Search Results (1,206)

Gastric cancer remains a major clinical challenge, underscoring the need for more effective drug delivery strategies. Approximately 10–20% of gastric cancers overexpress HER2, conferring aggressive tumor characteristics and poor survival, yet resistance to trastuzumab-based targeted therapy and limited intratumoral antibody penetration continue to restrict clinical outcomes. This study evaluated HER2-targeted exosomes as a delivery platform. Exosomes were engineered to express the p51 peptide, a high-affinity HER2-binding ligand, and loaded with 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a potent HSP90 inhibitor. The cellular uptake and antitumor efficacy of p51-Exo^17-DMAG were assessed in vitro using NCI-N87 and AGS cells and in vivo using a mouse xenograft model. p51-modified exosomes exhibited superior HER2 specific uptake. Treatment with p51-Exo^17-DMAG significantly increased apoptosis, as demonstrated by elevated PARP and caspase3 cleavage, and downregulated oncogenic signaling molecules, including p-AKT, CDK2, VEGF, and c-Myc. Furthermore, p51-Exo^17-DMAG increased the number of TUNEL-positive cells. In the NCI-N87 xenograft model, systemic administration of p51-Exo^17-DMAG significantly inhibited tumor growth without toxicity or histological damage to major organs. Tumor analysis confirmed increased apoptosis and reduced proliferation in vivo. These findings demonstrate that p51-engineered exosomes provide an efficient, selective, and safe platform for HER2-targeted delivery of 17-DMAG, offering a promising precision medicine strategy for HER2-positive gastric cancer. Full article

Background: Pathogenic BRCA1 and BRCA2 mutations confer a homologous recombination deficiency that underlies PARP inhibitor sensitivity. While BRCA1 mutation carriers more frequently develop triple-negative breast cancer (TNBC) and BRCA2 carriers hormone receptor-positive (HR+) disease, whether the specific protein domain harboring a pathogenic somatic mutation differs systematically between breast cancer subtypes remains uncertain. Apparent domain enrichment in earlier unfiltered analyses may be confounded by missense variants of uncertain significance (VUSs), which lack clinical actionability. Methods: We assembled three independent breast cancer cohorts via cBioPortal: TCGA-BRCA (brca_tcga_pub2015), METABRIC (brca_metabric), and MSK-CHORD (msk_chord_2024). All somatic BRCA1/2 mutations were mapped to UniProt-annotated functional domains and to Rebbeck-defined breast/ovarian cancer cluster regions (BCCR/OCCR). Per ENIGMA/ACMG guidance, pathogenic mutations (nonsense, frameshift, and canonical splice site) were analyzed inferentially, while missense and in-frame variants—predominantly VUSs—were only reported descriptively. Fisher’s exact tests with Benjamini–Hochberg FDR correction were applied across domain × subtype contingencies. Cohort heterogeneity was assessed via Cochran’s Q and I² statistics; pooled effect estimates were computed using inverse-variance fixed-effects meta-analysis. Results: A total of 394 somatic BRCA1/2 mutations were identified across the three cohorts (BRCA1 n = 166; BRCA2 n = 228), of which 147 (37.3%) met pathogenic criteria. Among 131 pathogenic mutations in HR+/HER2− or TNBC subtypes, 84 (64.1%) occurred in HR+/HER2− disease and 47 (35.9%) in TNBC. Domain-level distributions did not differ significantly between subtypes for any BRCA1 domain (BRCT: TNBC 20.0% vs. HR+ 18.8%, OR = 1.08, 95% CI 0.31–3.78, and FDR-adjusted p = 1.00) or BRCA2 domain (DBD: TNBC 17.6% vs. HR+ 30.8%, OR = 0.48, and FDR-adjusted p = 1.00). Cluster-region analyses (nine Rebbeck BCCR/OCCRs) similarly showed no significant enrichment. Post hoc power analysis indicated that the study could only reliably detect large effects (OR ≥ ~3.0 for the principal BRCT contrast), and formal equivalence testing (TOST) demonstrated equivalence within a prespecified ±20% margin for BRCA1 BRCT (TOST p = 0.031). Heterogeneity across cohorts was minimal (Cochran’s Q = 0.62, I² = 0.0%). Descriptive analyses of VUSs suggested the apparent enrichment of BRCA1 BRCT-localized missense variants in TNBC (31.8% vs. 17.9% in HR+), but this signal did not extend to pathogenic mutations. Conclusions: Within the statistical power available, our three-cohort analysis shows no evidence of large subtype-specific enrichment of pathogenic BRCA1/2 somatic mutations across protein domains or cluster regions; small to moderate effects cannot be excluded. Notably, the majority (64%) of pathogenic mutations occurred in HR+/HER2− disease, underscoring that BRCA1/2 testing should not be deprioritized in non-TNBC subtypes. The apparent BRCT enrichment observed in earlier unfiltered analyses appears to be driven by VUSs rather than pathogenic variants, highlighting the methodological necessity of pathogenicity filtering for clinically actionable inference. These findings provide cohort-scale supportive evidence for emerging clinical guidelines that recommend broader BRCA1/2 testing across breast cancer subtypes. Full article

Lactylation is an emerging lactate-derived post-translational modification that may link tumour metabolic reprogramming, epigenetic regulation and DNA damage repair. Enhanced glycolysis and lactate accumulation are common in many tumours, and lactate has been reported to induce histone and non-histone lactylation in specific experimental contexts. Recent studies suggest that lactylation is associated with several DNA repair pathways, including base excision repair/single-strand break repair, nucleotide excision repair, homologous recombination and non-homologous end joining, and may contribute to therapy resistance in selected cancer models. Specifically, XRCC1 lactylation has been reported to promote nuclear translocation and repair activity in glioblastoma models; H4K12 lactylation has been linked to PARP inhibitor resistance through RAD23A activation in ovarian cancer models; and BLM lactylation has been associated with enhanced homologous recombination repair in bladder cancer models. Lactylation of NBS1, RAD51 and XLF has also been implicated in DNA repair regulation in specific experimental systems, although some mechanistic links are inferred from pathway activation or functional rescue experiments rather than directly demonstrated across multiple tumour types. These findings suggest that lactylation may modulate DNA repair and therapeutic response in a context-dependent manner. Targeting lactate metabolism, transport and lactylation regulators, including LDHA, MCT1/4, ACAT1, AARS1 and GCN5, or using site-specific lactylation-inhibiting peptides may improve chemotherapy and PARP inhibitor efficacy, but clinical translation remains limited by heterogeneity, metabolic plasticity, toxicity and insufficient validation. Full article

Background/Objectives: Poly (ADP-ribose) polymerase (PARP1) has emerged as a promising therapeutic target in human breast cancer particularly in BRCA1/2 mutation carriers where a synthetic lethal interaction leads to massive tumor cell death upon specific inhibitors’ administration. Current clinically approved PARP inhibitors (Talazoparib and Olaparib) show outstanding therapeutic capabilities but suffer from severe side effects. Most importantly, some of them can cause life-threatening cardiotoxicity through hERG off-target effects. Here, we performed an extensive study to identify lead compounds with improved binding modes and favorable predicted pharmacokinetics using an integrated computational strategy. Methods: An artificial intelligence-driven drug design (AIDDISON™ v2023) workflow was employed to search ultra-large chemical space libraries for active compounds, which were then optimized via computer-aided methods to form a PARP-Tailored Database (PTD). This database was then analyzed through a virtual screening workflow, molecular docking studies, molecular dynamics (MD) simulations, MM/GBSA binding free energy calculations, DFT analysis and ADME/Tox predictions using the Schrödinger suite (v2023-2), MobaXterm v25.2, Gaussian 16.0, ProTox-3 and Pred-hERG v5.0 respectively. Results: Three compounds (1a–1c) were identified as promising candidates. Among them 1a appeared to be the most active compound with a favorable docking score (−9.488 kcal/mol) that is not only higher than 1b and 1c but also higher than that of Talazoparib (−6.778 kcal/mol). MD simulations of 1a–1c in the active site revealed an average RMSD of ~2.5–3.6 Å which is better compared to the parent Talazoparib (5.6 Å). Interestingly, on the 250 ns extended MD study, 1a exhibited a slightly reduced RMSD between 2.4 and 3.2 Å, whereas Talazoparib retained higher fluctuations of ~5 Å to 6 Å. MM/GBSA binding energy analysis indicated 1a to have better predicted binding affinity (−67.820 kcal/mol), which is also better than Talazoparib (−63.734 kcal/mol). DFT calculations showed good electronic properties and in silico ADMET studies also indicated 1a to have good drug-likeness and lower predicted hepatotoxicity and cardiotoxicity risk. Conclusions: These findings identify compound 1a as a promising lead, while compounds 1b and 1c remain viable candidates for further optimization. However, experimental validation is critical to confirm the predicted biological activity and safety profiles. Full article

The therapeutic landscape of advanced and recurrent endometrial cancer (EC) has evolved substantially in recent years due to the integration of molecular classification and novel systemic therapies. This review summarizes current treatment strategies in advanced EC, focusing on immunotherapy, targeted therapies, and molecularly guided approaches. Immune checkpoint inhibitors (ICIs) have become a cornerstone of treatment, particularly in mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) tumors, where durable clinical benefit has been observed. Recent phase III trials demonstrated that the addition of ICIs to platinum-based chemotherapy significantly improves progression-free survival in the first-line setting, especially in dMMR disease, with more modest but clinically meaningful benefit in mismatch repair-proficient (pMMR) tumors. In the post-platinum setting, combinations such as pembrolizumab plus lenvatinib have expanded treatment options for pMMR patients, despite increased toxicity. Advances in molecular profiling, including the ProMisE classification, are increasingly guiding treatment personalization. Emerging therapies, including PARP inhibitors and antibody–drug conjugates targeting HER2 and Trop-2, are showing promising activity. Despite these advances, challenges remain regarding resistance mechanisms, optimal treatment sequencing, and predictive biomarkers beyond MMR status. Full article

Metastatic triple-negative breast cancer (mTNBC) remains one of the most challenging therapeutic settings in oncology. Although it has traditionally been defined by the absence of hormone receptor expression—estrogen receptor (ER) and progesterone receptor (PR)—and HER2 amplification or overexpression, this simplified definition fails to capture the biological complexity that drives its marked clinical heterogeneity, therapeutic resistance, and prognostic variability. Over the past decade, multiple studies have challenged the notion of TNBC as a single disease entity, identifying distinct molecular subtypes, including Basal-like 1 (BL1), Basal-like 2 (BL2), Mesenchymal (M), Mesenchymal Stem-like (MSL), Immunomodulatory (IM), and Luminal Androgen Receptor (LAR), each characterized by specific biological programs and therapeutic vulnerabilities. In parallel, clinically oriented systems such as the Fudan classification have enabled the prospective evaluation of subtype-guided therapeutic strategies in metastatic disease, as illustrated by the FUTURE and FUTURE-SUPER trials. In this review, we examine the molecular classification and clinical behavior of mTNBC subtypes, integrating genomic, transcriptomic, epigenetic, immunologic, stromal, and biomechanical dimensions of tumor heterogeneity. We also discuss emerging tools, including single-cell RNA sequencing, spatial transcriptomics, circulating tumor DNA analysis, long non-coding RNA profiling, and surrogate immunohistochemistry-based classifiers, as well as their potential role in refining patient stratification. From a therapeutic perspective, we review subtype-guided strategies involving chemotherapy, platinum agents, PARP inhibitors, immunotherapy, antiandrogen therapy, PI3K/AKT/mTOR pathway inhibition, antiangiogenic approaches, and antibody–drug conjugates. Redefining mTNBC through biologically driven stratification represents a rational strategy to optimize treatment selection, support clinical trial design, and accelerate the development of precision oncology approaches. However, clinical implementation requires greater methodological standardization, validated predictive biomarkers, accessible diagnostic platforms, and dynamic monitoring strategies capable of capturing subtype evolution under therapeutic pressure. TNBC should therefore not be regarded as a single disease, but as a spectrum of biologically distinct and clinically evolving entities whose integrated characterization may be essential to improving outcomes in this historically poor-prognosis population. Full article

Background: Triple-negative breast cancer (TNBC) remains a clinical challenge due to its aggressive nature and the frequent emergence of therapeutic resistance. While the role of protein-coding genes in DNA repair is well-documented, the regulatory contributions of the non-coding genome, specifically long intergenic non-coding RNAs (lincRNAs), remain largely undefined. Objectives: In this study, we characterize the biological significance of LincRNA-BC7, a novel transcript identified within the breast cancer field effect. Methods: Through a combined in silico and in vitro approach, we investigated the transcriptional dynamics of the LincRNA-BC7/miR-663a/BRCA1 axis in response to the PARP inhibitor, Olaparib. Results: Our results demonstrate that Olaparib induces selective cytotoxicity in BRCA1-deficient MDA-MB-231 cells while sparing non-cancerous HEK293 cells, a response accompanied by a significant downregulation of LincRNA-BC7 and a reciprocal upregulation of BRCA1. Bioinformatics analysis through BLASTN, miRBase, and KEGG revealed that LincRNA-BC7 contains highly complementary binding sites for miR-663a, suggesting it functions as a competing endogenous RNA (ceRNA) or “molecular sponge.” Conclusions: By sequestering miR-663a, LincRNA-BC7 appears to modulate the expression of critical signaling nodes within the PI3K-AKT and TP53 pathways, thereby influencing cellular sensitivity to DNA-damaging agents. These findings suggest that LincRNA-BC7 is a key determinant of the aggressive TNBC phenotype and the response to PARP inhibition. Our study establishes the LincRNA-BC7/miR-663a axis as a novel biomarker for precision risk stratification and a promising therapeutic target to enhance treatment outcomes in BRCA1-associated breast cancers. Full article

Background/Objectives: PI3K/AKT/mTOR is a key pathway in cell proliferation, metabolism, and survival. Activating PIK3CA mutations are seen in up to 20% of colorectal cancers and are associated with increased cyclo-oxygenase-2 (COX-2) expression. Recent studies demonstrated a significant survival benefit from taking low-dose aspirin, a nonselective COX inhibitor, supporting further exploration of the synergistic effects of combined PI3Kα inhibitor (inavolisib) and COX-2 inhibitor (celecoxib) therapy. Methods: The effects of celecoxib–inavolisib combination treatment were tested on human colorectal cancer cell lines and patient-derived organoid models. Experiments included cell viability and colony formation assays, immunoblotting, and immunofluorescence. Results: We found that celecoxib and inavolisib demonstrated synergy in suppressing the growth of colorectal cancer cell lines, grown in both 2D and 3D cell culture, regardless of PIK3CA mutation status. In patient-derived organoid models, while synergy was seen in both organoids, growth of the PIK3CA mutated organoid was more potently suppressed. Immunoblotting of cells after combination treatment showed decreased expression of mitogenic signaling marker p-AKT across all 2D cell lines and in both cell lines grown as 3D spheroids, as well as increased expression of apoptotic marker cPARP in four out of five 2D cell lines and in both cell lines grown as 3D spheroids. Immunofluorescence staining of organoids after combination treatment, however, showed no significant increase in expression of apoptotic marker Cas-3 nor in mitogenic marker Ki-67 in either organoid. Furthermore, an apoptosis assay performed on two cell lines showed no significant increase in Annexin V or phosphatidylserine staining. Conclusions: Celecoxib and inavolisib demonstrated synergy in suppressing the growth of both colorectal cancer cell lines and patient-derived organoids, though PIK3CA mutation status did not appear to affect drug efficacy in cell lines as it did in patient-derived organoids. Potential compensatory or resistance mechanisms might include oncogene drivers in the MAPK/ERK pathway. When compared to monotherapy, combination therapy was the only drug condition to significantly increase the percentage of apoptotic cells based on Annexin V and phosphatidylserine staining, and this effect was only seen in the PIK3CA mutated cell line. Ultimately, our findings provide preliminary support for celecoxib–inavolisib combination treatment as a rational therapeutic avenue warranting further preclinical investigation. Full article

Epithelial ovarian cancer (EOC) remains one of the most lethal gynecologic malignancies, largely owing to advanced-stage presentation, high rates of relapse, and the eventual emergence of therapeutic resistance. Despite the transformative success of immune checkpoint inhibitors (ICIs) across multiple solid tumors, their clinical impact in ovarian cancer has been comparatively modest. This literature review provides a comprehensive synthesis of recent advances in ICI strategies for ovarian cancer (OC), with particular emphasis on phase II and III clinical trials evaluating programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), and T cell immunoglobulin and mucin-domain-containing-3 (TIM-3)-directed therapies. Accumulating evidence indicates that PD-1/PD-L1 monotherapy yields limited clinical activity in unselected OC populations, with low objective response rates and minimal survival benefit. Dual checkpoint blockade with PD-1 and CTLA-4 inhibitors demonstrates enhanced antitumor activity, particularly in clear cell ovarian carcinoma (CCOC), albeit at the expense of increased immune-related toxicity. Large randomized trials incorporating ICI into first-line chemotherapy or maintenance settings have largely failed to improve outcomes in biomarker-unselected cohorts. Available evidence demonstrates that combinatorial approaches integrating ICI with anti-angiogenic agents, PARP inhibitors, or neoadjuvant chemotherapy provide modest benefit in selected molecular and histologic subgroups. Early-phase investigations of TIM-3–targeting strategies further expand the immunotherapeutic landscape, although clinical efficacy remains preliminary. Current evidence underscores that OC is not uniformly responsive to immunotherapy and that rational combination strategies, biomarker-driven patient selection, and improved understanding of tumor immune microenvironment heterogeneity are essential to unlocking the full therapeutic potential of ICI in this disease. Full article

Background: Glioblastoma (GBM) remains a lethal malignancy due to temozolomide (TMZ) resistance and limited drug penetration across the blood–brain barrier, largely driven by hyperactive DNA damage repair mechanisms such as poly (ADP-ribose) polymerase (PARP). To address these challenges, we developed folic acid-targeted PLGA–zein hybrid core–shell nanoparticles for the codelivery of the alkylating agent TMZ and the natural PARP inhibitor Ellagic acid (FA-TMZ/EA-PZ-CS NPs), thereby enabling simultaneous enhancement of drug delivery and suppression of chemoresistance pathways. Methods and Results: The dual-drug nanoplatform was fabricated using a double-emulsion solvent evaporation method and functionalized via EDC/NHS-mediated folic acid conjugation to promote receptor-mediated uptake. Physicochemical characterisation confirmed uniform spherical morphology, high colloidal stability, efficient drug encapsulation, and sustained biphasic drug release consistent with a core–shell diffusion mechanism. In LN229 glioblastoma cells, folic acid conjugation significantly enhanced cellular internalisation and cytotoxic efficacy compared to free drugs and non-targeted nanoparticles. Combination index analysis revealed strong synergism between TMZ and ellagic acid, resulting in markedly reduced IC₅₀ values. Mechanistic studies demonstrated apoptosis induction, increased DNA damage, inhibition of cell migration at sub-cytotoxic concentrations, and downregulation of PARP gene expression. Conclusion: Overall, this study establishes a targeted core–shell nanotherapeutic strategy that integrates chemotherapy with DNA repair inhibition to overcome TMZ resistance, offering a mechanistically sound strategy that serves as a foundational framework for future translational research. Full article

Cancer is a complex and evolutionary disease, with the development of different types of cancers leading to various different defective gene mutations. Synthetic lethality is a genetic-level precision medical strategy. Currently, treating BRCA (BReast CAncer)-mutated breast or ovarian cancer cells with a chemical inhibitor (Poly(ADP-ribose) polymerase, PARPi) is a typical synthetic lethal application in clinical practice. However, PARPi therapy has been found to cause off-target effects and therapy-induced immune escape driven by PD-L1 upregulation, allowing for cancer cells to escape attack from the immune response. To overcome these challenges, we developed a core–shell structure comprising a hydrophobic core of quercetin (Q)-mediated PARP inhibition and iron oxide nanoparticles (IONPs), enveloped by a hydrophilic fucoidan (Fu) shell to encapsulate short hairpin RNA targeting Programmed Death Ligand 1 (shPD-L1) for efficient gene transfection (shPD-L1@QIO@Fu). Structurally, the incorporation of quercetin into the intermediate hydrophobic layer enables modulate of the PARP effect, while the inner aqueous core with shPD-L1 gene silencing can inhibit the expression of PD-L1 protein. In this study, we proved that shPD-L1@QIO@Fu demonstrated a dual therapeutic mechanism against BRCA-mutant cancer cells by inducing extensive DNA double-strand breaks and promoting apoptosis. Furthermore, the combined action of quercetin-mediated DNA damage and shPD-L1-driven PD-L1 suppression led to a significant reduction in PD-L1 mRNA to approximately 5% at 72 h and decreased surface PD-L1 below baseline by 96 h. This effectively suppresses PARPi-induced PD-L1 upregulation and enhances antitumor immunity. These findings demonstrate the therapeutic efficacy of shPD-L1@QIO@Fu nanomedicine, providing a promising foundation for advanced co-delivery strategies to synergize PARP inhibition mediated synthetic lethality with immune checkpoint blockade in next-generation precision medicine. Full article

Breast cancer is one of the leading causes of cancer deaths in women worldwide. Neoadjuvant chemotherapy (NACT) has increased rates of breast-conserving procedures and enabled the identification of patients with a particularly poor prognosis. Achieving a pathological complete response (pCR), an indicator of NACT efficacy, contrasts with residual disease (RD), which identifies patients at higher risk of recurrence. This review provides an overview of current evidence on the clinical and prognostic significance of pCR and RD in patients receiving NACT for breast cancer. The analysis is based on data from randomized clinical trials, meta-analyses, and current clinical guidelines for contemporary systemic treatment. Pathological complete response varies according to tumor subtype, with the highest rates observed in triple-negative and non-luminal HER2-positive breast cancer. In HER2-positive disease, the combination of chemotherapy with HER2-targeted therapies increases pCR rates, while the presence of RD supports escalation of postoperative treatment with antibody–drug conjugates. In triple-negative breast cancer (TNBC), the inclusion of platinum agents and immune checkpoint inhibitors improves treatment efficacy. In HER2-negative breast cancer and germline BRCA1/2 mutations, adjuvant PARP inhibitors improve survival independently of pCR, highlighting the complex relationship between pathological response and prognosis. Immunotherapy and targeted therapies are used alongside standard chemotherapy and hormone therapy in perioperative treatment. Further research is required to refine response assessment, integrate new biomarkers such as circulating tumor DNA (ctDNA), and optimize treatment selection, while clarifying the significance of reassessing hormone receptor and HER2 status in residual disease and its impact on subsequent treatment decisions. Full article

A circulating tumor DNA (ctDNA) assay is an emerging non-invasive diagnostic approach providing real-time insights into the heterogeneous tumor molecular landscape of advanced prostate cancer, overcoming the limitations of traditional tissue biopsies and PSA. Detection methods include droplet digital PCR, next-generation sequencing, and new epigenomic and fragmentomic strategies (investigational) designed to improve sensitivity in cases of low ctDNA shedding. While ctDNA’s role in localized prostate cancer is limited, it offers significant prognostic value in metastatic cases, where high ctDNA levels correlate with shorter survival. Additionally, longitudinal ctDNA monitoring can predict treatment response and identify emerging resistance mechanisms, including androgen receptor alterations associated with androgen receptor pathway inhibitor therapy and BRCA reversion mutations linked to PARP inhibitors. Importantly, liquid biopsy enables genomic characterization to inform treatment decision-making, particularly in clinical scenarios where tissue biopsy is challenging, such as bone-only disease. However, the widespread clinical implementation of ctDNA analysis is hindered by several analytical challenges, including low sensitivity in localized disease and low disease burden, and the risk of false positives due to clonal hematopoiesis. Furthermore, greater efforts are required to standardize pre-analytical workflows and post-analytical data interpretation and reporting across institutions. This review aims to summarize the evolving role of cfDNA technologies in localized and advanced prostate cancer, highlighting their prognostic and predictive value and their role in uncovering mechanisms of treatment resistance. Full article

Background: Uterine sarcomas are rare, heterogeneous malignancies with distinct pathological behaviors. This study aimed to identify clinicopathological characteristics, prognostic risk factors, and potential therapeutic targets to enhance clinical management. Methods: A retrospective analysis was conducted on 148 patients with uterine sarcoma treated at Peking University People’s Hospital between 1996 and 2025. Clinical outcomes, pathological subtypes, and immunohistochemical profiles were assessed. Additionally, bioinformatics analyses from RNA bulk sequencing of GEO datasets (GSE87581, GSE85383, GSE222045 and GSE64763) were performed to elucidate molecular characteristics across subtypes. Results: The most prevalent subtypes were uterine leiomyosarcoma (uLMS; 38.5%) and low-grade endometrial stromal sarcoma (LG-ESS; 29.7%). The 5-year recurrence rate was 50.5%, with frequent metastases to the pelvis and lungs. LG-ESS demonstrated the most favorable 5-year survival rate (90.3%), significantly higher than that of uLMS (61.8%) and undifferentiated uterine sarcoma (50.0%). Multivariate analysis identified histological subtype, stage, and coagulative necrosis as independent prognostic factors for overall and progression-free survival. Transcriptomic profiling revealed immunosuppression (CSF1R/CSF3R expression) in high-grade ESS, while uLMS exhibited activation of cell cycle and homologous recombination pathways. Conclusions: Histological subtype, stage, and coagulative necrosis were critical prognostic factors in uterine sarcoma. The findings suggest that vigilant pulmonary surveillance and further investigation into tailored therapeutic strategies may be warranted-including endocrine therapy for hormone-receptor-positive tumors, immunotherapy for high-grade ESS, and PARP inhibitors for uLMS. However, these hypotheses require thorough preclinical and clinical validation. Additionally, caution should be exercised to avoid overtreatment of chemotherapy in early-stage uLMS. Full article

Background and Objectives: Although clinically useful, homologous recombination deficiency (HRD) testing has recently been more broadly adopted in ovarian cancer (OC) management. The VALIDATE study evaluated HRD status and treatment patterns in patients with newly diagnosed advanced OC in Bulgaria to better understand HRD prevalence and disease management. Materials and Methods: This real-world, observational, multi-centre, medical chart review study included 100 adult patients with HRD testing results available at study entry. Data collected at least 30 days after HRD results and 6 months later were descriptively analysed in the full cohort and subgroups (HRD, BRCA mutation, and genomic instability score [GIS]). Results: Mean age at diagnosis: 61.3 years; stage III: 51.0%, prevalence of HRD+ 58.0% (95% confidence intervals [CI] 47.7–67.8%) and HRD− 42.0% (95% CI 32.2–52.3%). Among the 58 HRD+ patients, 20 (34.5%) were BRCA+, whereas 38 (65.5%) were BRCA−, and 52 (89.7%) were GIS+, and 6 (10.3%) GIS−. Overall, platinum–taxane chemotherapy plus antiangiogenics was the most common front-line (FL) treatment (77.0%), regardless of subgroups (range: 66.7–85.0%). Six months later, 81 patients were alive, and 73 (90%) started maintenance therapy (MT). Antiangiogenic monotherapy (32.0%) and antiangiogenic plus PARP inhibitor (34.0%) were the most common MTs. The latter was also common across subgroups (range: 33.3–60.5%), except for HRD− (61.9% received antiangiogenic monotherapy). Conclusions: In this dataset, more than half of advanced OC patients had HRD+ status. Our study provides relevant insights into recent clinical practice patterns in advanced OC in Bulgaria that could serve as an anchor for future, more robust research in this field. Full article