Cancers

36 pages, 1900 KB

Open AccessReview

Rho Small GTPase Family in Androgen-Regulated Prostate Cancer Progression and Metastasis

by Dontrel William Spencer Hairston, Maria Mudryj and Paramita Mitra Ghosh

Cancers 2025, 17(22), 3680; https://doi.org/10.3390/cancers17223680 (registering DOI) - 17 Nov 2025

Background/Objectives: Rho small GTPases (RSG), which regulates metastasis, constitute eight subfamilies—“classical” Rho, Rac, cdc42, and “atypical” Rif, Rnd, Wrch, RhoH, and RhoBTB. Their downstream signaling requires switching between GTP-bound active and GDP-bound inactive forms. Classical RSGs, but not atypical RSGs, require regulation [...] Read more.

Background/Objectives: Rho small GTPases (RSG), which regulates metastasis, constitute eight subfamilies—“classical” Rho, Rac, cdc42, and “atypical” Rif, Rnd, Wrch, RhoH, and RhoBTB. Their downstream signaling requires switching between GTP-bound active and GDP-bound inactive forms. Classical RSGs, but not atypical RSGs, require regulation by guanine nucleotide exchange factors (GEF), GTPase-activating proteins (GAP) and guanine nucleotide dissociation inhibitors (GDI) to achieve this switch. The objective of this review is to summarize the roles of RSGs in metastatic prostate cancer (mPCa) and their interaction with the androgen receptor (AR), which regulates this disease. Methods: We summarize the literature that describes the role of RSGs in mPCa, and their interaction with the AR. Results: Classical RSGs mostly promote metastasis (except RhoB), whereas atypical RSGs, with exceptions, mostly prevent it. Their role, however, is context-dependent—e.g. RhoB is tumor-suppressive in AR-null PCa but oncogenic in AR-positive tumors. The AR modulates RSG expression transcriptionally, but also affects their function through modulation of GEFs, GAPs, and GDIs. In turn, RSGs also regulate AR transcriptional activity. Interestingly, RSGs and the AR have non-genomic interactions via membrane-localized AR (mAR) not affected by AR inhibitors. Conclusions: Drugs that target RSGs are needed along with AR inhibitors to prevent mPCa progression. Full article

(This article belongs to the Special Issue Advancements in Molecular Research of Prostate Cancer)

23 pages, 943 KB

Open AccessArticle

The Preoperative Prognosticators of Surgical Margins (R0 vs. R1) in Pelvic Exenteration—A 14-Year Retrospective Study from a Tertiary Referral Centre

by Sabina Ioana Nistor, Roman Mykula, Richard Bell, William Gietzmann, Mahmoud Awaly, Alaa Elzarka, Jennifer Thorne, Jacopo Conforti, Federico Ferrari, Nicholas Symons and Hooman Soleymani majd

Cancers 2025, 17(22), 3679; https://doi.org/10.3390/cancers17223679 (registering DOI) - 17 Nov 2025

Abstract

Background/Objectives: Pelvic exenteration is a complex surgery considered for locally advanced or recurrent pelvic malignancies, entailing a radical en-block resection of multiple adjacent pelvic organs, followed by reconstructive surgery. Achieving R0 resection (complete removal of macroscopic and microscopic disease) is critical for improving [...] Read more.

Background/Objectives: Pelvic exenteration is a complex surgery considered for locally advanced or recurrent pelvic malignancies, entailing a radical en-block resection of multiple adjacent pelvic organs, followed by reconstructive surgery. Achieving R0 resection (complete removal of macroscopic and microscopic disease) is critical for improving survival outcomes. This study aimed to define patient, tumour, and surgical predictors of R0 resection in an irradiated field, thereby optimising patient selection and establishing a surgical roadmap for pelvic exenterations. Methods: Our retrospective observational cohort study includes consecutive patients undergoing exenteration post-radiotherapy for non-ovarian gynaecological malignancies at Oxford University Hospitals between 1 January 2011 and 31 December 2024. The primary outcome was margin status. Secondary outcomes were intraoperative and postoperative complications. Results: Twenty-seven patients were identified, with a median age of 63 years (range 41–81) and median BMI of 27 (range 17–45). Primary tumour sites included the vulva (11.1%), vagina (14.8%), cervix (40.7%), and uterus (33.3%). R0 was achieved in 77.8% (n = 21) of cases. Intraoperative complications occurred in 29.6%, and significant postoperative complications (Clavien-Dindo IIIA/IIIB) in 22.2% of patients. R0 resection was significantly associated with younger age (median 61 vs. 70 years, p = 0.035) and primary cervical tumours (p = 0.036). On univariable logistic regression, tumour size on imaging (p = 0.038, OR 2.9) and on histology (p = 0.020, OR 2.01), and estimated blood loss (p = 0.048, OR 1.002) were significant predictors of R0 resection. None of these variables retained significance in multivariable logistic regression. Conclusions: Tumour size, primary tumour site, and patient age should be considered when selecting patients for pelvic exenteration following radiotherapy, and blood loss should be kept minimal in order to maximise the chances of achieving R0 resection. Full article

(This article belongs to the Section Cancer Therapy)

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12 pages, 482 KB

Open AccessArticle

Social Burden and Healthcare Costs of Colorectal Cancer

by Izabela Gąska, Aleksandra Czerw, Monika Pajewska, Olga Partyka, Andrzej Deptała, Anna Badowska-Kozakiewicz, Natalia Czerw, Dominika Mękal, Katarzyna Sygit, Klaudia Malikowska, Jarosław Drobnik, Piotr Pobrotyn, Dorota Waśko-Czopnik, Tomasz Sowiński, Ewa Bandurska, Weronika Ciećko, Elżbieta Grochans, Anna Maria Cybulska, Daria Schneider-Matyka, Kamila Rachubińska, Petre Iltchev, Tomasz Czapla and Remigiusz Kozlowski Show full author list Hide full author list

Cancers 2025, 17(22), 3678; https://doi.org/10.3390/cancers17223678 (registering DOI) - 17 Nov 2025

Abstract

Background: Colorectal cancer is the third most common malignant cancer, and according to the predictions, the estimated number of new cases will grow in coming years. Therefore, an increase in the costs of the disease will increase as well. Therefore, there is a [...] Read more.

Background: Colorectal cancer is the third most common malignant cancer, and according to the predictions, the estimated number of new cases will grow in coming years. Therefore, an increase in the costs of the disease will increase as well. Therefore, there is a need for continuous research on the costs and the economic burden of colorectal cancer and for reviewing the research results systematically. The current paper presents a literature review regarding the state of knowledge about the costs of treatment and the economic burden of colorectal cancer. Methods: A total of 20 papers from MEDLINE database were included in the final analysis. The review is focused on the estimates of direct costs, i.e., treatment of colorectal cancer, screening after treatment, and indirect costs. Results: the vast majority of studies were focused on direct costs only, which clearly shows the literature gap. Metastatic colorectal cancer was the most frequent category for various treatment cost evaluation. The costs associated with the use of bevacizumab in various combinations were calculated most frequently. Conclusions: Further summarizing review and developing a methodology for standardized comparisons is necessary, specifically addressing indirect costs. Full article

(This article belongs to the Special Issue Cost-Effectiveness Studies in Cancers)

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13 pages, 1336 KB

Open AccessArticle

A Comparative Study of Clinical and Molecular Features of Microsatellite Stable Colorectal Cancer with and Without Liver Metastases

by Tara Magge, Svea Cheng, Shuaichao Wang, Masood Pasha Syed, Bhaghyasree Jambunathan, Ashley Mcfarquhar, Paola Zinser Peniche, Doga Kahramangil Baytar, Aatur Singhi, Anwaar Saeed and Ibrahim Halil Sahin

Cancers 2025, 17(22), 3677; https://doi.org/10.3390/cancers17223677 (registering DOI) - 17 Nov 2025

Abstract

Background: The molecular and clinical underpinnings of worse overall survival outcomes with liver metastasis of CRC are not well-defined. We therefore aimed to investigate molecular and clinical characteristics of liver metastasis of CRC in this comparative study. Methods: Patients diagnosed with metastatic CRC [...] Read more.

Background: The molecular and clinical underpinnings of worse overall survival outcomes with liver metastasis of CRC are not well-defined. We therefore aimed to investigate molecular and clinical characteristics of liver metastasis of CRC in this comparative study. Methods: Patients diagnosed with metastatic CRC from 2014 to 2022 were identified using the institutional molecular database of CRC. Demographic, clinical, and molecular data were collected and analyzed using Fisher’s exact tests for categorical variables, Kaplan–Meier analysis, and multivariate Cox regression analysis. Results: We identified 299 total patients with metastatic CRC, including patients with liver metastasis (n = 205) and non-liver metastasis (n = 94). We observed a significantly higher incidence of liver metastasis among patients with colon cancer compared to rectal cancer (74% vs. 48%, p = 0.00013). There was no significant difference in the incidence of common driver mutations, including KRAS, BRAF, and TP53, in the liver versus non-liver metastasis cohorts. There was a trend toward worse median overall survival among patients with liver metastasis, though this was not statistically significant (42.2 vs. 47.6 months, p = 0.27). Liver metastasis was identified as a significant predictor of shorter time on frontline therapy (HR 1.82, p < 0.001), a surrogate for treatment response, with a median time of 13 months from first- to second-line treatment compared to 19.7 months in the non-liver metastasis cohort (p = 0.00098). KRAS mutations were a significant predictor of worse survival in the liver metastasis cohort only (HR 2.01, p < 0.001), while BRAF mutations were a significant predictor in the non-liver metastasis cohort (HR 3.42, p = 0.006). Conclusions: Liver metastasis of CRC is associated with shorter time on frontline therapy, indicative of potential chemotherapy resistance. Given similar incidence of molecular alterations in patients with liver metastasis and non-liver metastasis, therapeutic resistance may instead be related to the tumor microenvironment of the liver. Most notably, this is the first study to reveal that despite a similar incidence of molecular alterations, driver alterations including BRAF and KRAS mutations may have a distinct impact on survival outcomes depending on the site of metastasis. Full article

(This article belongs to the Special Issue Recent Advance in Colorectal Cancer Liver Metastases)

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27 pages, 1410 KB

Open AccessReview

The Role of Quantitative Ultrasound in Monitoring Neoadjuvant Chemotherapy in Breast Cancer: A Narrative Review

by Hanna Piotrzkowska-Wróblewska

Cancers 2025, 17(22), 3676; https://doi.org/10.3390/cancers17223676 (registering DOI) - 17 Nov 2025

Abstract

Breast cancer remains the most commonly diagnosed malignancy and a leading cause of cancer-related mortality among women worldwide. Neoadjuvant chemotherapy (NAC) is increasingly used, particularly in aggressive subtypes such as HER2-positive and triple-negative breast cancer, where achieving a pathological complete response (pCR) is [...] Read more.

Breast cancer remains the most commonly diagnosed malignancy and a leading cause of cancer-related mortality among women worldwide. Neoadjuvant chemotherapy (NAC) is increasingly used, particularly in aggressive subtypes such as HER2-positive and triple-negative breast cancer, where achieving a pathological complete response (pCR) is strongly associated with improved outcomes. Early and accurate assessment of therapeutic response is therefore essential to enable timely treatment adaptation. Conventional imaging methods—including magnetic resonance imaging (MRI), computed tomography (CT), mammography, and B-mode ultrasound—mainly detect macroscopic tumor shrinkage and often lagging behind biological alterations, as they rely primarily on size-based assessment. Quantitative ultrasound (QUS) is an emerging, non-invasive technique that analyzes raw radiofrequency (RF) ultrasound data to extract spectral, scattering, and attenuation parameters, allowing detailed characterization of tumor microstructure. When combined with parametric mapping, texture analysis, and advanced radiomic or deep learning approaches, QUS can capture subtle tissue alterations at an early stage of therapy and help predict pathological response before conventional imaging detects morphologic change. Integration with molecular and clinical data further enhances predictive performance, enabling adaptive and personalized treatment strategies. This narrative review summarizes current evidence on the clinical utility of QUS in monitoring NAC response in breast cancer, outlines the methodological foundations of this technology, and discusses key challenges to its broader implementation—particularly the need for standardized acquisition and processing protocols, robust interpretive algorithms and large, prospective, multicenter validations to confirm its impact on clinical decision-making and patient outcomes, and to accelerate its translation into precision oncology practice. Full article

(This article belongs to the Special Issue Imaging in Breast Cancer Diagnosis and Treatment)

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22 pages, 4491 KB

Open AccessSystematic Review

Prognostic Significance of Endocrine-Related Adverse Events in Patients with Melanoma, Non-Small Cell Lung Cancer and Urothelial Cancer After Treatment with Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

by Stylianos Kopanos, Charalampos Filippatos, Pantelis Rousakis, Ioannis V. Kostopoulos, Constantin N. Baxevanis, Anastasios Tentolouris, Maria Gavriatopoulou, Ourania Tsitsilonis and Ioannis Ntanasis-Stathopoulos

Cancers 2025, 17(22), 3675; https://doi.org/10.3390/cancers17223675 (registering DOI) - 17 Nov 2025

Abstract

Background/Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized the management of several malignancies, including melanoma, non-small cell lung cancer, and urothelial carcinoma. However, these therapies frequently cause endocrine immune-related adverse events (irAEs), such as thyroid dysfunction, hypophysitis, or autoimmune diabetes, and may carry important [...] Read more.

Background/Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized the management of several malignancies, including melanoma, non-small cell lung cancer, and urothelial carcinoma. However, these therapies frequently cause endocrine immune-related adverse events (irAEs), such as thyroid dysfunction, hypophysitis, or autoimmune diabetes, and may carry important prognostic implications. This systematic review and meta-analysis aimed to determine the incidence, spectrum, and clinical significance of endocrine irAEs across major tumor types. Methods: Following PRISMA guidelines and PROSPERO registration (CRD42025646504), we systematically searched PubMed, Embase, Cochrane CENTRAL, Web of Science, and Scopus for studies reporting endocrine irAEs in ICI-treated patients. Random-effects meta-analyses estimated pooled hazard ratios (HRs) for overall (OS) and progression-free survival (PFS) and odds ratios (ORs) for adverse events. Subgroup and meta-regression analyses explored associations by cancer type, ICI class, and event severity. Results: Forty-three studies comprising 17,399 patients were included. Endocrine irAEs occurred in 11–30% of patients and were associated with improved OS (HR: 0.60, 95% CI: 0.54–0.67; p < 0.001) and PFS (HR: 0.61, 95% CI: 0.54–0.68; p < 0.001). Severe events were most frequent with pembrolizumab in melanoma and non-small cell lung cancer and with anti-programmed death-ligand 1 therapy in urothelial carcinoma. In exploratory meta-regression analyses accounting for cancer type, ICI subclass, and irAE severity, no statistically significant correlation was observed between the occurrence of endocrine irAEs (OR) and survival benefit (PFS HR: 0.20, 95% CI −0.10 to 0.51; p = 0.19; OS HR: 0.14, p > 0.05). Conclusions: The development of endocrine irAEs coincides with favorable long-term survival outcomes but may represent surrogate markers of immune activation rather than direct predictors of ICI efficacy. However, the lack of consistent ≥ 3-year follow-up across studies warrants cautious interpretation. Routine endocrine monitoring and interdisciplinary management are essential to optimize the safety and effectiveness of immunotherapy. Full article

(This article belongs to the Special Issue Immune-Related Adverse Events in Cancer Immunotherapy)

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Graphical abstract

5 pages, 4044 KB

Open AccessCorrection

Correction: Lin et al. Silencing CTNND1 Mediates Triple-Negative Breast Cancer Bone Metastasis via Upregulating CXCR4/CXCL12 Axis and Neutrophils Infiltration in Bone. Cancers 2021, 13, 5703

by Qun Lin, Xiaolin Fang, Gehao Liang, Qing Luo, Yinghuan Cen, Yu Shi, Shijie Jia, Juanmei Li, Wenqian Yang, Andrew J. Sanders, Chang Gong and Wenguo Jiang

Cancers 2025, 17(22), 3674; https://doi.org/10.3390/cancers17223674 (registering DOI) - 17 Nov 2025

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Cell Adhesion Molecules in Metastasis)

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12 pages, 1455 KB

Open AccessArticle

Comprehensive Molecular Diagnostic Tests in Non-Small Cell Lung Cancer: Frequency of ALK, ROS1, RET, and Other Gene Fusions/Rearrangements in a Romanian Cohort

by Ester-Andreea Cohn (Vizitiu), Ecaterina Tataru and Ortansa Csutak

Cancers 2025, 17(22), 3673; https://doi.org/10.3390/cancers17223673 (registering DOI) - 17 Nov 2025

Abstract

Background/Objectives: Lung cancer remains among the most frequently diagnosed malignancies in Romania, with a high mortality rate. Beyond EGFR mutations, clinically relevant genetic alterations in non-small cell lung cancer (NSCLC) include fusions involving ALK, ROS1, RET, and NTRK1/2/3. [...] Read more.

Background/Objectives: Lung cancer remains among the most frequently diagnosed malignancies in Romania, with a high mortality rate. Beyond EGFR mutations, clinically relevant genetic alterations in non-small cell lung cancer (NSCLC) include fusions involving ALK, ROS1, RET, and NTRK1/2/3. This study aimed to determine the prevalence of these mutations in a Romanian cohort and evaluate their associations with clinicopathological features. Methods: DNA and RNA were simultaneously extracted from formalin-fixed, paraffin-embedded (FFPE) tissue sections using the Genexus Purification System (ThermoFisher Scientific). Concentrations were quantified fluorometrically, and gene fusions were analyzed with Ion Torrent NGS (Ion GeneStudio S5) with the Oncomine Focus Assay (ThermoFisher Scientific). Library preparation was automated with the Ion Chef System, and data interpretation was conducted using Ion Reporter. Results: Among 721 newly diagnosed NSCLC patients, 28 (3.88%) harbored gene fusions. Adenocarcinoma prevailed among fusion-positive cases (85.7%). The subgroup included 15 males and 13 females, with a mean age of 63.25 years (range 43–83). ALK fusions were most frequent (1.66% of the cohort; 42.86% of positives), predominantly EML4::ALK. ROS1 fusions were detected in five patients (0.7%), most frequently CD74::ROS1. RET fusions occurred in 1.11%. Rare fusions included one ETV6::NTRK3, one PTPRZ1::MET, and one FGFR3::TACC3 co-occurring with EGFR L858R. Conclusions: Gene fusions were present in a minority of NSCLC cases, with ALK, ROS1, and RET being the most clinically relevant. These alterations were mutually exclusive with common drivers such as EGFR or KRAS. Detection of rare fusions highlights the therapeutic potential of comprehensive NGS profiling in Romanian NSCLC patients. Full article

(This article belongs to the Special Issue Clinical Pathology of Lung Cancer (2nd Edition))

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34 pages, 2643 KB

Open AccessReview

Interplay Between MicroRNAs and Breast Cancer Therapies: Personalized Therapeutic Potential for HER2-Low Breast Cancer

by Eduarda Carvalho, Fernando Schmitt and Nuno Vale

Cancers 2025, 17(22), 3672; https://doi.org/10.3390/cancers17223672 (registering DOI) - 16 Nov 2025

Abstract

HER2-low breast cancer has been recognized as a heterogenous group of tumors influenced by hormone receptor (HR) expression, giving rise to tumors with either a luminal-like phenotype or features resembling triple-negative breast cancer (TNBC). Despite the development of HER2-targeted therapies, several studies have [...] Read more.

HER2-low breast cancer has been recognized as a heterogenous group of tumors influenced by hormone receptor (HR) expression, giving rise to tumors with either a luminal-like phenotype or features resembling triple-negative breast cancer (TNBC). Despite the development of HER2-targeted therapies, several studies have demonstrated their limited efficacy in patients diagnosed with HER2-low breast cancer. However, recent research has led to the development of antibody-drug conjugates (ADCs), such as trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), with the latter showing promising results in treating these patients. Despite this breakthrough, the availability of a single effective therapy fails to account for tumor heterogeneity and may contribute to the emergence of therapy resistance, leaving HER2-low patients without treatment options. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at a post-transcriptional level and are capable of modulating key cellular processes. Recent studies have highlighted their potential as therapeutic targets, contributing to the advancement of personalized, patient-center therapies. In this context, the interplay between miRNAs and HER2-targeted therapies, particularly their modulation of common essential genes and signaling pathways, could reshape HER2-low therapy strategies to transform current practices aimed at improving the overall patient outcomes. Therefore, this review aims to elucidate the mechanisms underlying current HER2-targeted therapy and explore a potential crosstalk with miRNAs, ultimately serving as a guide for the development of personalized therapeutic strategies. Full article

(This article belongs to the Special Issue Novel Strategies to Fight Metastatic Breast Cancer)

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31 pages, 1423 KB

Open AccessReview

Transforming Liver Cancer Therapy: Integrating Molecular Profiling with Precision and Transplant-Based Care

by Seoung Hoon Kim

Cancers 2025, 17(22), 3671; https://doi.org/10.3390/cancers17223671 (registering DOI) - 16 Nov 2025

Abstract

Liver cancer, predominantly hepatocellular carcinoma (HCC), remains a leading cause of cancer-related mortality worldwide. Although systemic therapies have advanced in recent years, overall survival remains limited for many patients. A deeper understanding of the molecular and immunological landscape of HCC has driven the [...] Read more.

Liver cancer, predominantly hepatocellular carcinoma (HCC), remains a leading cause of cancer-related mortality worldwide. Although systemic therapies have advanced in recent years, overall survival remains limited for many patients. A deeper understanding of the molecular and immunological landscape of HCC has driven the emergence of new therapeutic paradigms, from molecularly targeted agents to immune checkpoint blockade. Concurrently, innovations in liver transplantation, liquid biopsy, and multi-omics profiling are reshaping the therapeutic algorithm for selected candidates. This review summarises recent progress in molecular classification, tumour microenvironment mapping, and immune modulation, and examines how these translational insights are redefining clinical practice. Particular emphasis is placed on the integration of molecular markers into transplant eligibility, downstaging strategies, and post-transplant immunosuppression, providing a comprehensive, precision-oriented framework that bridges basic discovery and patient-centred care. Full article

(This article belongs to the Special Issue Transforming Liver Cancer Care: From Molecular Understanding to Novel Therapeutic Strategies)

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13 pages, 772 KB

Open AccessArticle

Cigarette Smoking and Survival of Patients with Non-Melanoma Skin Cancer: A Systematic Literature Review and Meta-Analysis

by Chiara Andreon, Aurora Gaeta, Maddalena Carretti, Alice Graziani, Giulio Tosti, Chiara Doccioli, Maristella Saponara, Giuseppe Gorini, Mariano Suppa, Elisa Di Maggio, Sara Gandini and Saverio Caini

Cancers 2025, 17(22), 3670; https://doi.org/10.3390/cancers17223670 (registering DOI) - 15 Nov 2025

Abstract

Background: Non-melanoma skin cancer (NMSC) is the most frequent cancer in fair-skinned populations and represents a growing public health concern due to its impact in terms of morbidity and treatment costs. While some meta-analyses have investigated cigarette smoking as a risk factor for [...] Read more.

Background: Non-melanoma skin cancer (NMSC) is the most frequent cancer in fair-skinned populations and represents a growing public health concern due to its impact in terms of morbidity and treatment costs. While some meta-analyses have investigated cigarette smoking as a risk factor for NMSC, less is known about its prognostic implications in patients with NMSC. This systematic review and meta-analysis aims to fill this gap by assessing the association between smoking habits and survival in patients with NMSC. Methods: A systematic search was conducted in PubMed and EMBASE up to 25 February 2025, to identify prospective studies of patients with histologically confirmed NMSC that evaluated the association between smoking habits and survival. Study-specific hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were pooled using random effects meta-analysis models. Results: A total of five studies published between 2015 and 2022 were included. The meta-analysis revealed that being a current or ever smoker at diagnosis was associated with a worse overall survival (summary HR 2.42, 95% CI 1.91–3.06). A similar result was observed when smoking exposure was assessed in terms of pack-years or number of cigarettes per day (summary HR 2.44, 95% CI 2.02–2.93). Conclusions: Our findings indicate that cigarette smoking is a negative prognostic factor in these patients, despite the generally excellent prognosis of NMSC. It is reasonable to assume that this unfavourable effect is largely due to the increased risk of developing other life-threatening conditions, in which smoking plays a causal role. These results underscore the clinical relevance of systematically integrating smoking cessation counselling into the routine management of patients with NMSC. Full article

(This article belongs to the Special Issue Skin Cancer Prevention: Strategies, Challenges and Future Directions)

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15 pages, 769 KB

Open AccessArticle

Late Morbidity and Mortality in Survivors of Childhood Ependymoma: A Report from the Childhood Cancer Survivor Study (CCSS)

by Katharine R. Lange, Peter de Blank, Mengqi Xing, Sedigheh Mirzaei, Deo Kumar Srivastava, Kevin Oeffinger, Joseph Neglia, Kevin Krull, Paul C. Nathan, Rebecca Howell, Kirsten K. Ness, Lucie M. Turcotte, Wendy Leisenring, Gregory T. Armstrong, Tara Brinkman, Daniel C. Bowers and Mehmet Fatih Okcu

Cancers 2025, 17(22), 3669; https://doi.org/10.3390/cancers17223669 (registering DOI) - 15 Nov 2025

Abstract

Background/Objectives: Treatment of childhood ependymoma evolved from 1970 to 1999 by reducing radiation volumes and incorporating chemotherapy. The impact of these changes on long-term health outcomes remains unknown. In this report, we evaluated temporal changes in all-cause and cause-specific late mortality, chronic health [...] Read more.

Background/Objectives: Treatment of childhood ependymoma evolved from 1970 to 1999 by reducing radiation volumes and incorporating chemotherapy. The impact of these changes on long-term health outcomes remains unknown. In this report, we evaluated temporal changes in all-cause and cause-specific late mortality, chronic health conditions (CHCs), and subsequent neoplasms (SNs) in the Childhood Cancer Survivor Study (CCSS) cohort of adult survivors of pediatric ependymoma, diagnosed between 1970 and 1999. Methods: A total of 404 five-year survivors of ependymoma (47.5% female, 80.7% non-Hispanic White, median 6 (range 0–20) years at diagnosis, 22 (5–49) years from diagnosis) diagnosed between 1970 and 1999 and enrolled in the Childhood Cancer Survivor Study were evaluated for late (>5 years from diagnosis) mortality, SNs, and CHCs. Outcomes were analyzed by diagnosis decade, radiotherapy, and chemotherapy exposure. Gray’s test compared cumulative incidences. Multivariable piecewise exponential models estimated relative risks (RRs). Results: Whole-brain radiation exposure decreased over time (42.9% (1970s) to 2.7% (1990s)), while focal radiation (21.4% to 68.9%), and chemotherapy (29.5% to 50.2%) use increased. Fifteen-year all-cause late mortality (incidence, 95% CI) remained similar across decades: 1970s (9.3%, 3.4–18.8%), 1980s (14.7%, 9.4–21.2%), 1990s (10.3%, 6.7–14.9%). All-cause late mortality was higher after treatment with whole-brain radiation (22.5%, 11.2–36.5%) compared to focal radiation (11.4%, 7.5–16.1%) or no brain radiation (3.5%, 0.9–9.1%) (p < 0.001), and with chemotherapy (14.4%, 9.6–20.0%) versus without (6.8%, 3.8–11.0%) (p = 0.004). Compared to no brain radiation, the RR (95% CI) of grade 3–4 CHCs increased among survivors treated with focal (2.6, 1.3–5.4) and whole-brain radiation (3.5, 1.5–8.1), while chemotherapy was not associated with CHCs or SNs. Conclusions: Despite reduced radiation volumes and increased use of chemotherapy, late mortality and morbidity among pediatric ependymoma survivors remained largely unchanged across treatment decades. Full article

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

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11 pages, 244 KB

Open AccessArticle

From Sample to Sequencing: The Importance of Pre-Analytical Sample Treatment in NGS Analysis of Patients with Chronic Lymphocytic Leukemia

by Mirjana Suver Stević, Hrvoje Holik, Vlatka Periša, Saška Marczi, Nikolina Kolobarić and Marina Samardžija

Cancers 2025, 17(22), 3668; https://doi.org/10.3390/cancers17223668 (registering DOI) - 15 Nov 2025

Abstract

Background/Objectives: Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by uncontrolled accumulation of B lymphocytes. A key feature of CLL is the presence of genetic aberrations, particularly alterations of chromosome 17, such as deletion of 17q and/or mutations in the TP53 gene. [...] Read more.

Background/Objectives: Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by uncontrolled accumulation of B lymphocytes. A key feature of CLL is the presence of genetic aberrations, particularly alterations of chromosome 17, such as deletion of 17q and/or mutations in the TP53 gene. Since these abnormalities are highly relevant for therapeutic decision-making, assessment of TP53 mutational status is strongly recommended in routine diagnostics. This study aimed to evaluate the reliability of TP53 sequencing results depending on the type of DNA sample analyzed. Methods: DNA was isolated from two different sample types of the same patient: mononuclear cells (CLL1) and purified CD19+ cells (CLL2). The entire coding region of TP53 (exons 2–11), including splice sites (+/− 10 bp), was analyzed using capture-based next-generation sequencing (NGS). Reads were aligned to the GRCh37/hg19 reference genome, and variants were interpreted using DRAGEN Enrichment (Illumina) and Franklin (QIAGEN). Results: In sample CLL1, the NM_000546.6:c.626_627del mutation (Tier I) was identified with a variant allele frequency (VAF) of 57.06%. The same mutation was confirmed in CLL2, but with a higher VAF of 94.78%. Importantly, an additional Tier I mutation (NM_000546.6:c.825_826del) was detected exclusively in CLL2 at a VAF of 1.59%. Both findings met the required sequencing depth as well as coverage per sample, confirming their validity. Conclusions: The study demonstrates that inadequate starting material for DNA isolation may mask low-frequency TP53 mutations, resulting in false-negative results. Accurate detection requires ensuring sufficient CD19+ cell content, which is critical for reliable diagnostics and supports personalized treatment approaches in CLL. Full article

(This article belongs to the Special Issue Chronic Lymphocytic Leukemia: From Genetics to Therapy)

19 pages, 7499 KB

Open AccessArticle

Caught in the Act: Tumor-Immune Interactions in Circulation of Patients with Immune Marker Positive Circulating Tumor Cells

by Amin Naghdloo, Mohamed Kamal, Dean Tessone, Valerie Hennes, James Hicks and Peter Kuhn

Cancers 2025, 17(22), 3667; https://doi.org/10.3390/cancers17223667 (registering DOI) - 15 Nov 2025

Abstract

Background/Objectives: Circulating tumor cells (CTCs) and large extracellular vesicles (LEVs) are key components of the liquid biopsy that provide minimally invasive access to tumor biology. A clinically relevant subset of CTCs coexpressing epithelial and immune markers (im.CTCs) has been described, yet the origin [...] Read more.

Background/Objectives: Circulating tumor cells (CTCs) and large extracellular vesicles (LEVs) are key components of the liquid biopsy that provide minimally invasive access to tumor biology. A clinically relevant subset of CTCs coexpressing epithelial and immune markers (im.CTCs) has been described, yet the origin of this phenotype remains unclear. In this study, we investigated the cellular and molecular context underlying the emergence of immune marker expression on CTCs and LEVs. Methods: Using high-resolution immunofluorescence microscopy of patient-derived blood samples, we identified direct physical interactions between white blood cells (WBCs) and both im.CTCs and im.LEVs, exclusively in patients harboring im.CTCs. Results: In several cases, WBCs partially encapsulated CTCs and LEVs, and quantitative analysis revealed localized enrichment of immune membrane markers at the contact interface, distinguishing these events from random proximity. Proteomic profiling further identified CD4+ T cells as the predominant interacting immune cell type and confirmed the presence of CD45, CD3, and CD4 on the interacting CTCs and LEVs, matching their WBC counterparts. Conclusion: These findings support membrane transfer as a potential mechanism for the acquisition of immune markers by CTCs and LEVs and provide in vivo evidence of contact-dependent tumor-immune interactions in circulation with implications for immune modulation and clinical interpretation of the im.CTC phenotype. Full article

(This article belongs to the Special Issue Recent Advances in Liquid Biopsy Biomarkers of Cancer)

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21 pages, 7923 KB

Open AccessArticle

Epigenetic Regulation of NKT-Cell-Related Gene Signatures and Prognostic Implications in Oropharyngeal Squamous Cell Carcinoma

by Luka Minarik, Rita Khoueiry, Mirela Leskur, Vincent Cahais, Zdenko Herceg, Merica Glavina Durdov and Benjamin Benzon

Cancers 2025, 17(22), 3666; https://doi.org/10.3390/cancers17223666 (registering DOI) - 15 Nov 2025

Abstract

Background: Oropharyngeal squamous cell carcinoma (OPSCC) is a major subtype of head and neck cancer, with prognosis increasingly influenced by the tumour immune microenvironment. Although immune checkpoint inhibitors have improved outcomes for some patients, reliable predictive biomarkers remain limited. Methods: This study aimed [...] Read more.

Background: Oropharyngeal squamous cell carcinoma (OPSCC) is a major subtype of head and neck cancer, with prognosis increasingly influenced by the tumour immune microenvironment. Although immune checkpoint inhibitors have improved outcomes for some patients, reliable predictive biomarkers remain limited. Methods: This study aimed to investigate the prognostic relevance and epigenetic regulation of natural killer T (NKT)-cell-related gene signatures in OPSCC. Clinicopathological and transcriptomic data from 81 OPSCC patients were analysed using single-sample gene set enrichment analysis (ssGSEA) to evaluate immune-related gene set enrichment scores. Associations with overall survival and clinical features were assessed, and candidate prognostic genes were further explored through expression, methylation, and network analyses. Results: High NKT cell differentiation enrichment scores were significantly associated with improved survival and favourable clinical features. Gene-level analyses identified ITK, ZNF683, and ATF2 as key prognostic markers linked to T-cell signalling and epigenetic regulation. Methylation profiling revealed hypermethylation of ITK and hypomethylation of ZNF683 in tumour tissues, suggesting an epigenetic basis for altered gene expression. Conclusions: These findings highlight NKT cell differentiation as a strong prognostic indicator in OPSCC and support further exploration of epigenetic–immunologic interactions as potential therapeutic targets. Full article

(This article belongs to the Special Issue Cancer Genetics and Epigenetics: Their Roles and Clinical Implications (2nd Edition))

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12 pages, 1677 KB

Open AccessArticle

MRI Reflects Meningioma Biology and Molecular Risk

by Julian Canisius, Julia Schuler, Maria Goldberg, Olivia Kertels, Marie-Christin Metz, Chiara Negwer, Igor Yakushev, Bernhard Meyer, Stephanie E. Combs, Jan S. Kirschke, Denise Bernhardt, Benedikt Wiestler and Claire Delbridge

Cancers 2025, 17(22), 3665; https://doi.org/10.3390/cancers17223665 (registering DOI) - 15 Nov 2025

Abstract

Background/Objectives: Large-scale (epi)genomic studies have substantially advanced our understanding of the molecular landscape of meningiomas, most recently embedded in the cIMPACT-NOW update 8. As a result, molecular data are increasingly integrated into risk-adapted treatment algorithms. However, it remains uncertain to what extent [...] Read more.

Background/Objectives: Large-scale (epi)genomic studies have substantially advanced our understanding of the molecular landscape of meningiomas, most recently embedded in the cIMPACT-NOW update 8. As a result, molecular data are increasingly integrated into risk-adapted treatment algorithms. However, it remains uncertain to what extent non-invasive MRI can capture underlying molecular variation and risk. Methods: We assembled a large, single-institution cohort of 225 newly diagnosed meningiomas (WHO grades 1–3) with available preoperative MRI, as well as comprehensive epigenome-wide methylation and copy-number profiling. Tumors were segmented into core and edema regions using a state-of-the-art automated pipeline from the BraTS challenge. Radiomic features were extracted and used to train Random Forest classifiers to predict WHO grade, molecular risk, and specific alterations such as 1p loss in a hold-out test set. Results: Our models achieved accuracy above 91% for integrated molecular risk classification, 87.5% for 1p chromosomal status, and 76.8% for WHO grade prediction, with corresponding AUCs of 0.91, 0.90, and 0.89, underscoring the robustness of radiomic features in capturing histopathological and, especially, molecular characteristics. Conclusions: Preoperative MRI effectively captures the underlying molecular biology of meningiomas and may enable rapid molecular assessment to inform decision-making and prioritization of confirmatory testing. However, it is not yet ready for clinical use, showing lower accuracy for current WHO grade classification. Full article

(This article belongs to the Section Methods and Technologies Development)

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11 pages, 651 KB

Open AccessArticle

Geographic Disparities in Survival After Surgery for Metastatic Bone Disease: A Retrospective Analysis from a German Sarcoma Centre

by Wolfram Weschenfelder, Paula Maria Nickl, Friederike Weschenfelder, Christian Spiegel, Karin Gabriela Schrenk, Thomas Ernst and Mark Lenz

Cancers 2025, 17(22), 3664; https://doi.org/10.3390/cancers17223664 (registering DOI) - 15 Nov 2025

Abstract

Background/Objectives: Metastatic bone disease (MBD) poses an increasing challenge in orthopaedic oncology due to prolonged survival. While clinical prognostic factors are well established, the role of socio-economic determinants remains unclear, particularly within universal healthcare systems. Methods: We retrospectively analysed 243 patients who underwent [...] Read more.

Background/Objectives: Metastatic bone disease (MBD) poses an increasing challenge in orthopaedic oncology due to prolonged survival. While clinical prognostic factors are well established, the role of socio-economic determinants remains unclear, particularly within universal healthcare systems. Methods: We retrospectively analysed 243 patients who underwent surgery for MBD (excluding spine) between 2005 and 2024 at a German sarcoma centre. Socio-economic indicators were derived from national databases and linked to patients’ residential districts. Survival was analysed using Kaplan–Meier estimates and Cox regression, adjusting for clinical confounders. Results: Median postoperative survival was 22 months. Several socio-economic indicators—income, education, and employment—were associated with survival in univariate analysis. In multivariate models, only residential area size remained independently significant (p = 0.047). Patients from villages (<2000 inhabitants) and large cities (>100,000) had poorer survival than those from small or medium-sized towns. This effect persisted after adjustment for tumour type, pathological fractures, and year of surgery. Conclusions: Within a universal healthcare system, residential area size was associated with survival after surgery for MBD, suggesting that regional disparities may persist despite equal formal access to care. Further studies integrating individual-level socioeconomic data are needed to identify mechanisms and guide interventions to reduce geographic inequalities. Full article

(This article belongs to the Special Issue Health Disparities and Outcomes in Cancer Survivors)

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19 pages, 970 KB

Open AccessArticle

Genomic and Demographic Characteristics of Angiosarcoma as Described in the AACR Project GENIE Registry

by Eileen Leach, Amir Jafari, Elijah Torbenson, Beau Hsia and Abubakar Tauseef

Cancers 2025, 17(22), 3663; https://doi.org/10.3390/cancers17223663 - 14 Nov 2025

Abstract

Background: Despite the high mortality associated with angiosarcoma, its low prevalence has limited sample sizes in prior studies. To address these gaps, we analyzed the AACR Project GENIE registry, a large, multi-institutional database. Methods: 359 tumor samples from 346 patients with angiosarcoma were [...] Read more.

Background: Despite the high mortality associated with angiosarcoma, its low prevalence has limited sample sizes in prior studies. To address these gaps, we analyzed the AACR Project GENIE registry, a large, multi-institutional database. Methods: 359 tumor samples from 346 patients with angiosarcoma were identified from the AACR Project GENIE v18.0-public database using cBioPortal. Somatic mutations and copy number alterations were assessed. Statistical significance was assessed by t-test for continuous variables and a chi-squared test for categorical data, with significance set at p < 0.05. Results: Recurrent mutations included TP53 (20.6%), KDR (13.6%), and PIK3CA (10.6%). Copy number alterations occurred in MYC (27.3%), CRKL (10.4%), FLT4 (5.5%), and KDR (4.8%). Homozygous deletions occurred in CDKN2A (6.6%), CDKN2B (6.56%), and MTAP (3.81%). Significant co-occurrence included FAT1-NOTCH2, TP53-ATRX, and NOTCH1-ARID1A. Mutual exclusivity was seen with KDR-FLT4 and KDR-ATRX. Females exhibited enrichment in MYC and HRAS, while males exhibited enrichment in POT1, NTRK2, and FAT1. Compared with primary tumors, metastatic tumors more often displayed ZFHX4, FGFR1, MSI2, HIST1H1C, and TOP1 mutations, while MAPK7 mutations occurred only in primary tumors. Conclusions: In one of the largest genomic analyses of angiosarcoma to date, we identified recurrent alterations, suggesting potential future therapeutic targets. Full article

(This article belongs to the Section Cancer Informatics and Big Data)

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47 pages, 11865 KB

Open AccessReview

The Involvement of the Peptidergic Systems in Breast Cancer Development

by Manuel L. Sánchez, Prema Robinson, Zal Italia, Tan Hoang, Miguel Muñoz and Rafael Coveñas

Cancers 2025, 17(22), 3662; https://doi.org/10.3390/cancers17223662 - 14 Nov 2025

Abstract

The current known data on the involvement of the peptidergic systems in breast cancer progression is overwhelmingly vast. Peptidergic systems are useful tools for imaging, diagnosis, prognosis and treatment of breast cancer. These systems play a crucial role in both basic and clinical [...] Read more.

The current known data on the involvement of the peptidergic systems in breast cancer progression is overwhelmingly vast. Peptidergic systems are useful tools for imaging, diagnosis, prognosis and treatment of breast cancer. These systems play a crucial role in both basic and clinical breast cancer research by enabling the exploration of novel molecular mechanisms, signaling pathways, and the development of effective drug design strategies. Breast cancer cells overexpress peptide receptors; at the same time they are known to interact with peptides that (a) exert an oncogenic action (adrenomedullin 2, endothelin, gastrin-releasing peptide, neurokinin A, neuromedin, neuropeptide Y, neurotensin, substance P, vasoactive intestinal peptide), (b) exert an anticancer action (angiotensin (1–7), ghrelin, peptide YY) or (c) exert dual oncogenic and anticancer effects (adrenomedullin, angiotensin II, bradykinin, corticotropin-releasing factor, β-endorphin, glucagon-like peptide 1, gonadotropin-releasing hormone, kisspeptin, methionine-enkephalin, oxytocin). This indicates that peptides, as well as peptide receptor agonists and antagonists, may serve as antitumor agents due to their diverse actions against breast cancer development, including the inhibition of cell proliferation, migration and invasion, induction of apoptosis, and anti-angiogenesis. Multiple strategies have been developed to combat breast cancer, including peptide receptor silencing; antibodies conjugated to specific signaling proteins; antibodies targeting specific peptide receptors or oncogenic peptides; and the use of peptides or peptide receptor agonists/antagonists loaded with antitumor cargo. Future lines of research are suggested in breast cancer using promising anti-breast-cancer peptide receptor antagonists (HOE-140, exendin (9–39), bosentan, macitentan, PD168,368, CGP71,683A, SR48,692, aprepitant) or agonists (FR190,997, semaglutide, exendin 4, goserelin) mentioned in this review. Peptidergic systems have tremendous anti-breast-cancer clinical potential which must be exploited and developed. Taken together, the available data highlight the enormous promise of translational research into breast cancer and peptidergic systems for the development of effective treatments. A full understanding of the roles played by the peptidergic systems in breast cancer will serve to improve diagnosis and treatment. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies, 2nd Edition)

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