTR re-expression. One study described increased SSTR expression post-CAPTEM and explored mechanisms involving cell‐cycle alterations and DNA damage responses (). Collectively, these findings point to a “receptor restoration” phenomenon: systemic therapies can render initially SSTR-negative tumors receptor-positive, offering new therapeutic opportunities for refractory NET patients.
Although we could not obtain post-everolimus tumor tissue to confirm SSTR2 re-expression directly, several compelling lines of evidence support its plausibility. In bronchopulmonary NET lines (H720/H727), combined PI3K/mTOR inhibition with low-dose everolimus increased SSTR2 mRNA and immunoreactive score by > 2-fold, paralleled by heightened lanreotide sensitivity (). Earlier pancreatic-NET work showed that adding nanomolar everolimus to BYL-719 boosted SSTR2 transcription 12-fold in BON-1 and 1.5-fold in QGP-1 cells, quantified by RT-qPCR (). Murine xenograft models likewise displayed higher tumor-to-background ratios on [68Ga]Ga-DOTATATE PET after everolimus, consistent with drug-induced SSTR2 gene upregulation (). A multi-tumor xenograft model showed that everolimus pretreatment markedly increased cell-surface GPCR density, boosting radiolabeled minigastrin uptake and prolonging survival after PRRT (). Collectively, these studies justify prospective evaluation of an “everolimus-induction →SSA/PRRT” sequence and frame our single-patient observation within an emerging body of molecular evidence.
Current guidance agrees that PRRT with [^177Lu]Lu-DOTATATE is appropriate for metastatic or unresectable NETs provided the tumor is SSTR-positive on imaging (; ). Importantly, none of the major guidelines or labels list “re-expressed” SSTR as a contraindication. Absolute contraindications include pregnancy or acute unstable illness, whereas relative contraindications primarily involve severe renal or bone marrow involvement. In our patient, renewed SSTR2 positivity met the imaging criterion, and there were no biological or safety-based barriers to PRRT—the choice of SSA instead reflected adherence to the randomized trial protocol. The phase III COMPETE trial directly compared [^177Lu]Lu-edotreotide versus everolimus in SSTR-positive G1/2 GEP-NETs, demonstrating superior efficacy and safety for PRRT (median PFS 23.9 vs. 14.1 months) (). The present case suggests that an “induction + re-evaluation” approach—using everolimus to upregulate SSTR followed by repeat imaging—could allow PRRT or SSA rechallenge in patients originally deemed ineligible, thereby extending treatment options.
However, everolimus-induced re-expression of SSTR2 is supported only by preclinical work and a handful of small case series, including the present report. As a single-patient observation, our data are subject to selection bias and cannot reflect the biological and clinical heterogeneity of pancreatic neuroendocrine tumors. Variables such as tumor grade, molecular profile, prior treatments, and comorbidities may all modulate SSTR dynamics and treatment response. Rigorous validation will require prospective studies that serially measure SSTR2 gene and protein levels before and after everolimus and that test a sequenced “everolimus induction → PRRT/SSA” approach on survival outcomes in larger, well-characterised cohorts. If confirmed, such a strategy could shift NET management from passive tumor control toward deliberately priming tumors for more effective subsequent therapies.
4 Conclusion
In summary, this case underscores the importance of individualized, multidisciplinary management for pNETs and highlights the plasticity of tumor biology. Everolimus may upregulate SSTR expression, thereby creating a therapeutic window for receptor-targeted therapies in patients who were initially ineligible. Clinicians should therefore collaborate across specialties to develop personalized treatment plans and, when disease progresses, reconsider the tumor’s molecular imaging and biological profile. As the mechanisms underlying this “receptor re-expression” phenomenon are elucidated, we may be able to integrate it routinely into clinical practice and further improve outcomes for patients with neuroendocrine tumors.
Statements
Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.
Ethics statement
The studies involving humans were approved by The studies involving humans were approved by bioethics review board of West China Hospital, Sichuan University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author contributions
PZ: Writing – original draft. CZ: Writing – original draft. HX: Writing – review and editing. DC: Writing – review and editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This study was supported by Sichuan Science and Technology Program (2023NSFSC1895, 2025ZNSFSC1908) and the “Qimingxing” Research Fund for Young Talents (HXQMX0085) and the National Key Research and Development Program of China (2024YFB3311700).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fcell.2025.1658256/full#supplementary-material
Abbreviations
[68Ga]Ga-DOTATATE, Gallium-68-labeled DOTA-D-Phe1-Tyr3-octreotate; [177Lu]Lu-DOTATATE, Lutetium-177-labeled DOTA-D-Phe1-Tyr3-octreotate; CAPTEM, Capecitabine + Temozolomide; CD56, Cluster of Differentiation 56; CgA, Chromogranin A; GEP-NETs, Gastroenteropancreatic Neuroendocrine Tumors; Ki-67, A protein associated with cell proliferation; mTOR, Mammalian Target of Rapamycin; MRI, Magnetic Resonance Imaging; PD, Progressive Disease; PFS, Progression-Free Survival; PCK, Pancreatic Cytokeratin; PR, Partial Response; PRRT, Peptide Receptor Radionuclide Therapy; SD, Stable Disease; SSTR2, Somatostatin Receptor Subtype 2; SSTRs, Somatostatin Receptors; SSAs, Somatostatin Analogs; TACE, Transarterial Chemoembolization; VEGFR, Vascular Endothelial Growth Factor Receptor.
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Summary
Keywords
somatostatin receptor (SSTR), metastatic pancreatic neuroendocrine tumor, everolimus, SSA, PRRT
Citation
Zhang P, Zhang C, Xu H and Cao D (2025) A case report: enhanced somatostatin receptor expression in metastatic pancreatic neuroendocrine tumor following everolimus therapy. Front. Cell Dev. Biol. 13:1658256. doi: 10.3389/fcell.2025.1658256
Received
02 July 2025
Accepted
10 October 2025
Published
24 October 2025
Volume
13 - 2025
Edited by
Donatella Delle Cave, National Research Council (CNR), Italy
Reviewed by
Tabish Hasan Khan, Washington University in St. Louis, United States
Behrooz Hooshyar Yousefi, University of Marburg, Germany
Updates
Copyright
© 2025 Zhang, Zhang, Xu and Cao.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Dan Cao, caodan@scu.edu.cn; Huanji Xu, xuhuanji1990@163.com
† These authors have contributed equally to this work
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.