Cancer

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.

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.

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.

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.

BRAFV600-mutant metastatic colorectal cancer comprises a biologically distinct and clinically aggressive subset of metastatic colorectal cancer. Early attempts to apply single-agent BRAFV600 inhibition failed because of rapid acquired resistance and reactivation of mitogen-activated protein kinase signaling. Over the last decade, rational combinations (BRAF inhibitors and epidermal growth factor receptor inhibitors with or without mitogen-activated protein kinase kinase inhibitors) have become the standard of care in the refractory setting and are now being evaluated upfront, whereas a wave of next-generation approaches (extracellular signal-regulated kinase and SHP2 inhibitors, receptor tyrosine kinase-targeted agents, and immunotherapy combinations) aims to prevent or overcome resistance. The objective of this comprehensive review was to summarize historic therapeutic approaches, current standards, and the mechanistic rationale and clinical development of next-generation strategies to combat resistance in BRAFV600-mutant metastatic colorectal cancer.

BACKGROUND:Nucleophosmin 1-mutated (NPM1mt) acute myeloid leukemia (AML) is associated with a relatively favorable prognosis though long-term outcomes remain suboptimal without clear predictors identified by therapy. METHODS:In a retrospective analysis, the authors identified 396 patients (18%) with newly diagnosed (ND) NPM1mt AML treated at The University of Texas MD Anderson Cancer Center and analyzed their outcomes. Using a Cox regression model, they analyzed predictors of survival in newly diagnosed NPM1mt AML across various therapies. RESULTS:Those treated with high intensity chemotherapy had a median overall survival (OS) of 84.7 months with a 5-year rate of 53% (95% CI, 44%-61%) whereas those treated with a combination of a hypomethylating agent (HMA) and venetoclax had a median OS of 23.3 months with a 5-year rate of 19% (95% CI, 5%-39%). The combination of cladribine, low-dose cytarabine, and venetoclax alternating with azacitidine and venetoclax yielded better survival compared with HMA and venetoclax in an age-matched analysis (5-year OS rate of 74% vs. 24%) (p = .048). CONCLUSION:Among patients with NPM1mt treated with high-intensity chemotherapy, older age, a poor performance status, and presence of a FLT3-ITD mutation or extramedullary disease predicted a worse overall survival. For patients treated with a hypomethylating agent and venetoclax, older age was the only predictor of worse long-term outcomes. These findings can be used for risk-stratification of newly diagnosed NPM1mt AML and provide benchmarks of response and survival for this subtype.

BACKGROUND:Disease-free survival (DFS) is commonly used as a primary end point in trials for localized renal cell carcinoma (RCC), although its validity as a surrogate for overall survival (OS) remains uncertain. The objective of this study was to evaluate whether DFS is a reliable surrogate end point for OS in this setting. METHODS:The authors conducted a systematic review and trial-level meta-analysis of randomized controlled trials assessing systemic or perioperative therapies in patients with localized RCC. Databases were searched from inception to June 10, 2025. Trial-level surrogacy between DFS and OS was assessed using weighted least-squares meta-regression of log-transformed hazard ratios (HRs), and the surrogate threshold effect was estimated. RESULTS:In total, 25 randomized controlled trials were analyzed; 13 trials, analyzed as 15 study-level units comprising 9594 patients, reported HRs for both OS and DFS. DFS demonstrated a strong correlation with OS (weighted Pearson correlation coefficient, 0.75; 95% confidence level, 0.55-0.91; corresponding coefficient of determination, 0.57). The surrogate threshold effect analysis identified a DFS HR <0.914 as predictive of OS benefit. Funnel plots showed no clear asymmetry, and Egger tests did not indicate significant publication bias. CONCLUSIONS:DFS demonstrated a strong association with OS and may serve as a valid trial-level surrogate end point patients with in localized RCC. A DFS HR <0.914 was more likely to predict an OS benefit. These findings support the use of DFS as a primary end point in localized RCC trials, whereas continued long-term follow-up and future patient-level validation remain important.

In NRG Oncology/RTOG 1010, HER2‐targeted escalation did not improve survival or patient‐reported outcomes in localized esophageal adenocarcinoma. The study illustrates that biologic plausibility and metastatic success do not guarantee benefit in the curative‐intent setting and emphasizes the need for rigorous, patient‐centered end point design in future biomarker‐directed trials.

Patient navigation is generally defined as an individualized service that breaks down barriers to provide comprehensive and equitable cancer care. As the evidence base grows for patient navigation efficacy in diverse settings across the cancer continuum, navigation is increasingly recognized and adopted as an essential resource to aid in linking to and advocating for patient-centered services. To further patient navigation as a core component of cancer care, the American Cancer Society formed the Global Alliance for Cancer Patient Navigation to build awareness, evidence, and momentum and to coalesce around the core principles to aid sustainable implementation, keeping the voiced needs of people with lived experience at the forefront.

Lung cancer is the leading cause of cancer death in men and women. The goal of reducing mortality from lung cancer requires improvements in many aspects of the care pathway, beginning with early detection. Advances in imaging technologies and their application in clinical practice can contribute to addressing these challenges. As part of the American Cancer Society National Lung Cancer Roundtable's strategic plan, the roundtable's Advanced Imaging Across the Lung Cancer Care Continuum Task Group identified four advanced imaging technology topics as priority areas for development. These include novel (1) imaging technologies, (2) quantitative imaging biomarkers, (3) systems for sharing image data and/or algorithms, and (4) imaging-related artificial intelligence solutions. The authors provide background for each priority topic, describe key clinical problems along the lung cancer care pathway as use-case scenarios, and comment on challenges that impede implementation and dissemination of these potential advances.

Frontline blinatumomab combined with chemotherapy has resulted in improved outcomes in both pediatric and adult patients with acute lymphoblastic leukemia and is considered the new cornerstone of acute lymphoblastic leukemia treatment. The role of asparaginase in this new landscape of acute lymphoblastic leukemia treatment was extensively discussed by an expert panel of hemato-oncologists to reach a consensus on the safety and efficacy of asparaginase in diverse settings with and without blinatumomab. Herein, the following consensus topics are presented: (1) optimal dosing of asparaginase and therapeutic drug monitoring; (2) prevention of asparaginase hypersensitivity reactions and inactivation; (3) integration of frontline blinatumomab, asparaginase, and antimetabolites; and (4) special issues of asparaginase formulations and adaptations for resource-limited settings.

BACKGROUND:Multiple phase 3 metastatic castration-sensitive prostate cancer (mCSPC) studies consistently show a prostate-specific antigen (PSA) nadir of <0.2 ng/mL to be the preferred threshold for PSA response. However, in real-world practice, physicians often use other metrics such as percentage of PSA decline. METHODS:This retrospective analysis of Veterans Health Administration data (2006-2024) assessed the association between PSA response and overall survival (OS) in patients with mCSPC who initiated androgen deprivation therapy (ADT) ± other treatments, using landmark analyses with adjusted Cox regressions. PSA response metrics included ≥90% PSA decline and a PSA of <0.2 ng/mL within 9 months of starting therapy. RESULTS:Among 4890 patients, 44% reached a PSA of <0.2 ng/mL and 74% had ≥90% PSA decline. Patients with a PSA of <0.2 ng/mL within 9 months of ADT initiation had a reduced risk of death after this time point (adjusted hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.40-0.54) versus patients who did not. OS improvements with a PSA of <0.2 ng/mL were similar, regardless of ≥90% (adjusted HR, 0.43; 95% CI, 0.35-0.52) or <90% PSA decline (adjusted HR, 0.36; 95% CI, 0.23-0.56). Achieving ≥90% PSA decline without a PSA of <0.2 ng/mL was unrelated to improved OS. Patients who initiated ADT plus androgen receptor pathway inhibitors versus ADT alone were more likely to achieve a PSA of <0.2 ng/mL during PSA follow-up (adjusted HR, 1.71; 95% CI, 1.55-1.88). CONCLUSIONS:In a real-world mCSPC setting, achieving a PSA of <0.2 ng/mL (whether or not a PSA decline of 90% was reached) within 9 months of initiating ADT ± other treatments was associated with improved OS, which supports a PSA nadir of <0.2 ng/mL for optimizing mCSPC outcomes.