This news section offers Cancer readers timely information on events, public policy analysis, and topical issues. In this issue, the FDA approves a test that enables the identification of patients who are positive for ctDNA and can benefit from adjuvant atezolizumab after cystectomy. In addition, the HERMES trial supports a shortened stereotactic body radiation therapy schedule without added toxicity for patients with prostate cancer, and the FDA grants accelerated approval to BCL‐2 inhibitor sonrotoclax for mantle cell lymphoma.
Unresolved DNA lesions trigger replication stress, forcing cancer cells to hijack DNA damage tolerance (DDT) networks, specifically translesion synthesis (TLS) and template switching, to sustain replication. While DDT prevents lethal fork collapse, error-prone TLS drives mutagenesis, tumor evolution, chemoresistance and radioresistance. Proliferating cell nuclear antigen post-translational modifications dynamically govern pathway selection. Cancer cells exploit this plasticity, creating actionable vulnerabilities such as postreplicative single-stranded DNA gaps. Emerging inhibitors targeting TLS polymerases, upstream regulators such as ubiquitin-specific peptidase 1 (USP1), and critical protein-protein interactions offer unprecedented opportunities for precision oncology. By integrating DDT inhibition with biomarkers such as homologous recombination deficiency and tumor mutational burden, we can drive synthetic lethality, sensitize tumors to genotoxic agents, suppress treatment-induced mutagenesis, and potentially enhance responses to immunotherapy.
BACKGROUND:The role of peri-operative radiation therapy in thymic epithelial tumors remains controversial, and randomized data are lacking. The authors evaluated recurrence patterns, pathologic predictors of recurrence, and long-term survival among patients who underwent surgery and received peri-operative radiation at a high-volume tertiary center. METHODS:The authors conducted a retrospective cohort study of patients who had thymic malignancies treated surgically between 2004 and 2021. Clinical, pathologic, and treatment data were collected. Outcomes were assessed using Kaplan-Meier and Cox regression methods, and propensity score overlap weighting was applied to adjust for baseline differences between the radiation and no-radiation groups. RESULTS:In total, 360 patients were included, of whom 175 (48.6%) received peri-operative radiation. Among irradiated patients, 62 (35.4%) developed recurrence, most commonly in the pleura (76%); in-field recurrences were rare (5%). Tumor invasiveness was the strongest predictor of recurrence, particularly vascular invasion (odds ratio, 6.0; 95% confidence interval, 2.3-15.7). Histologic subtype was not associated with recurrence. Survival did not differ between groups on unadjusted comparison (hazard ratio, 1.02; 95% confidence interval, 0.63-1.67; p = .93). After overlap weighting, radiation was associated with overall survival (hazard ratio, 0.49; 95% CI, 0.26-0.90; p = .02). CONCLUSIONS:In patients with surgically treated thymic malignancies, tumor invasiveness, especially vascular invasion, was the strongest predictor of recurrence and should guide risk stratification. Failure was predominantly pleural, with rare in-field recurrence, indicating good local control but a need for better strategies against pleural relapse. Survival benefit from peri-operative radiation remains uncertain and should be tested prospectively.
Metastatic heterogeneity has traditionally been explained by tumor-intrinsic evolution. A recent study by Peng-Winkler et al. challenges this paradigm by demonstrating that hepatic steatosis instructs colorectal cancer liver metastasis through fatty acid-dependent myelocytomatosis oncogene protein (MYC) activation. These findings identify host metabolism as an independent determinant of metastatic fate and suggest that precision oncology should extend beyond tumor genomics.
RNA-binding motif protein 15 (RBM15) is a key regulator of hematopoiesis and leukemogenesis, linking RNA metabolism, epitranscriptomic regulation, and lineage specification. Identified through the RBM15::MKL1 fusion in acute megakaryoblastic leukemia (AMKL), RBM15 functions within the N6-methyladenosine (m6A) writer complex, where its RNA-recognition motifs and Spen paralog and ortholog C-terminal domain enable site-specific methylation and protein recruitment. In hematopoietic stem and progenitor cells, RBM15 supports stem cell quiescence, self-renewal, and balanced lineage output, with additional roles in B cell, myeloid, and megakaryocytic differentiation. Mechanistically, RBM15 links m6A deposition to chromatin regulation, RNA export, and splicing. This review summarizes RBM15 structure, function, and regulation and highlights its emerging roles in leukemia, including AMKL and myelodysplastic syndromes, while outlining key questions for future studies.
G-protein-coupled receptor class C group 5 member D (GPRC5D) has emerged as a crucial immunotherapy target in relapsed/refractory multiple myeloma. Although the T-cell-engaging bispecific antibody talquetamab is currently the only approved anti-GPRC5D therapy, numerous promising agents are undergoing clinical evaluation. While anti-GPRC5D chimeric antigen receptor T cells show potential, this review focuses specifically on T-cell-engaging bispecific and trispecific antibodies. We highlight how GPRC5D differs clinically from B-cell maturation antigen, explore mechanisms of resistance, discuss novel therapeutic strategies including combination regimens and talquetamab as bridging therapy to chimeric antigen receptor T cells, and review key investigational T-cell engagers currently in development.
Hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer is the most common biologic subtype and carries a persistent risk of recurrence, particularly in patients with high-risk, early-stage disease. Cyclin-dependent kinase 4 and 6 inhibitors, initially established as a standard component of first-line therapy in the metastatic setting based on improvements in progression-free and overall survival, have since been evaluated in the adjuvant setting. While adjuvant palbociclib did not improve invasive disease-free survival, the monarchE and NATALEE trials demonstrated that abemaciclib and ribociclib, respectively, reduce recurrence risk in patients with high-risk, early-stage disease, with emerging overall survival data further supporting their use. However, the absolute magnitude of benefit varies substantially with baseline risk, and treatment-related toxicity and adherence challenges must be considered, as approximately 20% to 25% of patients discontinue therapy before completion. The integration of these agents into clinical practice also intersects with ongoing efforts to deescalate axillary surgery, as treatment eligibility has been largely defined by anatomic staging, particularly nodal status. Available data suggest that the incremental impact of axillary surgery on identifying candidates for cyclin-dependent kinase 4 and 6 inhibition is modest, especially among the favorable-risk populations now eligible for surgical deescalation. As the field evolves, advances in molecular risk stratification, genomic profiling, and dynamic biomarkers are poised to shift treatment selection from anatomic staging toward biologically driven approaches. Multidisciplinary decision-making that integrates tumor biology, anticipated absolute benefit, toxicity, patient preferences, and surgical considerations will be essential to ensure individualized care.
Tumors represent a heterogeneous set of neoplastic diseases, each composed of an intricate network of cancer cells residing in multiple alternative phenotypic states. Transitions between these phenotypic states, often termed 'phenotypic plasticity', enable them to execute specific steps in tumor progression and to develop therapeutic resistance. The phenotypic plasticity of tumor cells is mediated, in part, by cellular processes that orchestrate normal embryonic development and are hijacked by tumors. In this review, we discuss the contributions of these developmental programs to cancer cell phenotypic plasticity. We focus on epithelial-mesenchymal transition and ciliogenesis programs and discuss new insights into the mechanistic roles of these cellular processes in cancer progression and response to treatment.
Targeting transcription factor fusion-positive cancers has proven challenging for decades. In SARC037, Grohar et al. show that histology-specific dosing of trabectedin and low-dose irinotecan is active in advanced Ewing sarcoma and downregulates EWSR1::FLI1 activity.
Clinically impactful data from medical oncology, radiation oncology, and surgical oncology from this year are highlighted.
Incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RA) and dual incretin agonists, are increasingly used for the management of diabetes, obesity, and cardiometabolic disease. Although their systemic benefits are well established, uncertainty remains regarding their safety in patients with neuroendocrine neoplasms (NENs), a biologically heterogeneous group of tumors with diverse molecular profiles. Preclinical studies suggest that GLP-1 receptor activation may promote tumor growth in select receptor-expressing models, although receptor expression varies widely across NEN subtypes and is often absent in common tumors such as ileal neuroendocrine tumors. Population-level and retrospective clinical data have not demonstrated a consistent increase in oncologic risk but are limited by methodological constraints. In this expert consensus statement, the authors synthesize current evidence and provide a practical framework for the use of incretin mimetics in patients with NENs. The authors emphasize individualized risk assessment, shared decision-making, and multi-disciplinary collaboration, balancing potential but unquantified oncologic risks against substantial cardiometabolic benefits. Until prospective data are available, careful patient selection, dose optimization, and close clinical and radiologic surveillance remain essential to guide safe and effective use of these agents in this population.
BACKGROUND:Nonmetastatic esophagogastric adenocarcinoma require multimodal treatment for management. However, real-world treatment patterns and outcomes in these patients are limited. We evaluated the survival outcomes associated with the common treatment combinations in the National Cancer Database. METHODS:A total of 4715 patients met the predefined inclusion and exclusion criteria. Four groups were created: group 1, preoperative chemotherapy; group 2, perioperative chemotherapy; group 3, preoperative chemotherapy followed by chemoradiation; and group 4, preoperative chemoradiotherapy. Kaplan-Meier curves were used to assess overall survival. Cox proportional hazard regression estimated hazard ratios (HR) and 95% CIs for associations between covariates and overall survival. Inverse probability of treatment weighting based on propensity scores were used to account for differences in baseline characteristics between treatment groups. RESULTS:The median age was 63 years; 75.9% were male and 82.9% were non-Hispanic White; overall, 47.5% had clinical stage III disease and 57.8% had regional lymph node involvement. Median follow-up was 79.5 months. Patients who received perioperative chemotherapy had improved median overall survival compared with patients who received preoperative chemoradiotherapy (79.1 vs 74.6 months; p < .001). After adjustment for age, race, Charlson-Deyo Score, facility type, year of diagnosis, presence of regional lymph nodes, clinical stage, the association remained statistically significant (HR = 0.78; 95% CI, 0.66-0.92; p = .003). CONCLUSION:Although several multimodality treatment strategies are used for esophagogastric adenocarcinoma, perioperative chemotherapy is associated with better overall survival compared to preoperative chemoradiotherapy.
Pharmacokinetic‐based busulfan administration improves the therapeutic window and in vivo T‐cell depletion with antilymphocyte globulins reduces graft‐versus‐host disease incidence. In this study, both were used, showing an improvement of clinical outcomes in patients with acute myeloid leukemia.
