bims-necame 2025-12-07 papers

bims-necame

Biomed News

on Metabolism in small cell neuroendocrine cancers

Issue of 2025–12–07
twelve papers selected by
Grigor Varuzhanyan, UCLA

Small cell neuroendocrine carcinoma of the cervix: diagnostic challenges and emerging molecular insights†.
Advancing small cell lung cancer metastasis research: innovations in preclinical mouse models.
PROCA11 early activation fuels prostate cancer neuroendocrine traits by regulating cell survival and migration.
Prognostic role of prognostic nutritional index change in patients with extensive stage small cell lung cancer treated with platinum-based chemotherapy.
KDM4A promotes NEPC progression through regulation of MYC expression.
Nitrobenzoyl-insulicolide A: a novel dinitrobenzoyl sesquiterpenoid, induces autophagic cell death in small cell lung cancer cells.
First-line immune checkpoint inhibitors combined with chemotherapy in advanced large-cell neuroendocrine carcinoma of the lung: a real-world retrospective study.
Clinical management and prognostic determinants of gallbladder neuroendocrine carcinoma: a single-institutional analysis of 31 cases.
IGFBP3-SphK1/S1P Signaling Axis Drives Enzalutamide Resistance in Advanced Prostate Cancer.
Chemoembolization using streptozotocin versus embolization in metastatic NETs.
Multi-omic profiling provides insights into the heterogeneity, microenvironmental features, and biomarker landscape of small-cell lung cancer.
Streptozotocin plus 5-fluorouracil followed by everolimus or the reverse sequence in patients with advanced pancreatic neuroendocrine tumors (SEQTOR-GETNE phase III study): a randomized clinical trial.

J Pathol. 2025 Nov 30.

Small cell neuroendocrine carcinoma of the cervix: diagnostic challenges and emerging molecular insights†.

Alphonse Charbel, Gaëlle Akiki, Sarah-Slim Diwan, Shuk On Annie Leung, Felix Kf Kommoss, Basile Tessier-Cloutier.

  Small cell neuroendocrine carcinoma of the cervix (SCNECC) is a rare and highly aggressive malignancy with poor prognosis that predominantly affects premenopausal women. Histopathological evaluation is central to diagnosis and clinical management; however, distinguishing SCNECC from other 'small blue round cell' malignancies often requires a multimodal approach that integrates morphology, immunohistochemistry, and advanced molecular testing. In the absence of specific and sensitive biomarkers, SCNECC largely remains a diagnosis of exclusion, underscoring the need for comprehensive diagnostic algorithms. A study by Pan, Yan, Yuan et al employed whole transcriptome profiling and identified three molecular subgroups within SCNECC. Importantly, one subgroup displayed an inflamed phenotype, characterized by high expression of MHC-II complex and IFN-α/β-related genes, suggesting potential susceptibility to immunotherapy, a finding that mirrors observations in small cell lung cancer. These findings highlight the biological heterogeneity of SCNECC and reinforce the importance of integrating molecular data to refine diagnostic accuracy and guide therapeutic decision-making. This commentary emphasizes the pressing need for comprehensive diagnostics and further research to advance treatment strategies for this rare and challenging malignancy. © 2025 The Pathological Society of Great Britain and Ireland.

Keywords:  cervix; gene expression; small cell neuroendocrine carcinoma; small round blue cell tumor; undifferentiated carcinoma

DOI:  https://doi.org/10.1002/path.6486
Cancer Metastasis Rev. 2025 Nov 29. 44(4): 86

Advancing small cell lung cancer metastasis research: innovations in preclinical mouse models.

Qiqi Zhao, Liang Hu, Hongbin Ji.

  Small cell lung cancer (SCLC) represents one of the most aggressive malignancies, featured with its extraordinary metastatic capacity. Preclinical mouse models have become indispensable systems for studying the molecular mechanisms underlying SCLC metastasis. This review summarizes recent advances in genetically engineered mouse models (GEMMs) and transplantation models for SCLC metastasis research, highlighting their unique advantages in investigating oncogenic drivers, tumor heterogeneity, immune interactions, and therapeutic responses. We further discuss emerging technologies capable of integrating with these models to advance both mechanistic and translational research. Lineage tracing and multi-omics approaches have provided unprecedented resolution in mapping clonal dynamics and phenotypic plasticity during SCLC metastasis. High-throughput in vivo screening has accelerated the systematic identification of novel metastasis regulators, and humanized mouse models offer clinically relevant systems for investigating human-specific tumor-immune interactions and supporting preclinical evaluation of immunotherapies. Collectively, these preclinical systems are reshaping our understanding of SCLC metastasis and providing powerful platforms to guide therapeutic discovery.

Keywords:  Allografts; Genetically engineered mouse models; Mouse models; Small cell lung cancer metastasis; Xenografts

DOI:  https://doi.org/10.1007/s10555-025-10301-2
iScience. 2025 Dec 19. 28(12): 113931

PROCA11 early activation fuels prostate cancer neuroendocrine traits by regulating cell survival and migration.

Rocco Cipolla, Marc Gabriel, Ugo Szachnowski, Zhimin Wang, Martina Romani, Giorgia Ianese Regin, Micaela Piemontese, Virginie Firlej, Marina Pinskaya, Antonin Morillon.

  Tumor plasticity drives the emergence of castration-resistant and neuroendocrine prostate cancer following androgen-deprivation therapy (ADT). Non-genetic determinants, including long non-coding (lnc)RNAs, preceding the acquisition of neuroendocrine traits, can disrupt androgen dependence and promote resistance. However, the precise transcriptome dynamics prior to therapy-induced neuroendocrine trans-differentiation remains unknown. Using a prostate cancer model mimicking the onset of castration-resistant and neuroendocrine phenotypes, we uncovered rapid lncRNA changes, with PROCA11 emerging as the most prominent. PROCA11 is highly expressed in advanced adenocarcinoma and neuroendocrine prostate cancer tumors. This predominantly nuclear lncRNA is rapidly activated upon hormone depletion and persists in neuroendocrine-like cells. PROCA11 promotes cell survival, proliferation, and motility by reducing apoptosis and enhancing adhesion, contributing to neuroendocrine traits. PROCA11 binds to the cell-cycle regulator CCAR2/DBC1 and to CTNNA1, controlling cell adhesion and cytoskeleton. We suggest that PROCA11 arises early during tumor plasticity and controls the development of castration-resistant and neuroendocrine phenotypes in prostate cancer.

Keywords:  Biological sciences; Cancer; Epigenetics; Genomics

DOI:  https://doi.org/10.1016/j.isci.2025.113931
BMC Cancer. 2025 Dec 02. 25(1): 1846

Prognostic role of prognostic nutritional index change in patients with extensive stage small cell lung cancer treated with platinum-based chemotherapy.

İrfan Buğday, Mevlüde İnanç, Metin Özkan, Oktay Bozkurt, Ramazan Coşar, Sedat Tarık Fırat, Emel Mutlu, Murat Eser, Ahmet Kürşad Dişli, Muhammet Cengiz.

   BACKGROUND: Small cell lung cancer (SCLC) accounts for approximately 15% of lung cancers and is characterized by rapid progression and early metastasis. The prognostic nutritional index (PNI), based on serum albumin and lymphocyte count, has emerged as a potential prognostic biomarker in various cancers.
OBJECTIVE: This study aimed to evaluate the prognostic value of changes in pre- and post-treatment PNI levels in patients with extensive-stage SCLC.
METHODS: A total of 177 treatment-naïve patients with extensive-stage SCLC diagnosed between September 2018 and October 2022 were included. Kaplan-Meier survival analysis and ROC curve analysis were used to assess overall survival (OS) and progression-free survival (PFS) according to PNI categories.
RESULTS: The median OS was 10.3 months and median PFS was 7.5 months in the entire cohort. Patients with persistently low PNI values had the poorest outcomes (median OS 6.4 months, PFS 5.7 months), whereas those with consistently high PNI values had the best prognosis (median OS 14.6 months, PFS 8.4 months; p < 0.001).
CONCLUSIONS: Dynamic changes in PNI are significantly associated with prognosis in extensive-stage SCLC. Patients with low pre- and post-treatment PNI values exhibited worse outcomes, while consistently high PNI predicted better survival. This study is the first to evaluate PNI changes in this patient population.

Keywords:  Extensive stage; Prognostic nutritional index; Small cell lung cancer

DOI:  https://doi.org/10.1186/s12885-025-15246-x
Cancer Lett. 2025 Nov 28. pii: S0304-3835(25)00756-6. [Epub ahead of print] 218184

KDM4A promotes NEPC progression through regulation of MYC expression.

Celia Sze Ling Mak, Ming Zhu, Jie Fu, Xin Liang, Xiaoxuan Wang, Fei Yuan, Feng Wang, Anh G Hoang, Xingzhi Song, Peter Shepherd, Derek Liang, Jessica Suh, Jordan Contreras, Thisawin Dang, Cindy Yan, Brandon Figueroa, Mathias Mazzocco, Athena Luo, Bijeta Pradhan, Jiwon Park, Mirrah Bashir, Miao Zhang, Eric Metzger, Roland Schüle, Abhinav K Jain, Ellen Karasik, Daniel Frigo, Barbara A Foster, Min Gyu Lee, Paul Corn, Christopher J Logothetis, Ana Aparicio, Nora Navone, Patricia Troncoso, Zhi Tan, Jianhua Zhang, Sue-Hwa Lin, Guocan Wang.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive and lethal subtype of prostate cancer (PCa) that often emerges in response to androgen receptor pathway inhibitors (ARPIs), which are widely used in treating metastatic castration-resistant and hormone-sensitive prostate cancer. The incidence of NEPC is increasing, yet effective therapeutic strategies remain limited due to an incomplete understanding of its molecular drivers. Through transcriptomic analyses of human prostate tumor samples, we identified the histone lysine demethylase KDM4A as uniquely overexpressed in human and mouse NEPC compared to prostate adenocarcinoma. Functional validation demonstrated that KDM4A is a key regulator of NEPC progression and a promising therapeutic target, as knockdown or knockout of KDM4A suppresses NEPC cell proliferation in vitro and tumor growth in vivo. Mechanistically, we found that KDM4A directly regulates the transcription of the oncogene MYC, which we show is essential for NEPC cell growth through knockdown and inhibitor studies. Importantly, pharmacologic inhibition of KDM4A using QC6352, a potent pan-KDM4 inhibitor, significantly reduced NEPC cell proliferation in vitro and tumor growth in vivo, providing proof-of-concept for therapeutic targeting. Collectively, our findings establish KDM4A as a critical epigenetic driver of NEPC through MYC regulation and demonstrate its therapeutic potential for this lethal disease that currently lacks effective treatments.

DOI: https://doi.org/10.1016/j.canlet.2025.218184
Mar Life Sci Technol. 2025 Nov;7(4): 949-961

Nitrobenzoyl-insulicolide A: a novel dinitrobenzoyl sesquiterpenoid, induces autophagic cell death in small cell lung cancer cells.

Yige Zhang, Xiaomin Zhang, Chunxiao Sun, Xin Qi, Dehai Li, Jing Li.

  Small cell lung cancer (SCLC) is a high-grade malignancy and prone to drug resistance, with limited progress in patient survival over the past 30 years. Therefore, there is an urgent need to explore new treatment strategies for SCLC patients. Autophagic cell death represents a novel therapeutic strategy for cancer cells with high apoptotic thresholds. Here, we demonstrate that nitrobenzoyl-insulicolide A (1), a new sesquiterpene, isolated from Antarctica sponge-derived fungus Aspergillus insulicola HDN151418, inhibits the proliferation of various SCLC cells including adriamycin- or cisplatin/etoposide-resistant cells, via autophagic death rather than apoptosis, necrosis and cell aging. Molecular mechanism analysis revealed that compound 1 induced autophagic cell death in the NCI-H446 and H69 AR cells dependent on activations of the AKT/mTOR/PARP and ERK1/2 signaling pathways. These findings provide an experimental basis for the further development of 1 as a lead compound against small cell lung cancer in future.
Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-025-00292-y.

Keywords:  Anticancer; Autophagy; Chemotherapy-resistance; Nitrobenzoyl-insulicolide A; SCLC

DOI:  https://doi.org/10.1007/s42995-025-00292-y
Front Oncol. 2025 ;15 1709544

First-line immune checkpoint inhibitors combined with chemotherapy in advanced large-cell neuroendocrine carcinoma of the lung: a real-world retrospective study.

Beibei Ji, Wei Luan, Rula Sha, Wenxin Li.

   Background: Large-cell neuroendocrine carcinoma of the lung (LCNEC) shares clinicopathological features with both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Owing to its neuroendocrine characteristics, the treatment of LCNEC often follows paradigms established for SCLC. Immune checkpoint inhibitors (ICIs) have become the standard first-line therapy for extensive-stage SCLC (ES-SCLC), but evidence supporting the use of ICIs in advanced LCNEC remains limited. This study aimed to evaluate the efficacy and prognosis of first-line ICIs in patients with advanced LCNEC.
Methods: We retrospectively analyzed 31 patients with stage IV LCNEC treated at Inner Mongolia People's Hospital from January 2019 to December 2024. Of these, 14 patients received ICIs plus platinum-based chemotherapy (the ICIs + Chemo group), and the other 17 patients received chemotherapy alone (the Chemo group). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events(AEs) were compared between the two groups.
Results: After a median follow-up of 24 months, the ICIs + Chemo group demonstrated significantly longer median PFS (10.5 months [95% CI, 7.6-12.4] vs. 6.0 months [95% CI, 4.3-7.7]; p=0.035) and median OS (15.0 months [95% CI, 11.4-18.6] vs. 11.0 months [95% CI, 9.3-12.6]; p=0.036) compared to the Chemo group. Multivariate Cox regression showed that the ICIs + Chemo group reduced the risk of progression by 49% (HR = 0.51; 95% CI, 0.28-0.92; p=0.026) and death by 45% (HR = 0.55; 95% CI, 0.30-1.01; p=0.054). The ORR and DCR were 50.0% and 85.7% in the ICIs + Chemo group, versus 29.4% and 76.5% in the Chemo group, respectively. Immune-related adverse events (irAEs) in the ICIs + Chemo group were grade 1-2, with no grade 3 or higher adverse events observed.
Conclusion: This study was based on real-world data from northern China. Preliminary findings suggest that ICIs combined with chemotherapy may be a promising treatment option for patients with advanced LCNEC, with potential survival benefits. However, as a single-center retrospective study with a limited sample size, further multi-center and large-sample prospective clinical trials are warranted to validate these results.

Keywords:  LCNEC; PD-1/PD-L1 inhibitor; immunotherapy; prognosis; real-world study; survival

DOI:  https://doi.org/10.3389/fonc.2025.1709544
Front Oncol. 2025 ;15 1686515

Clinical management and prognostic determinants of gallbladder neuroendocrine carcinoma: a single-institutional analysis of 31 cases.

Yuting Luo, Yu Zhou, Gang Wang, Saud Ahmad Saad, Dan Jiang, Zhen You.

   Background: Gallbladder neuroendocrine carcinoma (GB-NEC) is an exceptionally rare and highly aggressive malignancy, accounting for only 0.2% of gastrointestinal neuroendocrine neoplasms and 2.3% of gallbladder cancers. Due to its nonspecific clinical presentation and diagnostic challenges, most patients present with advanced disease at diagnosis, resulting in poor prognosis with median survival typically under 12 months. This study aimed to analyze clinicopathological characteristics and identify independent prognostic factors in GB-NEC patients.
Methods: We conducted a retrospective cohort study of 31 histologically confirmed GB-NEC cases treated at a tertiary referral center between 2015-2024. Comprehensive data including demographic characteristics, tumor markers, pathological features (differentiation, Ki-67 index, invasion patterns), treatment modalities (surgical approach, chemotherapy regimens), and survival outcomes were analyzed. Statistical methods included Kaplan-Meier survival analysis, log-rank tests, and multivariate Cox proportional hazards regression models.
Results: The cohort demonstrated median progression-free survival of 12 months and overall survival of 36 months. Multivariate analysis identified three independent poor prognostic factors: elevated alpha-fetoprotein (AFP) (HR 1.01, p=0.034), mixed neuroendocrine-non-neuroendocrine histology (HR 3.90, p=0.042), and delayed adjuvant chemotherapy (HR 15.62, p=0.006).
Discussion: This study establishes AFP elevation, mixed histology, and delayed chemotherapy as critical determinants of poor prognosis in GB-NEC. Our findings emphasize the importance of early diagnosis, aggressive surgical resection, and timely initiation of platinum-based adjuvant therapy.

Keywords:  gallbladder neuroendocrine carcinoma; platinum-based chemotherapy; prognostic factors; retrospective study; survival analysis

DOI:  https://doi.org/10.3389/fonc.2025.1686515
Mol Cancer Ther. 2025 Dec 05.

IGFBP3-SphK1/S1P Signaling Axis Drives Enzalutamide Resistance in Advanced Prostate Cancer.

Amy R Leslie, Shu Ning, Masuda Sharifi, Zachary A Schaaf, James P Maine, Wei Lou, Kristina D Leslie, Chengfei Liu, Hongyu Xu, Alan P Lombard, Hong-Wu Chen, Mamta Parikh, Marc Dall'Era, Allen C Gao.

Enzalutamide resistance remains a significant challenge in the treatment of advanced prostate cancer. Identifying molecular drivers of enzalutamide resistance is crucial for developing effective therapeutic strategies. In this study, we identify insulin-like growth factor binding protein 3 (IGFBP3) as a key driver of enzalutamide resistance in castration-resistant prostate cancer (CRPC). We demonstrate that IGFBP3 expression is significantly upregulated in enzalutamide-resistant C4-2B MDVR cells compared to parental C4-2B cells. This upregulation was consistently observed across multiple enzalutamide-resistant CRPC models, including LNCaP-derived 42D and 42F cells, as well as long-term enzalutamide-resistant cell lines derived from LNCaP, VCaP, LAPC-4, and CWR-R1 cells. Additionally, Enzalutamide treatment directly induced IGFBP3 expression in sensitive cells. Elevated IGFBP3 expression was also observed in CRPC patient samples post-enzalutamide treatment and was associated with higher Gleason scores and reduced disease-free survival. Mechanistically, IGFBP3 activates the sphingosine kinase 1 (SphK1)/sphingosine-1-phosphate (S1P) signaling pathway, which promotes cell survival and resistance to enzalutamide. IGFBP3 knockdown decreased SphK1 expression, reduced S1P secretion, and enhanced enzalutamide sensitivity, whereas IGFBP3 overexpression induced SphK1 expression and S1P production, conferring enzalutamide resistance. Inhibition of IGFBP3 via siRNA reduced cell viability, induced apoptosis, and re-sensitized resistant models to enzalutamide. Similarly, targeting SphK1 with the inhibitor SKI-II suppressed SphK1 activity, reduced S1P production, enhanced enzalutamide sensitivity, and significantly inhibited resistant tumor growth while enhancing enzalutamide sensitivity. Collectively, these findings highlight IGFBP3-mediated SphK1 signaling as a critical mediator of enzalutamide resistance and suggest that targeting the IGFBP3/SphK1/S1P axis represents a promising therapeutic strategy to overcome resistance in advanced prostate cancer.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-0644
Endocr Relat Cancer. 2025 Dec 03. pii: ERC-25-0298. [Epub ahead of print]

Chemoembolization using streptozotocin versus embolization in metastatic NETs.

Anne-Laure Védie, Francesco Matteini, Jérôme Cros, Marco Dioguardi Burgio, Jules Grégory, Olivia Hentic, Andréas Busse-Côté, Lucas Raynaud, Anne Couvelard, Vinciane Rebours, Philippe Ruszniewski, Maxime Ronot, Louis de Mestier.

  Locoregional therapies are a standard treatment for neuroendocrine tumors (NET) with predominant liver metastases. The efficacy of transarterial chemoembolization (TACE) using streptozotocin (STZ) has been poorly compared to transarterial embolization (TAE). Predictive biomarkers of TACE efficacy have never been explored. We studied all patients with pancreatic (panNET) or small intestine (siNET) NET and liver metastases treated between 2006 and 2022 using a standardized protocol of TACE-STZ (1,500 mg/m2) or TAE. The primary endpoint was the RECIST1.1-defined objective response rate (ORR). The variables associated with ORR were explored using a propensity score to account for confounding factors. Secondary endpoints included the impact of tumor expression of O6-methylguanine-methyltransferase (MGMT), alkylpurine-DNA-N-glycosylase (APNG), and carbonic anhydrase IX (CAIX), and progression-free survival (PFS). Among 116 patients, 58 received TACE (15 siNET and 43 panNET) and 58 received TAE (42 siNET and 16 panNET). TACE was associated with a higher ORR than TAE (43% vs. 22%, p=0.045), which remained statistically significant on propensity-adjusted multivariable analysis (OR 2.71, 95% CI [1.08-7.17], p=0.038). TACE provided longer PFS than TAE in panNET patients (12.9 vs. 6.4 months, p=0.026), but not in siNET patients (16.1 vs. 15.1 months, p=0.47). Low APNG expression was predictive of higher ORR with TACE (70% vs. 16%, p<0.001), while the expression of MGMT and CAIX had no impact. TACE-STZ provided a higher ORR than TAE, although yielded longer PFS only in patients with panNET. Low tumor expression of APNG might help select the best candidates for TACE-STZ, although this result was only exploratory.

Keywords:  biomarkers; liver metastases; neuroendocrine tumors; streptozotocin; transarterial chemoembolization

DOI:  https://doi.org/10.1530/ERC-25-0298
Mol Cancer. 2025 Dec 02.

Multi-omic profiling provides insights into the heterogeneity, microenvironmental features, and biomarker landscape of small-cell lung cancer.

Mingchao Xie, Miljenka Vuko, Shashank Saran, Siyu Liu, Andrew G Chambers, Hana Baakza, Helen K Angell, Felicia Ng, Carl M Gay, Robert J Cardnell, Felix J Segerer, Alma Andoni, Jaime Rodriguez-Canales, Paul M Waring, Markus Schick, J Carl Barrett, Lauren A Byers, Giulia Fabbri.

   BACKGROUND: Greater understanding of differential therapeutic sensitivity, specifically to immunotherapy, in small-cell lung cancer (SCLC) is required.
METHODS: We explored SCLC heterogeneity through integrated molecular characterization of tumor tissue samples from 159 treatment-naive patients, utilizing genetic, epigenetic, transcriptional, and proteomic profiling, immunohistochemistry staining for multiple biologically relevant markers including transcriptional subtype-defining proteins, and spatial immune profiling using multiplex immunofluorescence.
RESULTS: Multi-omics analysis confirmed high heterogeneity across/within neuroendocrine and non-neuroendocrine subtypes. Methylomics analysis identified four methylome clusters that may enhance subtype prediction, prognosis, and longitudinal monitoring of subtype evolution. Immunohistochemistry analysis showed high MHC-I expression in non-neuroendocrine subtypes, which have greatest potential benefit from adding immunotherapy to chemotherapy; high DLL3 expression associated with neuroendocrine subtypes and an immune-cold tumor microenvironment. Multiplex immunofluorescence demonstrated associations of MHC-I with spatial arrangement and phenotypic features of immune cells in the tumor microenvironment of high-MHC-I-expressing SCLC, providing mechanistic rationale for MHC-I as a potential biomarker of immunotherapy response.
CONCLUSIONS: This multimodal profiling analysis provides further insights into the biologic complexity of SCLC and highlights potential therapeutic vulnerabilities of distinct disease subtypes.

Keywords:  Biomarkers; Immune profiling; Immunotherapies; MHC-I; Methylomics; Molecular subtyping; Proteomics; SCLC subtypes; Small-cell lung cancer

DOI:  https://doi.org/10.1186/s12943-025-02514-4
ESMO Open. 2025 Dec 02. pii: S2059-7029(25)01792-2. [Epub ahead of print]10(12): 105922

Streptozotocin plus 5-fluorouracil followed by everolimus or the reverse sequence in patients with advanced pancreatic neuroendocrine tumors (SEQTOR-GETNE phase III study): a randomized clinical trial.

J Capdevila, S Tafuto, M Krogh, A Teulé, R Garcia-Carbonero, H-J Klümpen, B Cremer, I Sevilla, B Eriksson, E Tabaksblat, J-P Metges, N S Reed, J Schrader, V Navarro, V Valentí, J Hernando, A M Colao, L Vestermark, C Carnaghi, U P Knigge, P Jimenez-Fonseca, M Benavent, J de Vos-Geelen, M Venerito, A Von Werder, H Jann, A Rinke, D Smith, D Hörsch, N Starling, P Ruszniewski, E Baudin, F-X Caroli-Bosc, J L Manzano, M Martín, A Scarpa, R T Lawlor, C Ragulan, H Ps, A Sadanandam, A Carmona-Bayonas, R Salazar.

   BACKGROUND: Everolimus or streptozotocin plus 5-fluorouracil (STZ/5-FU) are approved treatments for patients with pancreatic neuroendocrine tumors (panNETs). The SEQTOR trial aimed to assess the optimal treatment sequence.
PATIENTS AND METHODS: SEQTOR was an international, open-label, randomized, crossover, phase III trial that recruited adults with unresectable or metastatic, advanced, well-differentiated panNET. Patients received 10 mg/day of everolimus followed upon progression by STZ/5-FU; or the reverse sequence. The primary endpoint was the 35-month progression-free survival (PFS) rate after first- and second-line treatment; however, due to slow accrual and longer survival, it was changed to the 12-month PFS rate following first-line treatment (12-mPFS1).
RESULTS: Patients were randomized to everolimus (n = 72) or STZ/5-FU (n = 69) first. The 12-mPFS1 was 71.4% [95% confidence interval (CI) 59.4% to 81.6%] and 61.8% (95% CI 49.2% to 73.3%) (odds ratio 0.65, 95% CI 0.32-1.32) with a median PFS1 of 19.4 versus 22.7 months for everolimus and STZ/5-FU, respectively. STZ/5-FU achieved a significantly higher overall response rate in first-line (11.6% versus 30.3%, P = 0.012) and second-line (30.6% versus 9.1%, P = 0.072) treatments. No differences were shown in overall survival (median 61.7 versus 50.6 months in everolimus first and STZ/5-FU first, respectively; hazard ratio 1.43, 95% CI 0.86-2.37). Discontinuations of everolimus were more frequent.
CONCLUSION: STZ/5-FU and everolimus were not statistically different in PFS rates, but STZ/5-FU achieved higher response rates.

Keywords:  5-fluorouracil; advanced pancreatic neuroendocrine neoplasm; everolimus; panNET; sequential strategy; streptozotocin

DOI:  https://doi.org/10.1016/j.esmoop.2025.105922