Cancers

15 pages, 1044 KiB

Open AccessArticle

Impact of Long-Term Chemotherapy on Outcomes in Pancreatic Ductal Adenocarcinoma: A Real-World UK Multi-Centre Study

by Umair Mahmood, Joanna Lynch, Simran Kaur Sandhu, Zahir Amin, John Bridgewater, Daniel Hochhauser, Kai-Keen Shiu, Paul Miller, Elizabeth C. Smyth and Khurum Khan

Cancers 2025, 17(11), 1896; https://doi.org/10.3390/cancers17111896 - 5 Jun 2025

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Abstract

Background: We reviewed outcomes of short and long-term chemotherapy with or without breaks in pancreatic ductal adenocarcinoma (PDAC) patients. Methods: PDAC patients receiving ≥3 chemotherapy cycles between 2019 and 2024 at three institutions were included. Progression-free survival after first-line chemotherapy (PFS1), overall survival [...] Read more.

Background: We reviewed outcomes of short and long-term chemotherapy with or without breaks in pancreatic ductal adenocarcinoma (PDAC) patients. Methods: PDAC patients receiving ≥3 chemotherapy cycles between 2019 and 2024 at three institutions were included. Progression-free survival after first-line chemotherapy (PFS1), overall survival (OS) and best overall response (BOR) to chemotherapy were assessed using the Wilcoxon test, Kaplan–Meier test, and univariate and multivariate Cox regression models. Results: We screened 237 patients, and 135 patients met the study criteria. Among these patients, 25 had resectable disease, and 110 had unresectable/metastatic disease (13% borderline resectable (BRPC), 20% locally advanced (LAPC), 10% localised developing metastases, 57% de novo metastatic). Ten patients (7%) underwent genetic profiling; KRAS aberrations (N = 4), actionable PLAB2/BRCA2/FGFR2 mutations (N = 3), ATM/BRIP1 alteration (N = 1). Two patients were managed with PARP inhibitors after receiving multiple lines of chemotherapy. Median PFS1 and OS were concordant with the published literature, but select patient groups achieved prolonged survival outcomes. Among the 36 BRPC/LAPC patients, we observed >1-year PFS1 in 9 (25%) patients and >2-year OS in 3 (8%) patients. Among the 63 de novo metastatic patients, we observed >1-year PFS1 and >2-year OS in 6 (10%) patients. Among patients with localised disease, smoking history was a poor prognostic factor with respect to OS (p = 0.03). Improved PFS1 and OS was associated with ≥6 cycles of first-line chemotherapy, its duration of ≥3.66 months, and local treatment after first chemotherapy (p < 0.05 for all). Stereotactic body radiotherapy following first-line chemotherapy was delivered in N = 6 (27%) and N = 1 (7%) of patients with LAPC and BRPC, respectively. Chemotherapy interruption duration, but not number, was associated with PFS1 and OS only in the localised cohort (p < 0.05). In patients with de novo metastatic disease, prevalence of type 2 diabetes was adversely associated with OS (p = 0.03). Improved PFS and OS was associated with ≥6 cycles of first-line chemotherapy, its duration of ≥4.37 months, and BOR to it (only in this cohort) (p < 0.05 for all). A favourable OS was associated with >1 line of chemotherapy (p = 0.003). Conclusion: Despite challenges, extended chemotherapy and multiple treatment lines may improve survival, with localised treatments benefiting select patients. Full article

(This article belongs to the Special Issue Management of Pancreatic Cancer)

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17 pages, 2251 KiB

Open AccessSystematic Review

Comparison of Erlotinib vs. Osimertinib for Advanced or Metastatic EGFR Mutation-Positive Non-Small-Cell Lung Cancer Without Prior Treatment: A Network Meta-Analysis

by Fernando M. Runzer-Colmenares, Rossana Ruiz, Lorenzo Maco, Mike Maldonado, Luis Puma-Villanueva, Marco Galvez-Nino, Carlos Aliaga, Vicente A. Benites-Zapata, Carlos Diaz-Arocutipa, Luis Mas and Diego Urrunaga-Pastor

Cancers 2025, 17(11), 1895; https://doi.org/10.3390/cancers17111895 - 5 Jun 2025

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Abstract

Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases globally and most patients receive their diagnosis at advanced or metastatic disease stages. The use of tyrosine kinase inhibitors (TKIs) such as erlotinib (first-generation) and osimertinib (third-generation) to treat NSCLC is [...] Read more.

Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases globally and most patients receive their diagnosis at advanced or metastatic disease stages. The use of tyrosine kinase inhibitors (TKIs) such as erlotinib (first-generation) and osimertinib (third-generation) to treat NSCLC is possible because of activating mutations in the epidermal growth factor receptor (EGFR). Although osimertinib has shown better results in recent trials, direct and updated comparisons with erlotinib, especially in combination regimens, are still limited. Background/Objectives: This study aimed to compare the efficacy and safety of osimertinib versus erlotinib, both as monotherapies and in combination, in treatment-naïve patients with advanced or metastatic EGFR-mutated NSCLC. Methods: A systematic review and network meta-analysis were conducted following PRISMA-NMA guidelines and registered in PROSPERO (CRD42025649761). PubMed, EMBASE, and Scopus were searched up to February 2025 for randomized controlled trials (RCTs) that compared erlotinib- or osimertinib-based regimens in previously untreated EGFR-mutated advanced NSCLC. Outcomes included overall survival (OS), progression-free survival (PFS), and grade ≥ 3 adverse events. A frequentist random-effects model was used, and treatments were ranked using p-scores. Results: Eleven RCTs (2341 patients) were included. Osimertinib, alone or with chemotherapy, resulted in significantly longer OS compared to erlotinib-based regimens (HR for OS vs. erlotinib: 1.59, 95% CI 1.09–2.31). All osimertinib and erlotinib regimens outperformed chemotherapy for PFS, but no statistically significant differences were observed between osimertinib and erlotinib. Severe adverse events were comparable, though osimertinib ranked highest for safety. The combination of osimertinib with chemotherapy achieved the highest p-scores for both OS and PFS. Conclusions: Osimertinib is associated with superior overall survival and comparable safety versus erlotinib-based strategies in first-line treatment of advanced EGFR-mutated NSCLC. These findings reinforce osimertinib as the preferred first-line option in this setting. Full article

(This article belongs to the Section Systematic Review or Meta-Analysis in Cancer Research)

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13 pages, 874 KiB

Open AccessArticle

The Prognostic Value of FOXL2 Mutant Circulating Tumor DNA in Adult Granulosa Cell Tumor Patients

by Geertruid J. Brink, Nizar Hami, Hans W. Nijman, Jurgen M. J. Piek, Luc R. C. W. van Lonkhuijzen, Eva Maria Roes, Ward Hofhuis, Christianne A. R. Lok, Cor D. de Kroon, Eelke H. Gort, Petronella O. Witteveen, Ronald P. Zweemer and Jolijn W. Groeneweg

Cancers 2025, 17(11), 1894; https://doi.org/10.3390/cancers17111894 - 5 Jun 2025

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Abstract

Objectives: The purpose of the study is to determine whether FOXL2 circulating tumor DNA can be used as a prognostic biomarker and marker for monitoring treatment response in patients with an adult-type granulosa cell tumor (aGCT). Methods: Plasma samples of patients included in [...] Read more.

Objectives: The purpose of the study is to determine whether FOXL2 circulating tumor DNA can be used as a prognostic biomarker and marker for monitoring treatment response in patients with an adult-type granulosa cell tumor (aGCT). Methods: Plasma samples of patients included in the multicenter GRANULOSA study were collected before and after surgery for primary or recurrent aGCT, during follow-up, and during systemic treatment. The presence of ctDNA containing the FOXL2 402C>G mutation was analyzed in 284 samples from 20 primary and 34 recurrent aGCT patients, using digital droplet PCR. Clinical data were retrieved from electronic patient records, and patients were followed through January 2025. Results:FOXL2 mutant ctDNA was detected in 28 of 54 patients (48%). In primary aGCT, recurrences were more frequently seen in patients with detectable ctDNA (33% vs. 18%), and ctDNA remained detectable postoperatively in some cases despite complete cytoreduction. In recurrent aGCT patients, detectable ctDNA was associated with significantly worse overall survival (p = 0.023), and the postoperative presence of ctDNA following complete debulking surgery was significantly associated with a shorter recurrence-free survival (4.7 vs. 11.6 months, p = 0.025). Conclusions:FOXL2 mutant ctDNA could be a prognostic biomarker in aGCT, being associated with worse overall survival in recurrent aGCT patients. In addition, the presence of ctDNA after surgery could reflect the presence of minimal residual disease, negatively impacting the disease course. The implementation of FOXL2 ctDNA measurement in clinical practice may help to identify high-risk aGCT patients. Full article

(This article belongs to the Special Issue Rare Gynecological Cancers)

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Graphical abstract

18 pages, 4646 KiB

Open AccessReview

Endometrial Stromal Sarcoma: An Update

by Giulio Ricotta, Silvio Andrea Russo, Anna Fagotti, Alejandra Martinez, Elodie Gauroy, Mathilde Del, Valentin Thibaud, Bataillon Guillaume and Gwenaël Ferron

Cancers 2025, 17(11), 1893; https://doi.org/10.3390/cancers17111893 - 5 Jun 2025

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Abstract

Endometrial stromal sarcoma (ESS) is a rare malignant tumor of uterine mesenchyme, accounting for 15–20% of uterine sarcomas. It is classified into low-grade (LG-ESS) and high-grade (HG-ESS) subtypes, each defined by distinct histopathological and molecular features. LG-ESS exhibits slow progression, resembling proliferative-phase endometrial [...] Read more.

Endometrial stromal sarcoma (ESS) is a rare malignant tumor of uterine mesenchyme, accounting for 15–20% of uterine sarcomas. It is classified into low-grade (LG-ESS) and high-grade (HG-ESS) subtypes, each defined by distinct histopathological and molecular features. LG-ESS exhibits slow progression, resembling proliferative-phase endometrial stroma, with genetic alterations like JAZF1-SUZ12 fusions. HG-ESS is more aggressive, characterized by high mitotic activity, necrosis, and genetic markers such as BCOR internal tandem duplication, often leading to advanced-stage diagnosis. Surgical resection is the cornerstone for managing early-stage ESS. A total hysterectomy with bilateral salpingo-oophorectomy (BSO) is recommended to prevent recurrence. Fertility-preserving approaches may be considered in LG-ESS but are associated with high recurrence rates. Lymphadenectomy is not routinely performed, given its limited prognostic value. HG-ESS, due to its aggressiveness, often requires additional treatment, including chemotherapy. Adjuvant therapy varies by subtype. LG-ESS responds well to hormonal treatments such as aromatase inhibitors and progestins, while tamoxifen is contraindicated. HG-ESS, lacking hormonal receptor expression, is managed with chemotherapy, often incorporating doxorubicin-based regimens. Radiotherapy may improve local control in select cases but shows limited impact on overall survival. Advanced-stage ESS treatment focuses on complete cytoreduction, supplemented by systemic therapies. Hormonal therapy remains the standard for advanced LG-ESS, whereas HG-ESS relies on chemotherapy. Prognosis depends on the subtype and stage. LG-ESS has favorable outcomes, with five-year survival exceeding 90% in early stages, but recurrent disease remains common. HG-ESS is associated with poorer survival due to its aggressive nature. Advances in molecular profiling offer promising avenues for personalized therapies, integrating genomic insights with targeted treatments to improve outcomes in this rare malignancy. Full article

(This article belongs to the Special Issue Diagnosis, Staging, and Management for Gynecologic Oncology)

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26 pages, 4445 KiB

Open AccessReview

Effectiveness of Artificial Intelligence Models in Predicting Lung Cancer Recurrence: A Gene Biomarker-Driven Review

by Niloufar Pourakbar, Alireza Motamedi, Mahta Pashapour, Mohammad Emad Sharifi, Seyedemad Seyedgholami Sharabiani, Asra Fazlollahi, Hamid Abdollahi, Arman Rahmim and Sahar Rezaei

Cancers 2025, 17(11), 1892; https://doi.org/10.3390/cancers17111892 - 5 Jun 2025

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Abstract

Background/Objectives: Lung cancer recurrence, particularly in NSCLC, remains a major challenge, with 30–70% of patients relapsing post-treatment. Traditional predictors like TNM staging and histopathology fail to account for tumor heterogeneity and immune dynamics. This review evaluates AI models integrating gene biomarkers (TP53, KRAS, [...] Read more.

Background/Objectives: Lung cancer recurrence, particularly in NSCLC, remains a major challenge, with 30–70% of patients relapsing post-treatment. Traditional predictors like TNM staging and histopathology fail to account for tumor heterogeneity and immune dynamics. This review evaluates AI models integrating gene biomarkers (TP53, KRAS, FOXP3, PD-L1, and CD8) to enhance the recurrence prediction and improve the personalized risk stratification. Methods: Following the PRISMA guidelines, we systematically reviewed AI-driven recurrence prediction models for lung cancer, focusing on genomic biomarkers. Studies were selected based on predefined criteria, emphasizing AI/ML approaches integrating gene expression, radiomics, and clinical data. Data extraction covered the study design, AI algorithms (e.g., neural networks, SVM, and gradient boosting), performance metrics (AUC and sensitivity), and clinical applicability. Two reviewers independently screened and assessed studies to ensure accuracy and minimize bias. Results: A literature analysis of 18 studies (2019–2024) from 14 countries, covering 4861 NSCLC and small cell lung cancer patients, showed that AI models outperformed conventional methods. AI achieved AUCs of 0.73–0.92 compared to 0.61 for TNM staging. Multi-modal approaches integrating gene expression (PDIA3 and MYH11), radiomics, and clinical data improved accuracy, with SVM-based models reaching a 92% AUC. Key predictors included immune-related signatures (e.g., tumor-infiltrating NK cells and PD-L1 expression) and pathway alterations (NF-κB and JAK-STAT). However, small cohorts (41–1348 patients), data heterogeneity, and limited external validation remained challenges. Conclusions: AI-driven models hold potential for recurrence prediction and guiding adjuvant therapies in high-risk NSCLC patients. Expanding multi-institutional datasets, standardizing validation, and improving clinical integration are crucial for real-world adoption. Optimizing biomarker panels and using AI trustworthily and ethically could enhance precision oncology, enabling early, tailored interventions to reduce mortality. Full article

(This article belongs to the Special Issue Bridging the Gap: Integrating AI into Clinical Practice for Oncological PET/CT Imaging)

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26 pages, 1024 KiB

Open AccessReview

Changes Connected to Early Chronic Pancreatitis and Early Pancreatic Cancer in Endoscopic Ultrasonography (EUS): Clinical Implications

by Natalia Pawelec, Łukasz Durko and Ewa Małecka-Wojciesko

Cancers 2025, 17(11), 1891; https://doi.org/10.3390/cancers17111891 - 5 Jun 2025

Viewed by 278

Abstract

Chronic pancreatitis (CP) is a progressive condition that is associated with severe complications. Diagnosis of late CP is easy due to characteristic clinical presentation and pathognomonic imaging findings, such as pancreatic calcifications. Early changes, such as lobularity and a dilated main pancreatic duct, [...] Read more.

Chronic pancreatitis (CP) is a progressive condition that is associated with severe complications. Diagnosis of late CP is easy due to characteristic clinical presentation and pathognomonic imaging findings, such as pancreatic calcifications. Early changes, such as lobularity and a dilated main pancreatic duct, are very subtle and challenging to detect with ultrasonography (US) or even computed tomography (CT). Data were accumulating on the usefulness of EUS in the early diagnosis of CP. The sensitivity values for detecting early CP (ECP) by US, MRI, and EUS were 67–69%, 77–78%, and 81–84%, respectively. The specificity values for detecting ECP by US, MRI, and EUS were 90–98%, 83–96%, and 90–100%, respectively. Pancreatic cancer (PDAC) is one of the leading cancers worldwide, with increasing morbidity. Due to its poor prognosis and survival, early diagnosis is crucial. For this indication, EUS also shows better outcomes compared to other imaging methods, especially in tumors < 2 cm. The sensitivity and specificity for diagnosing PDAC with MRI and EUS were 52.3–93%, 77.1–89%, 72–100%, and 90%, respectively. In addition, EUS can detect precancerous conditions that are associated with a higher risk of PDAC. EUS-assisted new techniques, like elastography and contrast enhancement, facilitate the diagnosis of pancreatic lesions and make it even more accurate. Early PDAC changes, such as main pancreatic duct dilatation or irregular margins of pancreatic solid masses, may be detected with EUS. This review describes the efficacy of different imaging techniques in the early detection of CP and PDAC. In addition, we describe the useful interventions made possible by early diagnosis of PDAC and CP. Full article

(This article belongs to the Collection Targeting Solid Tumors)

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21 pages, 1061 KiB

Open AccessArticle

Prognostic Validity of the Eighth Edition of the U.S. Joint Committee on Cancer TNM Staging System for Pancreatic Adenocarcinomas: An Analysis of 214 Patients at a Spanish Center

by A. M. Colino-Gallardo, M. J. Fernández-Aceñero, M. de la Torre-Serrano, J. Vega-González, M. P. Díaz-Suárez and J. Martínez-Useros

Cancers 2025, 17(11), 1890; https://doi.org/10.3390/cancers17111890 - 5 Jun 2025

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Abstract

Introduction: Accurate staging is essential in pancreatic adenocarcinoma due to its aggressive nature and poor prognosis. The 8th edition of the AJCC TNM staging system introduced changes in tumor size criteria and nodal classification. This study compares the prognostic performance of the [...] Read more.

Introduction: Accurate staging is essential in pancreatic adenocarcinoma due to its aggressive nature and poor prognosis. The 8th edition of the AJCC TNM staging system introduced changes in tumor size criteria and nodal classification. This study compares the prognostic performance of the 7th and 8th editions in resected patients. Material and Methods: A retrospective analysis was conducted on 214 patients with pancreatic adenocarcinoma who underwent curative surgery. TNM staging was assigned according to both AJCC editions. Kaplan–Meier analysis and multivariate Cox regression, stratified by adjuvant therapy, were used to assess disease-free survival (DFS) and overall survival (OS). Results: The 8th edition TNM staging was significantly associated with lower risk of recurrence, with TNM stages I and II independently predicting better DFS (p < 0.05). In contrast, the 7th edition TNM stage I remained the only independent predictor of OS (HR = 0.376; p = 0.023). Reclassification between editions altered stage distribution, particularly within stage II. Conclusions: The 8th edition improves early recurrence stratification, while the 7th edition retains stronger prognostic value for overall survival. Both systems offer complementary insights, supporting outcome-specific staging use. Full article

(This article belongs to the Section Cancer Pathophysiology)

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18 pages, 2636 KiB

Open AccessArticle

A Triple Oral Combination of Bendamustine, Acalabrutinib, and Venetoclax Demonstrates Efficacy Against Mantle Cell Lymphoma In Vitro and In Vivo

by Dimitrios Filioglou, Nina Santa-Cruz, Geovana S. F. Leite, Dan W. Davini, Megan J. Cracchiolo, Forrest L. Baker, Muhammad Husnain, Richard J. Simpson, Vasilios Voudouris and Emmanuel Katsanis

Cancers 2025, 17(11), 1889; https://doi.org/10.3390/cancers17111889 - 5 Jun 2025

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Abstract

Background/Objectives: Bendamustine (BEN) combined with rituximab (RTX) remains a standard first-line therapy for transplant-ineligible patients with newly diagnosed mantle cell lymphoma (MCL). Meanwhile, novel targeted therapies such as Bruton tyrosine kinase inhibitors (BTKis) are increasingly used in the treatment of relapsed/refractory (R/R) [...] Read more.

Background/Objectives: Bendamustine (BEN) combined with rituximab (RTX) remains a standard first-line therapy for transplant-ineligible patients with newly diagnosed mantle cell lymphoma (MCL). Meanwhile, novel targeted therapies such as Bruton tyrosine kinase inhibitors (BTKis) are increasingly used in the treatment of relapsed/refractory (R/R) MCL. We recently reported that a novel oral formulation of BEN exhibits comparable efficacy to the intravenous counterpart. In this study, we investigated the efficacy of oral BEN administered alone or in combination with the oral BCL-2 inhibitor Venetoclax (VEN) and/or the oral BTKi Acalabrutinib (ACAL), against two human MCL cell lines (Jeko-1 and Z-138) representative of the R/R disease subtype. Methods: We performed in vitro analyses using MTS viability and Annexin V/PI apoptosis assays. For the in vivo studies, all treatments were administered via oral gavage in xenograft mouse models. Therapeutic efficacy was evaluated by monitoring tumor growth and survival. Results: BEN induced significant cytotoxicity in both cell lines at low, clinically relevant concentrations. In contrast, VEN demonstrated limited efficacy as monotherapy, with Z-138 showing sensitivity only at high doses. However, combining BEN with VEN with or without ACAL, enhanced apoptosis and cytotoxicity, with more pronounced effects in Z-138. In vivo, oral BEN significantly reduced tumor growth and prolonged survival in both xenograft models. In the Z-138 model, the addition of VEN ± ACAL further improved survival outcomes. Conclusions: Our findings support the efficacy of oral BEN as both a monotherapy and as part of an all-oral treatment regimen for MCL. These results warrant further investigation into the clinical potential of oral BEN, particularly in combination with targeted agents. Full article

(This article belongs to the Special Issue Pre-Clinical Studies of Personalized Medicine for Cancer Research)

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19 pages, 547 KiB

Open AccessReview

The Immunomodulatory Role of Galectin-1 in the Tumour Microenvironment and Strategies for Therapeutic Applications

by Alice Griffiths, Palita Udomjarumanee, Andrei-Stefan Georgescu, Muruj Barri, Dmitry A. Zinovkin and Md Zahidul I. Pranjol

Cancers 2025, 17(11), 1888; https://doi.org/10.3390/cancers17111888 - 5 Jun 2025

Viewed by 309

Abstract

With the morbidity of cancer currently on a perpetual rise, there is a critical need for new treatment options. Current therapeutic options, such as chemotherapy and radiotherapy, are frequently employed; however, the high rate of recurrence underscores the incomplete understanding of tumour growth, [...] Read more.

With the morbidity of cancer currently on a perpetual rise, there is a critical need for new treatment options. Current therapeutic options, such as chemotherapy and radiotherapy, are frequently employed; however, the high rate of recurrence underscores the incomplete understanding of tumour growth, progression, and the intricacies of their microenvironments. In this study, we review the roles that galectin-1 (Gal1) plays in suppressing immune surveillance in the tumour microenvironment. Studies have shown that Gal1 changes the immune system parameters: suppressing T cell function, sensitising resting T lymphocytes to Fas/FasL, decreasing cell proliferation, reducing adhesion to extracellular matrix, inhibiting Th1 cytokines, increasing M2 phenotype macrophages, and promoting angiogenesis. Gal1 has garnered increasing attention as a potential therapeutic target due to its involvement in tumour progression and immune evasion. Given the limitations and toxic side effects associated with current treatment options, alternative strategies targeting Gal1 have been explored for their therapeutic potential. Approaches such as OTX008, anti-Gal1 monoclonal antibodies, and Gal1-targeted vaccines have demonstrated the ability to downregulate tumour progression by inhibiting Gal1 activity. These findings highlight the therapeutic promise of Gal1 not only as a novel target for cancer therapy but also as a potential prognostic biomarker, offering opportunities for the development of more effective and less toxic treatment strategies. Full article

(This article belongs to the Special Issue Targeting the Tumor Microenvironment (Volume II))

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20 pages, 3604 KiB

Open AccessArticle

LMP7-Specific Inhibitor M3258 Modulates the Tumor Microenvironment of Triple-Negative Breast Cancer and Inflammatory Breast Cancer

by Xuemei Xie, Jangsoon Lee, Ganiraju C. Manyam, Troy Pearson, Gina Walter-Bausch, Manja Friese-Hamim, Sheng Zhao, Julia Jabs, Angela A. Manginelli, Nadine Piske, Thomas Mrowiec, Corinna M. Wolf, Bharat S. Kuntal, Debu Tripathy, Jing Wang, Michael P. Sanderson and Naoto T. Ueno

Cancers 2025, 17(11), 1887; https://doi.org/10.3390/cancers17111887 - 4 Jun 2025

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Abstract

Triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC) are the most aggressive molecular subtypes of breast cancer. Poor clinical outcomes highlight the pressing need to discover novel targets for the effective treatment of these diseases. LMP7 (β5i/PSMB8), a proteolytic subunit of the [...] Read more.

Triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC) are the most aggressive molecular subtypes of breast cancer. Poor clinical outcomes highlight the pressing need to discover novel targets for the effective treatment of these diseases. LMP7 (β5i/PSMB8), a proteolytic subunit of the immunoproteasome, is implicated in the pathogenesis of multiple myeloma, autoimmune and inflammatory diseases, and inflammation-related cancers. However, the role of LMP7 in TNBC and IBC remains poorly characterized. Here, we evaluated the function of LMP7 in TNBC and IBC using the selective LMP7 inhibitor M3258. In human TNBC patient samples, LMP7 expression correlated strongly with CD8⁺ T cell infiltration and activation markers. M3258 inhibited LMP7 activity, reduced viability, and induced apoptosis in TNBC/IBC cell lines in vitro. In a novel immunocompetent in vivo model of TNBC/IBC, M3258 reduced tumor growth and the tumor abundance of M2 macrophages. Additionally, M3258 activated tumor-infiltrating CD8⁺ T cells and suppressed the expression of specific inflammatory pathway gene signatures in immune cells. Co-culture with M2 macrophages enhanced the invasiveness of TNBC/IBC cells, which was effectively suppressed by M3258 treatment. Our results demonstrate for the first time that LMP7 shapes the pro-tumorigenic microenvironment of TNBC/IBC, in part by modulating the pathogenic role of M2 macrophages. These findings suggest that LMP7 may represent a novel target for therapeutic intervention in TNBC/IBC. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology and Therapeutics)

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19 pages, 1924 KiB

Open AccessArticle

Predicting Pancreatic Ductal Adenocarcinoma Occurrence Up to 10 Years in Advance Using Features of the Main Pancreatic Duct in Pre-Diagnostic CT Scans

by Lixia Wang, Yu Shi, Touseef Ahmad Qureshi, Yibin Xie, Srinivas Gaddam, Linda Azab, Chaowei Wu, Yimeng He, Zengtian Deng, Sehrish Javed, Garima Diwan, Camila Lopes Vendrami, Alex Rodriguez, Katherine Specht, Christie Y. Jeon, Humaira Chaudhry, James L. Buxbaum, Joseph R. Pisegna, Vahid Yaghmai, Wolfram Goessling, Yasmin G. Hernandez-Barco, Frank H. Miller, Temel Tirkes, Stephen J. Pandol and Debiao Li Show full author list Hide full author list

Cancers 2025, 17(11), 1886; https://doi.org/10.3390/cancers17111886 - 4 Jun 2025

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Abstract

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) prediction in high-risk individuals is essential for early detection and improved outcome. While prior studies have utilized pancreatic radiomics for PDAC prediction, the added value of main pancreatic duct (MPD) features remains unclear. This study aims to assess [...] Read more.

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) prediction in high-risk individuals is essential for early detection and improved outcome. While prior studies have utilized pancreatic radiomics for PDAC prediction, the added value of main pancreatic duct (MPD) features remains unclear. This study aims to assess the additional value of features of the main pancreatic duct (MPD) for predicting PDAC occurrence across different timeframes in advance. Methods: In total, 321 contrast-enhanced CT scans of the MPD and pancreas carried out across control, pre-diagnostic, and diagnostic cohorts were segmented, and radiomics were extracted. A support vector machine (SVM) classifier was used to classify the control and pre-diagnostic cohorts, with model performance assessed using area under the receiver operating characteristic (ROC) curves (AUCs) Results: The MPD diameter and volume significantly increased from the control to the pre-diagnostic and diagnostic CT scans (p < 0.05). The addition of features of the MPD to the pancreas improved the PDAC prediction AUC from 0.83 to 0.96 for subjects 6 months to 3 years in advance, from 0.81 to 0.94 for 3–6 years in advance, and 0.75 to 0.84 for 6–10 years in advance of diagnosis. Additionally, integrating MPD radiomics with diameter and volume significantly improved the AUC from 0.81 to 0.88 for subjects 6 months to 3 years in advance. Conclusions: Radiomic features from abdominal CT scans allow PDAC prediction up to 10 years in advance. Integrating MPD features, including diameter and volume, significantly improves PDAC prediction compared to using radiomics of the pancreas alone. Full article

(This article belongs to the Special Issue Medical Imaging and Artificial Intelligence in Cancer)

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17 pages, 1543 KiB

Open AccessArticle

A Meta-Analysis of Patient-Reported Outcomes of Sacituzumab Govitecan Versus Treatment of Physician’s Choice in Previously Treated HR+/HER− mBC Using Two Phase 3 (TROPiCS-02 and EVER-132-002) Trials

by Hope S. Rugo, Binghe Xu, Anandaroop Dasgupta, Ankita Kaushik, Wendy Verret and Barinder Singh

Cancers 2025, 17(11), 1885; https://doi.org/10.3390/cancers17111885 - 4 Jun 2025

Viewed by 224

Abstract

Background: The patient-reported outcomes (PROs) of sacituzumab govitecan (SG) were compared with chemotherapy using two phase 3 trials (TROPiCS-02, EVER-132-002) involving patients with HR+/HER2− locally recurrent inoperable or metastatic breast cancer. Methods: A meta-analysis was performed to compare change from baseline (CFB) scores [...] Read more.

Background: The patient-reported outcomes (PROs) of sacituzumab govitecan (SG) were compared with chemotherapy using two phase 3 trials (TROPiCS-02, EVER-132-002) involving patients with HR+/HER2− locally recurrent inoperable or metastatic breast cancer. Methods: A meta-analysis was performed to compare change from baseline (CFB) scores and time-to-deterioration (TTD) between SG and chemotherapy using EORTC QLQ-C30 and EQ-5D-5L VAS in the overall, prior CDK4/6i-treated, and fast-progressor populations. Results of CFB and TTD analyses were summarized using hazard ratio (HR) and mean difference measures. Results: Statistically significant improvement (p < 0.05) in CFB scores was observed with SG over chemotherapy in five EORTC QLQ-C30 domains: physical (mean difference: 2.64), role functioning (mean difference: 2.70), fatigue (mean difference: −2.51), pain (mean difference: −3.25) and dyspnea (mean difference: −3.27), and EQ-5D-5L VAS (mean difference: 1.58). In the overall population, longer TTD (p < 0.05) was observed with SG versus chemotherapy on six domains of EORTC QLQ-C30: GHS/QoL (HR: 0.76), physical (HR: 0.72), emotional functioning (HR: 0.73), fatigue (HR: 0.80), pain (HR: 0.82), and dyspnea (HR: 0.71). Results from EORTC QLQ-C30 domains were mostly consistent among the overall, prior CDK4/6i treated and fast-progressor populations. SG demonstrated longer TTD (p < 0.05) over chemotherapy for EQ-5D-5L-VAS across all studied populations (HR range: 0.63–0.69). PROs significantly worsened with SG in the domains of diarrhea and nausea and vomiting (commonly reported adverse events of SG, manageable by following established guidelines). Conclusions: SG significantly improved PROs versus chemotherapy for several subdomains of EORTC QLQ-C30 and EQ-5D-5L-VAS. The consistency of these results in the overall population and subgroups supports the generalizability of the meta-analytic evidence and reinforces the PRO benefits associated with SG versus chemotherapy. Full article

(This article belongs to the Section Cancer Survivorship and Quality of Life)

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11 pages, 351 KiB

Open AccessArticle

Effect of Intolerance of Uncertainty on Perceived Cognitive Function Among Breast Cancer Patients Before Chemotherapy

by Yesol Yang, Alai Tan, Sagar D. Sardesai, Nicole O. Williams, Margaret Gatti-Mays, Daniel G. Stover, Preeti K. Sudheendra, Robert Wesolowski, Stephanie M. Gorka and Leah M. Pyter

Cancers 2025, 17(11), 1884; https://doi.org/10.3390/cancers17111884 - 4 Jun 2025

Viewed by 216

Abstract

Background: Cancer-related cognitive impairment (CRCI) is one of the most frequently reported symptoms by breast cancer patients. However, it remains unclear precisely what contributing factors are present among chemotherapy-naïve breast cancer patients that contribute to CRCI. Thus, it is essential to identify [...] Read more.

Background: Cancer-related cognitive impairment (CRCI) is one of the most frequently reported symptoms by breast cancer patients. However, it remains unclear precisely what contributing factors are present among chemotherapy-naïve breast cancer patients that contribute to CRCI. Thus, it is essential to identify potential factors related to CRCI that may occur before chemotherapy so that interventions can be employed to help prevent the worsening of CRCI. Objective: This study examined the association between intolerance of uncertainty (IU) and cognitive function among breast cancer patients before chemotherapy and explored whether anxiety mediates this association. Methods: A total of 58 females diagnosed with stage I-III breast cancer and scheduled for chemotherapy were included in this study. Data on cognitive function, IU, anxiety, and other relevant information were analyzed. Results: We found that higher IU was associated with higher anxiety and such higher anxiety was subsequently associated with lower cognitive function being reported by breast cancer patients who were scheduled for chemotherapy. The association between IU and cognitive function was largely mediated through anxiety with standardized β = −0.19 (SE = 0.07) for the indirect association via anxiety and β = −0.2 (SE = 0.12) for the total association. Conclusions: IU shows an impact on cognitive function. Therefore, it is necessary to assess IU before chemotherapy, which may help detect patient risk for cognitive impairment early. Full article

(This article belongs to the Special Issue Novel Insights into Cancer-Related Cognitive Impairment)

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2 pages, 165 KiB

Open AccessCorrection

Correction: Aghaei et al. The Role of BiP and the IRE1α-XBP1 Axis in Rhabdomyosarcoma Pathology. Cancers 2021, 13, 4927

by Mahmoud Aghaei, Ahmad Nasimian, Marveh Rahmati, Philip Kawalec, Filip Machaj, Jakub Rosik, Bhavya Bhushan, S. Zahra Bathaie, Negar Azarpira, Marek J. Łos, Afshin Samali, David Perrin, Joseph W. Gordon and Saeid Ghavami

Cancers 2025, 17(11), 1883; https://doi.org/10.3390/cancers17111883 - 4 Jun 2025

Viewed by 140

Abstract

There was an error in the original publication [...] Full article

(This article belongs to the Special Issue Targeted Therapies for Pediatric Solid Tumors)

11 pages, 561 KiB

Open AccessReview

Current Progress and Future Perspectives of RNA-Based Cancer Vaccines: A 2025 Update

by Matthias Magoola and Sarfaraz K. Niazi

Cancers 2025, 17(11), 1882; https://doi.org/10.3390/cancers17111882 - 4 Jun 2025

Viewed by 329

Abstract

RNA-based cancer vaccines have emerged as transformative immunotherapeutic platforms, leveraging advances in mRNA technology and personalized medicine approaches. Recent clinical breakthroughs, particularly the success of mRNA-4157 combined with pembrolizumab in melanoma patients, have demonstrated significant improvements in efficacy, with a 44% reduction in [...] Read more.

RNA-based cancer vaccines have emerged as transformative immunotherapeutic platforms, leveraging advances in mRNA technology and personalized medicine approaches. Recent clinical breakthroughs, particularly the success of mRNA-4157 combined with pembrolizumab in melanoma patients, have demonstrated significant improvements in efficacy, with a 44% reduction in recurrence risk compared to checkpoint inhibitor monotherapy. Breakthrough results from pancreatic cancer vaccines and novel glioblastoma treatments using layered nanoparticle delivery systems mark 2024–2025 as a pivotal period for RNA cancer vaccine development. Current RNA vaccine platforms include conventional mRNA, self-amplifying RNA, trans-amplifying RNA, and emerging circular RNA technologies, with over 120 clinical trials currently underway across various malignancies. Critical advances in delivery optimization include next-generation lipid nanoparticles with tissue-specific targeting and novel nanoengineered systems achieving rapid immune system reprogramming. Manufacturing innovations focus on automated platforms, reducing production timelines from nine weeks to under four weeks for personalized vaccines, while costs remain challenging at over $ 100,000 per patient. Artificial intelligence integration is revolutionizing neoantigen selection through advanced algorithms and CRISPR-enhanced platforms, while regulatory frameworks are evolving with new FDA guidance for therapeutic cancer vaccines. Non-coding RNA applications, including microRNA and long non-coding RNA therapeutics, represent emerging frontiers with potential for enhanced immune modulation. With over 60 candidates in clinical development and the first commercial approvals anticipated by 2029, RNA cancer vaccines are positioned to become cornerstone therapeutics in personalized oncology, offering transformative hope for cancer patients worldwide. Full article

(This article belongs to the Special Issue Advances in Drug Delivery for Cancer Therapy)

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19 pages, 2800 KiB

Open AccessReview

The Metabolic Orchestration of Immune Evasion in Glioblastoma: From Molecular Perspectives to Therapeutic Vulnerabilities

by Ravi Medikonda, Matthew Abikenari, Ethan Schonfeld and Michael Lim

Cancers 2025, 17(11), 1881; https://doi.org/10.3390/cancers17111881 - 4 Jun 2025

Viewed by 307

Abstract

Glioblastoma (GBM) is a highly aggressive primary brain cancer with dismal prognoses despite current standards of care. Immunotherapy is being explored for GBM, given its promising results in other solid malignancies; however, the results from early clinical studies in GBM are disappointing. It [...] Read more.

Glioblastoma (GBM) is a highly aggressive primary brain cancer with dismal prognoses despite current standards of care. Immunotherapy is being explored for GBM, given its promising results in other solid malignancies; however, the results from early clinical studies in GBM are disappointing. It has been discovered that GBM has numerous mechanisms of immune resistance, including the physical blood–brain barrier, high intratumoral and intertumoral heterogeneity, and numerous cellular and molecular components in the tumor microenvironment (TME) that promote immunosuppression. Furthermore, GBM utilizes numerous metabolic pathways to establish a survival advantage in the TME. Recently, it has begun to become evident that these complex metabolic pathways that promote GBM growth and invasion also contribute to tumor immune resistance. Aerobic glycolysis provides tumor cells with ample ATP while depleting key glucose and increasing acidity in the TME. Increased glutamine, tryptophan, and arginine metabolism deprives T cells of these necessary amino acids for proper anti-tumor function. Sphingolipid metabolism promotes an immunosuppressive phenotype in the TME and affects immune cell trafficking. This review will discuss, in detail, the key metabolic pathways relevant to GBM pathophysiology which also modulate host immunosuppression. Full article

(This article belongs to the Special Issue Immune Microenvironment and Immunotherapy in Malignant Brain Tumors)

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40 pages, 4276 KiB

Open AccessSystematic Review

The Impact of Genetic Variations on Radiotherapy Toxicity in Breast Cancer Patients: A Meta-Analysis of Acute and Late Skin Adverse Effects

by Andreea Cătană, Andrada-Adelaida Pătrășcanu, Daniela Laura Martin, Mariela Sanda Militaru, Irina Ioana Iordănescu, Alexandru Țîpcu, Patriciu Achimaș-Cadariu and Lorin-Manuel Pîrlog

Cancers 2025, 17(11), 1880; https://doi.org/10.3390/cancers17111880 - 4 Jun 2025

Viewed by 253

Abstract

Background/Objectives: Radiotherapy is a cornerstone in the treatment of breast cancer, yet its use is frequently accompanied by skin toxicities that vary in severity and timing among patients. The objective of this meta-analysis is to systematically evaluate the pooled impact of genetic variations [...] Read more.

Background/Objectives: Radiotherapy is a cornerstone in the treatment of breast cancer, yet its use is frequently accompanied by skin toxicities that vary in severity and timing among patients. The objective of this meta-analysis is to systematically evaluate the pooled impact of genetic variations on the risk and severity of acute and late skin side effects from radiotherapy in breast cancer patients. Materials and Methods: A systematic literature search was conducted across PubMed, Embase, and Scopus to identify studies published between 2014 and 2024 that examined associations between genetic polymorphisms and radiotherapy-induced skin toxicity. Studies were selected based on predefined inclusion and exclusion criteria, and data were synthesized using a random-effects meta-analysis model. The risk of bias was evaluated using the ROBINS-I tool, and publication bias was assessed through funnel plots and Egger’s test. Results: A total of 11 studies involving breast cancer patients were included, identifying associations between various gene polymorphisms and skin toxicity. The pooled analysis revealed that patients with specific genetic variants had a 53% increased risk of acute skin side effects and a 44% increased risk of late effects. Notable implicated genes included XRCC2, IFNG, ATM, TGFB1, and PER3. Significant heterogeneity and publication bias were noted across studies, warranting cautious interpretation. Conclusions: This meta-analysis highlights the role of genetic variation in predicting radiotherapy-induced skin toxicity in breast cancer patients. These findings support the future development of predictive biomarkers and personalized radiotherapy strategies to minimize treatment-related toxicity. Full article

(This article belongs to the Special Issue Breast Cancer: Biomarkers of Diagnosis and Prognosis)

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12 pages, 1060 KiB

Open AccessReview

Role of B-Mode and Contrast-Enhanced Ultrasound in the Diagnostic Workflow of Gastro-Entero-Pancreatic Neuroendocrine Tumors (GEP-NETs)

by Linda Galasso, Maria Grazia Maratta, Valeria Sardaro, Giorgio Esposto, Irene Mignini, Raffaele Borriello, Antonio Gasbarrini, Maria Elena Ainora, Giovanni Schinzari and Maria Assunta Zocco

Cancers 2025, 17(11), 1879; https://doi.org/10.3390/cancers17111879 - 4 Jun 2025

Viewed by 234

Abstract

Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) represent a rare and varied class of neoplasms, characterized by diverse clinical presentations and prognostic trajectories. Accurate and prompt diagnosis is vital to inform and optimize therapeutic decisions. Ultrasound, including standard B-mode imaging and advanced methods such as contrast-enhanced [...] Read more.

Gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) represent a rare and varied class of neoplasms, characterized by diverse clinical presentations and prognostic trajectories. Accurate and prompt diagnosis is vital to inform and optimize therapeutic decisions. Ultrasound, including standard B-mode imaging and advanced methods such as contrast-enhanced ultrasound (CEUS) and endoscopic ultrasound (EUS), serves as a key component in the diagnostic evaluation of these tumors. B-mode US and CEUS provide non-invasive, accessible methods for early detection and characterization. On B-mode imaging, GEP-NETs typically present as well-defined, hyperechoic, or iso-echoic lesions, while CEUS highlights their characteristic vascularity, marked by arterial-phase hyperenhancement and venous-phase washout. Compared to CT and MRI, ultrasound offers real-time, dynamic imaging without ionizing radiation or nephrotoxic contrast agents, making it particularly advantageous for patients requiring frequent monitoring or with contraindications to other imaging modalities. CT and MRI are widely regarded as the preferred methods for staging and surgical planning due to their detailed anatomical visualization. However, ultrasound, especially CEUS, provides a significant adjunctive role in both early detection and the follow-up on GEP-NETs. This analysis delves into the strengths, challenges, and innovations in ultrasound technology for diagnosing pancreatic NETs, focusing on its contribution to comprehensive imaging strategies and its impact on patient care decisions. Full article

(This article belongs to the Special Issue Developments in the Management of Gastrointestinal Malignancies (2nd Edition))

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Open AccessReview

Development in Esophagectomy for Esophageal Cancer: The Current Standing Point of Robotic Surgery

by Yosuke Morimoto, Satoru Matsuda, Yuki Hirata, Yuki Hoshi, Masashi Takeuchi, Hirofumi Kawakubo and Yuko Kitagawa

Cancers 2025, 17(11), 1878; https://doi.org/10.3390/cancers17111878 - 4 Jun 2025

Viewed by 319

Abstract

Despite advancements in multidisciplinary treatment, esophagectomy remains the primary curative treatment for esophageal cancer. Given that lymph node metastases can spread from the cervical to abdominal regions, three-field lymph node dissection has been established as a standard approach. However, this highly invasive procedure [...] Read more.

Despite advancements in multidisciplinary treatment, esophagectomy remains the primary curative treatment for esophageal cancer. Given that lymph node metastases can spread from the cervical to abdominal regions, three-field lymph node dissection has been established as a standard approach. However, this highly invasive procedure involves multiple anatomical regions—thoracic, abdominal, and cervical—leading to significant surgical burden. To reduce surgical invasiveness, minimally invasive esophagectomy (MIE) has become increasingly common worldwide. With its adoption and advancements in multidisciplinary therapy, discussions have emerged regarding the potential omission of lymph node dissection in selected cases. Since the introduction of robot-assisted minimally invasive esophagectomy (RAMIE) in 2004, this technique has progressively replaced conventional MIE. Robotic systems—equipped with a magnified 3D camera, articulated instruments, and tremor filtering—allow surgeons to perform complex procedures with greater precision than manual techniques. One randomized controlled trial (RCT) has demonstrated fewer postoperative complications with RAMIE compared to open esophagectomy. Additionally, RAMIE has been shown to enable more extensive lymph node dissection around the left recurrent laryngeal nerve than conventional MIE. However, the long-term oncological benefits of RAMIE remain unproven, as no RCTs have definitely confirmed its impact on long-term survival in esophageal cancer patients. Ongoing randomized trials are expected to provide further insights into its prognostic benefits. Full article

(This article belongs to the Special Issue Current Treatments of Esophageal and Esophagogastric Junction Cancers)

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11 pages, 810 KiB

Open AccessArticle

Intravenous Iron for Perioperative Anaemia in Colorectal Cancer Surgery: A Nested Cohort Analysis

by Dominic Fritche, Frances Wensley, Yanika L. Johnson, Callum Robins, Mai Wakatsuki, Imogen C. Fecher-Jones, Lisa Sheppard, Malcolm A. West, Alice Aarvold, Mark R. Edwards, Michael P. W. Grocott, James Plumb and Denny Z. H. Levett

Cancers 2025, 17(11), 1877; https://doi.org/10.3390/cancers17111877 - 3 Jun 2025

Viewed by 204

Abstract

Background/Objectives: Iron deficiency anaemia (IDA) is a common complication in patients with colorectal cancer presenting for surgery. Perioperative IDA is associated with increased post-operative mortality and morbidity. The impact on clinical outcomes for the active management of anaemia before surgery, with treatments such [...] Read more.

Background/Objectives: Iron deficiency anaemia (IDA) is a common complication in patients with colorectal cancer presenting for surgery. Perioperative IDA is associated with increased post-operative mortality and morbidity. The impact on clinical outcomes for the active management of anaemia before surgery, with treatments such as intravenous (IV) iron, is uncertain. Methods: We performed a single-centre nested cohort study, analysing prospectively collected data from patients with colorectal cancer who were treated with IV iron prior to elective major abdominal surgery. Cox proportional hazard models were used to quantify the effect of anaemia treatment on length of stay. Other outcomes, including transfusion rates, were estimated using logistic regression analyses. Models were adjusted for age, sex, comorbidities and surgical details. Results: The length of stay was longer for patients with untreated anaemia compared to patients without anaemia (adjusted hazard ratio, HR 0.66 [95% confidence interval, CI 0.45, 0.95]). For patients with anaemia, the length of stay was shorter in those treated when compared to those not treated (adjusted HR 0.59 [95% CI 0.45, 0.78]). Patients with untreated anaemia had higher transfusion rates than patients with treated anaemia (adjusted odds ratio, OR 0.35 [95% CI 0.18, 0.66]) and non-anaemic patients (adjusted odds ratio, OR 0.20 [95% CI 0.07, 0.55]). Conclusions: This study suggests that treating iron deficiency anaemia with IV iron pre-operatively reduces length of stay and transfusion rates in colorectal cancer patients. Full article

(This article belongs to the Special Issue Perioperative and Surgical Management of Gastrointestinal Cancers)

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26 pages, 2730 KiB

Open AccessReview

Cysteine Alkylation in Enzymes and Transcription Factors: A Therapeutic Strategy for Cancer

by Celia María Curieses Andrés, Fernando Lobo, José Manuel Pérez de la Lastra, Elena Bustamante Munguira, Celia Andrés Juan and Eduardo Pérez-Lebeña

Cancers 2025, 17(11), 1876; https://doi.org/10.3390/cancers17111876 - 3 Jun 2025

Viewed by 159

Abstract

Metabolic enzymes and cancer-driving transcriptions factors are often overexpressed in neoplastic cells, and their exposed cysteine residues are amenable to chemical modification. This review explores cysteine alkylation as a cancer treatment strategy, focusing on Michael acceptors like curcumin and helenalin, which interact with [...] Read more.

Metabolic enzymes and cancer-driving transcriptions factors are often overexpressed in neoplastic cells, and their exposed cysteine residues are amenable to chemical modification. This review explores cysteine alkylation as a cancer treatment strategy, focusing on Michael acceptors like curcumin and helenalin, which interact with transcription factors NF-κB, STAT3 and HIF-1α. Molecular docking studies using AutoDockFR revealed distinct binding affinities: curcumin showed strong interactions with STAT3 and NF-κB, while helenalin exhibited high affinity for STAT3 and HIF-1α. Synthetic compounds like STAT3-IN-1 and CDDO-Me demonstrated superior binding in most targets, except for CDDO-Me with HIF-1α, suggesting unique structural incompatibilities. Natural products such as zerumbone and umbelliferone displayed moderate activity, while palbociclib highlighted synthetic-drug advantages. These results underscore the importance of ligand−receptor structural complementarity, particularly for HIF-1α’s confined binding site, where helenalin’s terminal Michael acceptor system proved optimal. The findings advocate for integrating computational and experimental approaches to develop cysteine-targeted therapies, balancing synthetic precision with natural product versatility for context-dependent cancer treatment strategies. Full article

(This article belongs to the Special Issue Research on Targeted Drugs in Cancer)

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12 pages, 1941 KiB

Open AccessArticle

Breast Cancer Orbital Metastases: Clinical and Histopathological Characteristics, Imaging Features, and Disease-Related Survival in a Multicentric Retrospective Case Series

by Sofia Peschiaroli, Adriana Iuliano, Giovanni Cuffaro, Francesco M. Quaranta Leoni, Tommaso Tartaglione, Monica Maria Pagliara, Maria Grazia Sammarco, Carmela Grazia Caputo, Angela Santoro, Matteo Barchitta, Vittoria Lanni, Diego Strianese and Gustavo Savino

Cancers 2025, 17(11), 1875; https://doi.org/10.3390/cancers17111875 - 3 Jun 2025

Viewed by 188

Abstract

Background: This study aims to analyze the clinical, radiological, and histopathological features, as well as the long-term follow-up, of patients with breast carcinoma orbital metastases. Methods: The study was a multicentric retrospective observational case series. The medical records of 32 female [...] Read more.

Background: This study aims to analyze the clinical, radiological, and histopathological features, as well as the long-term follow-up, of patients with breast carcinoma orbital metastases. Methods: The study was a multicentric retrospective observational case series. The medical records of 32 female patients affected by breast carcinoma orbital metastases referred to three tertiary referral centers from January 2016 to December 2023 were reviewed. The demographic characteristics of the population, clinical ophthalmological presentation, histological features, orbital metastasis latency, disease-related survival (DRS), and mortality rate were analyzed. Results: The median age of the patients was 62.50 years (interquartile range (IQR): 74.50–57.50). The prevalent histotype of the orbital metastases of breast cancer was lobular carcinoma (75.00% of cases). The median orbital metastasis latency time was 39.50 months (IQR: 134.00–10.25). The median disease-related survival (DRS) during the observational period was 35 months, and the 24-month survival rate was 70.73%. The overall mortality rate in our population was 50%. Conclusions: The most frequent histotype of breast cancer orbital metastasis is lobular carcinoma. The primary tumor precedes the onset of orbital metastasis in most cases and usually presents as a mass occupying space and infiltrating the orbit. Orbital metastases are a sign of an advanced stage of the disease, which has a high mortality rate and a low DRS. Full article

(This article belongs to the Special Issue Novel Treatments for Ocular and Periocular Cancers)

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17 pages, 773 KiB

Open AccessArticle

Routes to Diagnosis in Lung Cancer—Do Socio-Demographics Matter? An English Population-Based Study

by Ruth P. Norris, Elizabeth Fuller, Alastair Greystoke, Adam Todd and Linda Sharp

Cancers 2025, 17(11), 1874; https://doi.org/10.3390/cancers17111874 - 3 Jun 2025

Viewed by 215

Abstract

Objectives: Survival from lung cancer is worse in the UK than in some other countries, with late stage at diagnosis implicated in poor prognosis. The route and referral urgency by which patients obtain a diagnosis influence outcomes. This study investigated whether socio-demographic factors [...] Read more.

Objectives: Survival from lung cancer is worse in the UK than in some other countries, with late stage at diagnosis implicated in poor prognosis. The route and referral urgency by which patients obtain a diagnosis influence outcomes. This study investigated whether socio-demographic factors are associated with lung cancer routes to diagnosis in England. Materials and Methods: A total of 181,763 primary invasive lung cancers (ICD-10 C34.0-C34.9) diagnosed from 1 January 2012 to 31 December 2016 were abstracted from the English National Cancer Registration Database. Multivariable logistic regression was used to examine associations between patients’ socio-demographic characteristics and likelihood (adjusted odds ratios) of (i) emergency presentation versus all primary care-initiated routes and (ii) urgent (“two-week wait”/2WW) versus standard primary care-initiated referral. Models included the following factors: deprivation quintile of area of residence at diagnosis (IMD income domain); sex; age; ethnic group; rural/urban residence; and (in the emergency model) region. Results: Socio-demographic variations in diagnosis routes were observed. Patients presenting as emergencies (35.2%) were more likely to be 80 years of age or older, female, of non-White ethnicity, and resident in areas of greater deprivation or the London region. In contrast, 2WW patients (28.3%) were more likely to be aged between 50 and 69 years old, of White ethnicity, and resident in an area of greater deprivation or resident outside of an urban centre; diagnosis through 2WW did not vary by sex. Conclusions: Routes to diagnosis are subject to distinct socio-demographic patterning. Action is needed to ensure that new referral guidelines and lung cancer screening roll-out do not widen socio-demographic inequalities in diagnosis. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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22 pages, 58309 KiB

Open AccessArticle

An Organoid Model for Translational Cancer Research Recapitulates Histoarchitecture and Molecular Hallmarks of Non-Small-Cell Lung Cancer

by Camilla T. Ekanger, Maria P. Ramnefjell, Maren S. F. Guttormsen, Joakim Hekland, Kristin Dahl-Michelsen, Maria L. Lotsberg, Ning Lu, Linda E. B. Stuhr, Laurence Hoareau, Pirjo-Riitta Salminen, Fabian Gärtner, Marianne Aanerud, Lars A. Akslen, James B. Lorens and Agnete S. T. Engelsen

Cancers 2025, 17(11), 1873; https://doi.org/10.3390/cancers17111873 - 3 Jun 2025

Viewed by 291

Abstract

Background: Organoid cultures have received much attention in recent years due to the promise of patient-derived organoid cultures for exploration of personalized cancer treatment strategies. Organoid cultures have been established from a variety of malignancies; however, lack of a thorough histopathological analysis [...] Read more.

Background: Organoid cultures have received much attention in recent years due to the promise of patient-derived organoid cultures for exploration of personalized cancer treatment strategies. Organoid cultures have been established from a variety of malignancies; however, lack of a thorough histopathological analysis has limited the acceptance of organoid models as translational tools. Methods: Here, we aimed to establish patient-derived tumor-organoid (PDTO) models from human non-small-cell lung cancer (NSCLC) resection specimens and provide a thorough histopathological evaluation of the cultures. Results: We show that we were able to establish organoid cultures of lung adenocarcinomas (LUADs) and lung squamous cell carcinomas (LUSCs) successfully, and that the organoid cultures of different subtypes of NSCLC preserved the histoarchitecture and growth pattern of the tumors they derive from. Immunohistochemistry and AB-PAS staining confirmed the subtype-specific protein expression pattern and preserved mucin production in LUAD organoids. The genetic abnormalities of the tumors assessed by immunohistochemistry (IHC-P) were preserved in the organoid cultures. Conclusions: Our thorough study reveals conserved PDTO histopathology, supports further exploration, and encourages using PDTO models in translational research projects. PDTO models hold remarkable promise as patient-specific models and may be applied to predict therapy response in cases where molecular–pathological analyses pose significant management dilemmas, and they also may provide a platform for exploring the molecular mechanisms of therapy resistance in a biologically relevant model system. Full article

(This article belongs to the Special Issue Multicellular 3D Models of Cancer)

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14 pages, 1109 KiB

Open AccessSystematic Review

Impaired Overall Survival of Melanoma Patients Due to Antibiotic Use Prior to Immune Checkpoint Inhibitor Therapy: Systematic Review and Meta-Analysis

by Thilo Gambichler, Sera S. Weyer-Fahlbusch, Jan Overbeck, Nessr Abu Rached, Jürgen C. Becker and Laura Susok

Cancers 2025, 17(11), 1872; https://doi.org/10.3390/cancers17111872 - 3 Jun 2025

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Abstract

Background: The gut microbiome plays a pivotal role in shaping systemic immunity and modulating anti-tumor responses. Preclinical and clinical studies have shown that higher gut microbial diversity and the presence of specific commensal taxa correlate with improved responses to immune checkpoint inhibitors (ICI) [...] Read more.

Background: The gut microbiome plays a pivotal role in shaping systemic immunity and modulating anti-tumor responses. Preclinical and clinical studies have shown that higher gut microbial diversity and the presence of specific commensal taxa correlate with improved responses to immune checkpoint inhibitors (ICI) in melanoma. Conversely, broad-spectrum antibiotics can induce dysbiosis, reducing T cell activation and cytokine production, and have been linked to diminished ICI efficacy in several cancer types. Methods: We conducted a systematic review and meta-analysis of seven retrospective cohorts (total n = 5213) comparing overall survival in cutaneous melanoma (CM) patients who did or did not receive systemic antibiotics within six weeks before ICI initiation. From each study, we extracted hazard ratios (HRs) for death, antibiotic-to-ICI interval, ICI regimen (PD-1 monotherapy vs. PD-1 + CTLA-4 combination), cohort size, and country. Pooled log-HRs were estimated under fixed-effect and random-effects (REML) models. Statistical heterogeneity was quantified by Cochran’s Q and I² statistics, and τ². We performed leave-one-out sensitivity analyses, generated a Baujat plot to identify influential studies, applied trim-and-fill to assess publication bias, and ran meta-regressions for regimen, antibiotic timing, sample size, and geography. Results: Under the fixed-effect model, antibiotic exposure corresponded to a pooled HR of 1.26 (95% CI 1.13–1.41; p < 0.001). The random-effects model yielded a pooled HR of 1.55 (95% CI 1.21–1.98; p = 0.0005) with substantial heterogeneity (Q = 25.1; I² = 76%). Prediction intervals (0.78–3.06) underscored between-study variability. Leave-one-out analyses produced HRs from 1.50 to 1.75, confirming robustness, and the Baujat plot highlighted two cohorts as primary heterogeneity drivers. Trim-and-fill adjusted the HR to 1.46 (95% CI 1.08–1.97). In subgroup analyses, combination therapy studies (k = 4) showed a pooled HR of ~1.9 (I² = 58%) versus ~1.3 (I² = 79%) for monotherapy. Meta-regression attributed the largest variance to the regimen (R² = 32%; β(monotherapy) = −0.35; p = 0.13). Conclusions: Pre-ICI antibiotic use in CM is consistently associated with a 26–55% increase in mortality risk, particularly with PD-1 + CTLA-4 combinations, reinforcing the mechanistic link between microbiome integrity and ICI success. Looking ahead, integrating prospective microbiome profiling into clinical trials will be critical to personalize ICI therapy, clarify causality, and identify microbial biomarkers for optimal treatment selection. Prospective, microbiome-integrated trials promise to refine melanoma immunotherapy by tailoring antibiotic stewardship and microbial interventions to enhance patient outcomes. Full article

(This article belongs to the Special Issue Oncology: State-of-the-Art Research in Germany)

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18 pages, 4899 KiB

Open AccessReview

Targeting the Undruggable: Recent Progress in PROTAC-Induced Transcription Factor Degradation

by Hyein Jung and Yeongju Lee

Cancers 2025, 17(11), 1871; https://doi.org/10.3390/cancers17111871 - 3 Jun 2025

Viewed by 344

Abstract

Transcription factors (TFs) play central roles in gene regulation and disease progression but have long been considered undruggable due to the absence of well-defined binding pockets and their reliance on protein–protein or protein–DNA interactions. Proteolysis-targeting chimeras (PROTACs) offer a novel strategy to overcome [...] Read more.

Transcription factors (TFs) play central roles in gene regulation and disease progression but have long been considered undruggable due to the absence of well-defined binding pockets and their reliance on protein–protein or protein–DNA interactions. Proteolysis-targeting chimeras (PROTACs) offer a novel strategy to overcome these limitations by inducing selective degradation of TFs via the ubiquitin–proteasome system. This review highlights recent advances in TF-targeting PROTACs, focusing on key oncogenic TFs such as androgen receptor (AR), estrogen receptor alpha (ERα), BRD4, c-Myc, and STAT family members. Strategies for ligand design—including small molecules, peptides, and nucleic acid-based elements—are discussed alongside the use of various E3 ligases such as VHL, CRBN, and IAP. Several clinically advanced PROTACs, including ARV-110 and ARV-471, demonstrate the therapeutic potential of this technology. Despite challenges in pharmacokinetics and E3 ligase selection, emerging data suggest that PROTACs can successfully target TFs, paving the way for new treatment strategies across oncology and other disease areas. Full article

(This article belongs to the Special Issue Recent Advances in PROteolysis TArgeting Chimeras (PROTACs))

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23 pages, 643 KiB

Open AccessArticle

The Prognostic Value of Tumor Fibrosis in Patients Undergoing Hepatic Metastasectomy for Colorectal Cancer: A Retrospective Pooled Analysis

by Xavier Hernández-Yagüe, Santiago López-Ben, Joan Martínez-Sancho, Maria Rosa Ortíz-Durán, Margarida Casellas-Robert, Ana Aula-Olivar, Cristina Meléndez-Muñoz, Maria Buxó Pujolràs, Bernardo Queralt-Merino and Joan Figueras i Felip

Cancers 2025, 17(11), 1870; https://doi.org/10.3390/cancers17111870 - 3 Jun 2025

Viewed by 202

Abstract

Background: Colorectal cancer (CRC) is a significant global health burden, with liver metastases representing a key prognostic factor. Neoadjuvant chemotherapy (NAC) has improved outcomes in metastatic CRC (mCRC), and tumor regression is commonly assessed using the Rubbia–Brandt classification. The Poultsides classification defines ≥40% [...] Read more.

Background: Colorectal cancer (CRC) is a significant global health burden, with liver metastases representing a key prognostic factor. Neoadjuvant chemotherapy (NAC) has improved outcomes in metastatic CRC (mCRC), and tumor regression is commonly assessed using the Rubbia–Brandt classification. The Poultsides classification defines ≥40% fibrosis as an independent prognostic factor, particularly in patients treated with cetuximab (45.71%). However, the predictive value of this threshold remains under debate, warranting further investigation. Methods: This study evaluates the extent of fibrosis (≥40%) induced by NAC plus anti-epidermal growth factor receptor (anti-EGFR) therapy vs. NAC plus anti-vascular endothelial growth factor (anti-VEGF) therapy in mCRC patients. It also examines the prognostic relevance of the Poultsides and Rubbia–Brandt classifications. A total of 108 patients undergoing liver resection for CRC metastases were included. Statistical analyses were performed using SPSS 28.0 version and R software 4.5 version to compare fibrosis rates and survival outcomes. Results: From September 2005 to January 2023, 108 patients were analyzed: 54 received chemotherapy plus anti-EGFR (Cohort 1), and 54 received chemotherapy plus anti-VEGF (Cohort 2). Fibrosis was significantly higher in Cohort 1 (median 40.0%, IQR: 25.4–53.2) than in Cohort 2 (median 20.6%, IQR: 8.07–36.9), p < 0.001. Overall survival was similar between both cohorts (p = 0.96), with a median follow-up of 41.6 months. Conclusions: Anti-EGFR therapy is associated with greater fibrosis than anti-VEGF, despite similar survival outcomes. The Poultsides classification may be a useful prognostic tool for resected liver metastases in mCRC. Full article

(This article belongs to the Section Clinical Research of Cancer)

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3 pages, 151 KiB

Open AccessCorrection

Correction: Sczelecki, S.; Pitman, J.L. The Validation of a Precursor Lesion of Epithelial Ovarian Cancer in Fancd2-KO Mice. Cancers 2023, 15, 2595

by Sarah Sczelecki and Janet L. Pitman

Cancers 2025, 17(11), 1869; https://doi.org/10.3390/cancers17111869 - 3 Jun 2025

Viewed by 134

Abstract

There was an error in the original publication [...] Full article

(This article belongs to the Topic Animal Model in Biomedical Research, 2nd Volume)

40 pages, 5595 KiB

Open AccessArticle

Neural Network-Based Composite Risk Scoring for Stratification of Fecal Immunochemical Test-Positive Patients in Colorectal Cancer Screening: Findings from South-West Oltenia

by Alexandra-Georgiana Bocioagă, Carmen-Nicoleta Oancea, Dumitru Rădulescu, Bogdan Silviu Ungureanu, Vlad Florin Iovănescu, Dan Nicolae Florescu, Irina-Paula Doica, Victor-Mihai Sacerdoțianu, Liliana Streba, Tudorel Ciurea and Dan-Ionuț Gheonea

Cancers 2025, 17(11), 1868; https://doi.org/10.3390/cancers17111868 - 2 Jun 2025

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Abstract

Background: Colorectal cancer (CRC) remains a major cause of cancer-related mortality worldwide, underscoring the need for more efficient and resource-conscious screening strategies. Methods: We screened 51,437 individuals (50–74 y) in South-West Oltenia, Romania, with FIT values of ≥20 µg Hb/g. Of [...] Read more.

Background: Colorectal cancer (CRC) remains a major cause of cancer-related mortality worldwide, underscoring the need for more efficient and resource-conscious screening strategies. Methods: We screened 51,437 individuals (50–74 y) in South-West Oltenia, Romania, with FIT values of ≥20 µg Hb/g. Of the 2825 FIT-positive individuals, 1550 completed colonoscopy, and we recorded their age, sex, residence, education, comorbidities, medications, and FIT values. After imputing < 8% missing data via multiple imputation, we reduced dimensionality with an autoencoder (ReLU, dropout 0.5, L2, 100 epochs, batch 32) and applied K-Means clustering (k = 5). The following are examples of actionable clusters: Cluster 0 (“High-FIT malignant”): FIT > 200 µg/g, age > 65, diabetes; Cluster 2 (“Low-risk mixed”): FIT 100–199 µg/g, age < 60, no comorbidities; Cluster 3 (“Intermediate-risk older”): FIT 150–200 µg/g, ≥3 comorbidities, rural. Cluster labels were then predicted by a feed-forward neural network (64–32 neurons, dropout 0.6) and validated via 5-fold cross-validation plus a temporal hold-out. Results: Five distinct patient clusters were identified, enabling the development of a composite risk score. Notably, Cluster 0, characterized by elevated FIT levels, exhibited a malignancy rate of 50.91%, while the overall CRC diagnostic rate among colonoscoped patients was approximately 13.87%. This stratification model enhances the diagnostic yield by prioritizing high-risk patients for urgent colonoscopy and sparing low-risk individuals from unnecessary invasive procedures. Conclusions: The AI-driven composite risk score offers a refined framework for CRC risk stratification and optimized resource allocation. Its implementation can lead to earlier detection of advanced lesions, thereby improving patient outcomes. Further external validation on independent cohorts and regions is essential to confirm its broad utility, with potential future integration of additional biomarkers (e.g., genetic or omics-based indicators) to further enhance predictive accuracy. Full article

(This article belongs to the Section Clinical Research of Cancer)

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22 pages, 640 KiB

Open AccessReview

Innovative Approaches to Early Detection of Cancer-Transforming Screening for Breast, Lung, and Hard-to-Screen Cancers

by Shlomi Madar, Reef Einoch Amor, Sharon Furman-Assaf and Eitan Friedman

Cancers 2025, 17(11), 1867; https://doi.org/10.3390/cancers17111867 - 2 Jun 2025

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Abstract

Early detection of cancer is crucial for improving patient outcomes. Traditional modalities such as mammography and low-dose computed tomography are effective but exhibit inherent limitations, including radiation exposure and accessibility challenges. This review explores innovative, non-invasive cancer screening methods, focusing on liquid biopsy [...] Read more.

Early detection of cancer is crucial for improving patient outcomes. Traditional modalities such as mammography and low-dose computed tomography are effective but exhibit inherent limitations, including radiation exposure and accessibility challenges. This review explores innovative, non-invasive cancer screening methods, focusing on liquid biopsy and volatile organic compound (VOC)-based detection platforms. Liquid biopsy analyzes circulating tumor DNA and other biomarkers in bodily fluids, offering potential for early detection and monitoring of treatment response. VOC-based detection leverages unique metabolic signatures emitted by cancer cells, detectable in exhaled breath or other bodily emissions, providing a rapid and patient-friendly screening option. We provide a comprehensive overview of these advanced multi-cancer detection techniques to enhance diagnostic accuracy, accessibility, and patient adherence, and ultimately enhance survival rates and patient outcomes. Full article

(This article belongs to the Section Cancer Causes, Screening and Diagnosis)

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Cancers, Volume 17, Issue 11 (June-1 2025) – 166 articles

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