Search Results (203)

Bone metastasis remains a significant cause of morbidity and diminished quality of life in patients with advanced breast, prostate, and lung cancers. Emerging research highlights the pivotal role of reversible epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling complex dysregulation, and non-coding RNA networks, in orchestrating each phase of skeletal colonization. Site-specific promoter hypermethylation of tumor suppressor genes such as HIN-1 and RASSF1A, alongside global DNA hypomethylation that activates metastasis-associated genes, contributes to cancer cell plasticity and facilitates epithelial-to-mesenchymal transition (EMT). Key histone modifiers, including KLF5, EZH2, and the demethylases KDM4/6, regulate osteoclastogenic signaling pathways and the transition between metastatic dormancy and reactivation. Simultaneously, SWI/SNF chromatin remodelers such as BRG1 and BRM reconfigure enhancer–promoter interactions that promote bone tropism. Non-coding RNAs, including miRNAs, lncRNAs, and circRNAs (e.g., miR-34a, NORAD, circIKBKB), circulate via exosomes to modulate the RANKL/OPG axis, thereby conditioning the bone microenvironment and fostering the formation of a pre-metastatic niche. These mechanistic insights have accelerated the development of epigenetic therapies. DNA methyltransferase inhibitors (e.g., decitabine, guadecitabine) have shown promise in attenuating osteoclast differentiation, while histone deacetylase inhibitors display context-dependent effects on tumor progression and bone remodeling. Inhibitors targeting EZH2, BET proteins, and KDM1A are now advancing through early-phase clinical trials, often in combination with bisphosphonates or immune checkpoint inhibitors. Moreover, novel approaches such as CRISPR/dCas9-based epigenome editing and RNA-targeted therapies offer locus-specific reprogramming potential. Together, these advances position epigenetic modulation as a promising axis in precision oncology aimed at interrupting the pathological crosstalk between tumor cells and the bone microenvironment. This review synthesizes current mechanistic understanding, evaluates the therapeutic landscape, and outlines the translational challenges ahead in leveraging epigenetic science to prevent and treat bone metastases. Full article

Background/Objectives This systematic review and network meta-analysis aimed to determine the most effective therapeutic exercise modality for improving quality of life (QoL) in patients with advanced-stage cancer. Specifically, the study compared the effects of aerobic training, strength training, and combined aerobic and strength training on QoL outcomes. Methods A systematic literature search was conducted in PubMed, Embase, Cochrane Reviews, and the Cochrane Central Register of Controlled Trials up to 24 February 2023. The review adhered to PRISMA guidelines. Included studies were randomized controlled trials (RCTs) involving adult patients with advanced-stage cancers (e.g., pancreatic, colorectal, lung, breast, prostate, gastrointestinal, gynecological, hematological, head and neck, melanoma, or cancers with bone metastases). The primary outcome was post-intervention QoL, while the secondary outcome assessed was the dropout rate across exercise modalities. Results Aerobic training demonstrated the greatest improvement in QoL with a standardized mean difference (SMD) of 0.30 (95% CI: 0.00 to 0.61), followed by strength training (SMD = 0.13; 95% CI: −0.41 to 0.66) and combined training (SMD = 0.07; 95% CI: −0.11 to 0.24). However, none of the interventions showed statistically significant superiority. Dropout rates were comparable across all exercise modalities and control groups, suggesting strong adherence and feasibility of these interventions in advanced cancer populations. Conclusions While all exercise modalities were associated with improved QoL in patients with advanced-stage cancer, no single intervention emerged as significantly superior. Aerobic exercise may offer a slight advantage, although this effect was not statistically significant. These results highlight the importance of individualized exercise prescriptions based on patient preference, functional status, and treatment context. Further research is warranted to identify patient subgroups that may benefit most from specific exercise interventions and to explore QoL subdomains such as fatigue, emotional well-being, and physical functioning. Full article

Background/Objectives: Prolonged use of denosumab in patients with metastatic breast cancer has raised concerns about the development of medication-related osteonecrosis of the jaw (MRONJ). However, the threshold at which the risk increases remains unclear. Methods: This retrospective cohort study analyzed patients with breast cancer and bone metastases who received denosumab between May 2012 and August 2024. Associations between cumulative denosumab administration and MRONJ were evaluated using univariate and multivariate logistic regression analyses. A receiver operating characteristic (ROC) analysis was used to determine the optimal cutoff for cumulative doses. Results: MRONJ developed in 101 patients (31.2%). Multivariate analysis identified cumulative denosumab administration (odds ratio [OR]: 1.05, 95% confidence interval [CI]: 1.03–1.06; p < 0.001) and a history of tooth extraction (OR: 4.40, 95% CI: 2.23–8.71; p < 0.001) as independent risk factors for MRONJ. ROC analysis determined an optimal cutoff of 32 cumulative doses, with an area under the curve of 0.83 (95% CI: 0.78–0.88; p < 0.0001). Conclusions: Cumulative denosumab administration and history of tooth extraction were independent risk factors for MRONJ in patients with breast cancer and bone metastases. The risk of MRONJ increased after 32 cumulative doses, providing a clinically actionable threshold for risk assessment and patient monitoring. Full article

De novo metastatic breast cancer (dnMBC) accounts for 3–10% of newly diagnosed cases, with 20–40% presenting as a bone-only metastatic disease, which can achieve survival outcomes exceeding 10 years with multimodal therapy. However, the role of multimodal therapy remains controversial in the guidelines. Objective: This study aims to identify dnBOMBC subgroups to develop a pragmatic staging system for guiding locoregional therapy decisions. Materials and Methods: Data from the MF07-01 phase III randomized trial (2021, median follow-up time (mFT): 40 months (range 1–131)) and the BOMET prospective multi-institutional registry trial (2021, mFT: 34 months (range 25–45)) were combined for analysis, including only patients who presented with bone-only metastases. Exclusion criteria were patients under 18 and those with a history of prior cancer or cancer metastases. Patients with missing data and positive surgical margins were excluded. Out of 770 patients, 589 were included. Survival analyses were first conducted according to molecular subgroups, after which patients were further stratified by hormone receptor status, human epidermal human epidermal growth factor receptor 2 (HER2) status, tumor grade, and clinical T (cT) stage. Group A (GrA) included hormone receptor (HR)-positive, low- or intermediate-grade tumors at any cT; HR-positive, high-grade tumors with cT0–3; or any HER2-positive tumors. Group B (GrB) included HR-positive, high-grade tumors with cT4 disease or any triple-negative (TN) tumors. Results: The hazard of death (HoD) was 43% lower in GrA than in GrB. Median OS was 65 months (39–104) for GrA patients and 44 months (28–72) for GrB patients (HR 0.57, 95% CI 0.41–0.78, p = 0.0003). Primary tumor surgery (PTS) significantly improved OS in GrA patients, regardless of the number of metastases (solitary: HR, 0.375, 95% CI 0.259–0.543, p < 0.001; multiple: HR 0.435, 95% CI 0.334–0.615, p < 0.001). Conversely, GrB patients did not experience a significant benefit from PTS. Conclusions: This study demonstrates that GrA patients have better OS than GrB patients, and PTS reduces the HoD in GrA patients compared to systemic therapy alone. These findings support using a modified staging system in dnBOBMC to identify patients who may benefit from multimodal therapy including PTS. Full article

Breast cancer (BC) frequently metastasizes to bone, leading to poor patient prognosis. The infiltration of cancer cells in bone impairs its homeostasis, triggering a pathological interaction between tumors and resident cells. Preclinical models able to mimic the bone microenvironment are needed to advance translational findings on BC mechanisms and treatments. We designed strontium-doped calcium phosphate cement to be employed for culturing cancer and bone cells and developed an in vitro bone metastasis model. The platform was established step by step, starting with the monoculture of cancer cells, mature osteoblasts (OBs) differentiated from mesenchymal stem cells, and mature osteoclasts (OCs) differentiated from Peripheral Blood Mononuclear Cells. The model was implemented with the co-culture of cancer cells with OBs or OCs, or the co-culture of OBs and OCs, allowing us to discriminate the interaction between the actors of the bone metastatic niche. The biomimetic material was further challenged with bone metastasis patient-derived material, showing good versatility and biocompatibility, suggesting its potential use as bone substitute. Overall, we developed a bone-mimicking model able to reproduce reciprocal interactions between cancer and bone cells in a biomimetic environment suitable for studying the biomolecular determinants of bone metastasis and, in the future, as a drug efficacy platform. Full article

In this article, we present a case of a 49-year-old woman presenting with a recurrent metastatic neuroendocrine tumor. Background: Insulinomas are neuroendocrine tumors derived from beta cells of the pancreas that secrete insulin. Usually, they are benign tumors; however, metastatic insulinomas are an extremely rare malignant form of these tumors, carrying a significantly worse prognosis. Case Presentation: A 49-year-old woman, a patient in the University Hospital in Wroclaw in the Department of Endocrinology, Diabetes and Isotope Therapy, first presented with abdominal pain in 2009, when ultrasound and further examination led to the diagnosis of a tumor in the pancreas (a solid pseudopapillary tumor of the pancreas—meta NET G2), and the patient underwent distal pancreatectomy with splenectomy. For ten years, she was under observation, and her symptoms, such as abdominal pain, nausea, weight loss, and general weakness, reappeared in 2019. Then, magnetic resonance imaging (MRI) showed a lesion in the liver, and further histopathology revealed neuroendocrine tumor (NET) metastasis to the liver. In 2022, the patient presented with loss of consciousness and convulsion, loss of weight, and hypoglycemia after meals. In April 2022, the daily glycemic profile was recorded and a 72 h fasting test was performed; however, their results excluded insulinoma. Positron emission tomography–computed tomography (PET-CT) with 18F-fluorodeoxyglucose (18F-FDG) and PET with gallium-68-DOTA-(Tyr3)-octreotate (68Ga-DOTA-TATE) showed a metastatic proliferative process in the liver. Persistent hypoglycemia led to another hospitalization in May 2022, and repeated tests allowed for the diagnosis of insulinoma. Treatment with somatostatin analogs and diazoxide was started. A CT scan in November 2022 and a PET scan in January 2023 showed new metastases to the liver, bones, and cervical lymph nodes, and it was decided to intensify the treatment. In May 2023, the patient was qualified for Lutathera treatment for insulinoma at the University Clinical Hospital in Poznań. In June 2023, another disturbing symptom was reported by the patient, a painful lump in the breast. During diagnostics, metastases with high proliferation markers were found in both breasts. Two months later, in August 2023, the patient received another dose of Lutathera. In October 2023, significant progression of liver lesions, metastases to bones of the spine, ribs, and pelvis, and periaortic and pelvic lymphadenopathy were found as well as elevated values of neuron-specific enolase and calcitonin. The patient was also referred to the Palliative Medicine Home Hospice. In consultation with the Lower Silesian Cancer Center, the decision was made to forgo further treatment with PRRT and initiate systemic chemotherapy. Despite the chosen treatment, the patient died on 27/DEC/2023. Conclusions: This case report can serve clinicians, as it presents a case of an extremely rare and insidious tumor, metastatic insulinoma. Full article

The applicability of RHT in the treatment and supportive care of tumors has been discussed for years in many publications. There are hundreds of articles that have reported on the good acceptance and feasibility of HT, as well as its value in terms of controlling malignant diseases, enhancing response and, in some randomized controlled trials (RCTs), clear improvements in OS. Despite this, HT has never fully been accepted as a standard treatment among radiation and medical oncologists. The increased activity that HT offers in the context of chemotherapy (CHT), radiotherapy (RT), chemoradiotherapy (CRT), and immunotherapy, thus facilitating programmed cell death (PCD), has been documented in many studies. This aspect has been demonstrated in many tumors, including soft tissue sarcoma, cancers of the cervix, esophagus, stomach, colon/rectum, pancreas, breast, head and neck, and prostate, and bone metastases. HT improves cancer cell death through many modalities, targeting both the tumor microenvironment (TME) and the cancer cells directly. Targeted HT increases the temperature of the primary tumor and surrounding tissues to 39–43 °C, causing the tumor cells to become more immune-responsive. HT can also activate the immune response of the TME through inducing heat shock proteins (HSPs), which also promote an immunological response and PCD. HT can oxygenate hypoxic tumors, facilitating RT-induced DNA damage in cancer cells. At present, it seems that the combination of HT and RT, CHT, and immunotherapy might lead to immune enhancement effects in the TME, making cancer cells more responsive to immunotherapies. This narrative review presents the novel aspects of HT reported in recent years. Full article

Receptor activator of nuclear factor-κB ligand (RANKL) is essential for osteoclast formation and bone resorption, in osteolytic conditions such as osteoporosis and bone metastases. However, its role in metastasis progression remains incompletely understood. Herein, we examined whether the overexpression of human RANKL in transgenic mice (TgRANKL) affects their susceptibility to breast cancer bone metastasis compared to their wild-type (WT) littermates. Bone metastasis was induced by injecting EO771 mouse mammary adenocarcinoma cells into the caudal artery of syngeneic WT and TgRANKL mice. RANKL overexpression led to an earlier onset and increased burden of bone metastasis in EO771-bearing TgRANKL mice compared to WT mice. It also exacerbated the bone destruction caused by metastasis-associated osteolysis. The prophylactic inhibition of RANKL activity with denosumab, a monoclonal antibody targeting human RANKL, prevented osteolysis and significantly reduced the incidence and progression of bone metastases in TgRANKL mice. However, the therapeutic denosumab treatment had no effect on metastasis incidence or tumor burden, although it alleviated osteolysis. The treatment with zoledronic acid, an anti-resorptive agent inhibiting osteoclast activity, yielded results similar to those of denosumab. These findings emphasize the significance of initiating early treatment with anti-resorptive agents such as denosumab or zoledronic acid to reduce the risk of bone metastasis in patients at high risk. Full article

Background: Cutaneous toxicities associated with CDK4/6 inhibitors are uncommon but may affect treatment adherence. We present the case of a patient with advanced breast cancer who developed vitiligo-like lesions after initiating ribociclib, contributing to the growing evidence of this under-recognized adverse effect. Methods: We present the case of a 72-year-old woman diagnosed in 2007 with early-stage, luminal A, HER2-negative breast cancer, initially treated with surgery and tamoxifen. In 2022, she experienced locoregional recurrence with bone metastases. In January 2023, she began treatment with ribociclib plus letrozole. Two months later, she developed intense pruritus, xerosis, and paresthesia, followed by hypopigmented lesions on her face and upper extremities. Clinical evaluation, supported by photographs and a skin biopsy (led to a diagnosis of ribociclib-induced vitiligo. Management included dose adjustments to the ribociclib and dermatologic treatments, including topical corticosteroids, antihistamines, and short courses of oral prednisone. Results: By September 2024, her skin lesions had stabilized and her pruritus improved with a reduced dose of ribociclib (one tablet per day). However, the hypopigmented patches persisted, mainly on her face and extremities. Despite these cutaneous effects, she maintained an acceptable quality of life and continued effective oncologic treatment. Conclusions: This case highlights the importance of early recognition and management of ribociclib-related cutaneous toxicities. A multidisciplinary approach is essential to minimize adverse effects without compromising therapeutic efficacy. Further research into the dermatologic manifestations of targeted therapies is needed to optimize patient care. Full article

Background and Objectives: Standard treatment in metastatic breast cancer with positive estrogen receptors and negative HER2neu is represented by CDK4 inhibitors combined with aromatase inhibitors or fulvestrant. Palliative radiotherapy is indicated for symptoms or local–regional control. Multiple preclinical data suggest a potential synergistic effect when CDK4/6 inhibitors and radiotherapy are administered concurrently. We are trying to address some questions and/or to establish correlations within a subgroup of patients with unusual toxicities, the safety of combined treatments, the correlation with radiotherapy techniques and fractionation schemas. Also, we are aware that some organs at risk of a rapid turnover are more vulnerable to the occurrence of acute toxicities. Materials and Methods: This retrospective study includes 20 patients with metastatic breast cancer, treated with CDK4 inhibitors and radiotherapy on 29 disease sites; we followed the compliance and toxicities of combined treatments. Results: Regarding the recorded hematological toxicities, grade 1 associated with CDK4 inhibitors, occurring anterior radiotherapy was recorded; grade 2, leucopenia during radiotherapy presented in three cases without radiotherapy interrupting and leucopenia with neutropenia grade 3 presented in one case after pleural secondary lesion’s irradiation. Non-hematological grade 3 toxicities occurred in two cases: one case with grade 3 enteritis, at 2 weeks from bone metastases irradiation—iliac bone (in field toxicity) and one case with radiodermitis during radiotherapy on the breast and lymph node level, in the second week of external radiotherapy (RTE). Conclusions: In all analyzed cases, we obtained control of irradiated lesions. Secondary toxicities occurred only in irradiated areas. A close monitoring of patients during combined treatment must be considered and we are confident that in the future it will be possible to identify the subgroup of patients with a high risk of unusual toxicities occurring; additionally, we hope that using more conforming radiotherapy techniques minimizes the organ being at risk from radiation doses. Full article

Bone metastases represent a critical complication in oncology, frequently indicating advanced malignancy and substantially reducing patient quality of life. This review provides a comprehensive analysis of the complex interactions between tumor cells and the bone microenvironment, emphasizing the relevance of the “seed and soil” hypothesis, the RANK/RANKL/OPG signaling axis, and Wnt signaling pathways that collectively drive metastatic progression. The molecular and cellular mechanisms underlying the formation of osteolytic and osteoblastic lesions are examined in detail, with a particular focus on their implications for bone metastases associated with breast, prostate, lung, and other cancers. A central component of this review is the categorization of pathological biomarkers into four types: diagnostic, prognostic, predictive, and monitoring. We provide a comprehensive evaluation of circulating tumor cells (CTCs), bone turnover markers (such as TRACP-5b and CTX), advanced imaging biomarkers (including PET/CT and MRI), and novel genomic signatures. These biomarkers offer valuable insights for early detection, enhanced risk stratification, and optimized therapeutic decision-making. Furthermore, emerging strategies in immunotherapy and bone-targeted treatments are discussed, highlighting the potential of biomarker-guided precision medicine to enhance personalized patient care. The distinctiveness of this review lies in its integrative approach, combining fundamental pathophysiological insights with the latest developments in biomarker discovery and therapeutic innovation. By synthesizing evidence across various cancer types and biomarker categories, we provide a cohesive framework aimed at advancing both the scientific understanding and clinical management of bone metastases. Full article

Bone metastases are a prevalent and debilitating consequence of various cancers, including breast and prostate carcinomas, which significantly compromise patient quality of life due to pain, fractures, and other skeletal-related events (SREs). This review examines the pathophysiology of bone metastases, emphasizing the role of the bone microenvironment in tumor progression through mechanisms such as osteotropism and the dysregulated bone remodeling cycle. The primary focus is on the emerging nano-drug delivery systems (DDS) designed to target the bone microenvironment and improve the therapeutic index of anticancer agents. Current treatments, mainly comprising bisphosphonates and radiotherapy, provide palliative benefits but often have limited efficacy and significant side effects. Innovative strategies, such as bisphosphonate-conjugated nanoparticles and targeted therapies that utilize the unique bone marrow niche, are explored for their potential to enhance drug accumulation at metastatic sites while minimizing systemic toxicity. These approaches include the use of liposomes, polymeric nanoparticles, and inorganic nanoparticles, which can be functionalized to exploit the biological barriers within the bone microenvironment. This review also discusses the challenges and future directions for nano-DDS in clinical settings, emphasizing the need for multidisciplinary research to effectively integrate these technologies into standard care protocols. Full article

Background/Objectives: The goal of this study is to characterize the survival patterns and outcomes of women with early-stage breast cancer, with a particular emphasis on the distinction between HER2-low and HER2-zero expression. There is limited real-world data on how patients with HER2-negative or HER2-low metastatic or recurrent breast cancer are treated. Methods: We retrospectively analyzed the medical records of 1500 breast cancer patients diagnosed between January 2020 and December 2024. From this cohort, 99 patients with HER2-low and 34 patients with HER2-zero early-stage breast cancer were included in our analysis. HER2 low was defined as Immunohistochemistry (IHC) 1+ or IHC 2+ with negative Silver In situ Hybridization (SISH), while HER2 zero was defined as IHC 0. Statistical analyses, including Kaplan–Meier survival analyses and log-rank tests for group comparisons, were performed using IBM SPSS Statistics. Results: The median age of patients was 55 years. The HER2-zero group exhibited a higher incidence of brain, liver, bone, and lung metastases (p < 0.001 for all) and increased use of CDK4/6 inhibitors (p < 0.001). In univariate analyses, younger age, an HER2-zero status, and the absence of metastases were associated with improved disease-free survival (DFS) and overall survival (OS). However, in multivariate analyses, an HER2-zero status independently predicted longer DFS (HR = 0.14, 95% CI: 0.05–0.41, p < 0.001) and OS (HR = 0.16, 95% CI: 0.042–0.6, p = 0.007). Conclusions: Our study revealed distinct metastatic patterns and survival outcomes between HER2-low and HER2-zero early-stage breast cancers. Despite a higher metastatic burden in univariate analyses, HER2 zero status was independently associated with longer DFS and OS in multivariate analyses, highlighting their biological heterogeneity and the need for further research to inform tailored strategies. Full article

A 56-year-old female with a history of Luminal A breast cancer, previously treated with surgery, radiotherapy, and systemic therapy, underwent palliative re-irradiation in November 2024 for painful bone metastases. Three weeks later, following the initiation of Fulvestrant, she developed a grade 3 erythematous reaction localized to the re-irradiated area. The reaction persisted with minimal improvement over two months, despite symptomatic management. No infectious or allergic etiologies were identified, and dosimetric analysis confirmed that the delivered radiation dose to the skin was insufficient to directly induce such a reaction. Notably, the erythema was most pronounced along a pre-existing surgical scar, suggesting a localized inflammatory response. Given the temporal relationship with Fulvestrant administration, we hypothesize a drug-induced recall-like phenomenon, though no previous reports have specifically linked Fulvestrant to such an event. This case underscores the need for awareness of unexpected cutaneous reactions following re-irradiation and highlights the potential role of systemic therapies in modulating local tissue responses. Full article

Bone metastases are a major concern in cancer management since they significantly contribute to morbidity and mortality. Metastatic lesions, commonly arising from breast, prostate, lung, and kidney cancers, affect approximately 25% of cancer patients, leading to severe complications such as pain, fractures, and neurological deficits. This narrative review explores contemporary approaches to bone metastases, emphasizing a multidisciplinary strategy and the evolving concept of oligometastatic disease. Oligometastases, defined by limited metastatic spread (1–5 lesions), offer a potential window for curative treatment through aggressive interventions, including stereotactic ablative radiotherapy and resection surgery. Tumor boards, integrating systemic therapies with local interventions, are crucial to optimize treatment. Despite promising results, gaps remain in defining optimal treatment sequences and refining patient selection criteria. Future research should focus on personalized approaches, leveraging biomarkers and advanced imaging to enhance outcomes and the quality of life in patients with bone metastases. Full article