JCO Precision Oncology

PURPOSEPediatric supportive care trials frequently rely on analyses of multiple clinically relevant outcomes, posing challenges for overall trial interpretation. Hierarchical composite endpoints (HCEs) rank relevant outcomes by prespecified clinical importance and offer potential advantages such as harmonizing trial conclusions. METHODSWe reanalyzed two randomized supportive care trials utilizing post-hoc HCE, each conducted through the Childrens Oncology Group. ACCL0934 evaluated levofloxacin for prevention of bloodstream infection (BSI) in patients with acute leukemia (AL) or undergoing hematopoietic cell transplant (HCT) and was chosen because of observed multidimensional benefits of levofloxacin. ACCL0431 evaluated sodium thiosulfate (STS) for prevention of cisplatin-induced hearing loss. ACCL0431 analyses were performed for overall and localized disease subgroups, chosen due to conflicting effect directionality on hearing vs survival by cohort. We estimated treatment effects on HCEs using win-odds ratios (WO). For ACCL0934, the primary HCE included death, severe infection, BSI, and neutropenic fever. For ACCL0431, the HCE included death, relapse/progression, and hearing loss. RESULTSIn ACCL0934, levofloxacin reduced BSI incidence, but only with corresponding p-value <0.05 in the AL cohort (22% vs 43% on control; P=0.003; HCT: 11% versus 17% on control; P=0.06). Using HCE reanalysis, the estimated win-odds achieved statistical significance in both cohorts (AL: WO=1.74, P=0.002; HCT: WO=1.28, P=0.031). In ACCL0431, HCE analyses resulted in an estimated null effect (WO=1) in the overall cohort but resulted in beneficial effects (WO>1) for analyses of the localized cohort. CONCLUSIONHCEs can provide a harmonized framework for interpreting complex supportive care trials by integrating outcomes of varying clinical importance. These post-hoc analyses should not be used to reinterpret either trial but motivate consideration of prospective use of HCE going forward.

A recent randomized clinical trial in non-small cell lung cancer1 confirms what numerous observational studies have reported time of day (ToD) may dramatically influence treatment outcomes in cancer patients. In this recent trial median overall survival (OS) decreased from 28 months in the early ToD arm to 16.8 months in the late ToD arm. We raise the concern that clinical trial outcomes may be influenced by seemingly minor biases in treatment time across arms. We also suggest that by measuring or randomizing treatment-time in clinical trials, we may identify beneficial ToD dependent treatments that would otherwise be overlooked.

This study aimed to identify drugs disproportionately reported with malignant neoplasm progression, an uncommon but clinically important endpoint, using large spontaneous reporting systems. Public reports were analyzed from the FDA Adverse Event Reporting System (FAERS; 2004Q1-2024Q4) and the Japanese Adverse Drug Event Report database (JADER; 2004-2024). Cases were defined using MedDRA Preferred Terms for malignant neoplasm/tumour progression, and reports in which progression was recorded as an indication or medical history were excluded. Suspected drugs were standardized to generic names, and disproportional reporting was quantified using reporting odds ratios (RORs). Signals identified in FAERS were examined in JADER for cross-validation.FAERS contained 321, 020 progression-related reports, corresponding to 84, 977 unique cases after deduplication. Reporting increased over time and was associated with severe outcomes (death 27.63%; hospitalization 13.66%). Among the 50 drugs prioritized by report volume and signal strength, most were anticancer or immunomodulating agents (64%), and the highest report counts involved pembrolizumab, nivolumab, carboplatin, and enzalutamide. Disproportionality analysis detected positive signals for 41 drugs, with the strongest signals observed for afatinib, gefitinib, and osimertinib. In JADER (8, 929 cases), 22 of the 41 FAERS-positive signals were replicated with consistent direction but different magnitude.These findings are hypothesis-generating and suggest that tumor progression reporting clusters around specific therapies, particularly immunotherapies and targeted agents.These results support closer post marketing monitoring of selected drug event pairs and incentivize epidemiological and case-control studies to validate signals and elucidate clinical significance.

BackgroundOlder age and comorbidities complicate initial therapy in non-small-cell lung cancer (NSCLC), as platinum ineligibility has not been systematically characterized. MethodsAll 2592 patients presenting with metastatic NSCLC between 2018-2023 at Thoraxklinik Heidelberg were analyzed. ECOG status (PS), comorbidities, molecular testing, therapy, toxicities, and outcomes were verified from individual patient records. ResultsAmong 1306 patients with PD-L1 0-49%, systemic therapy was initiated in 74%. With availability of monoimmunotherapy, the treatment rate for patients with PD-L1[&ge;]50% (n=507) was higher by 5% (p=0.01), while best supportive care (BSC) by own choice was reduced (1.8% vs. 4.5%, p=0.005) more than medical BSC (mBSC 14.6% vs. 17.8%, p=0.11), and early death remained unchanged (ca. 4%). Initial suitability for systemic therapy was documented for 70% of cases eventually receiving mBSC after deterioration associated with comorbidities, metastatic burden, longer workup duration, or radiotherapy upfront (all p<0.001). The atezolizumab Summary of Medicinal Product Characteristics (SmPC) criteria, i.e. >80 years, or PS [&ge;]3, or comorbidities with PS [&ge;]2 or with age [&ge;]70, were fulfilled by 38% of patients (n=501) and associated with a >3-fold higher risk of BSC or early death (230/501), as well as significantly higher toxicity under platinum and shorter survival, which for a platinum dose ratio [&le;]60% across 4 cycles (9% of 1306) was similar to that with single-agent chemotherapy (median 5.1 months, p<0.001). SmPC criteria correlated better than comorbidity scores with foregoing platinum, but predictive performance for individual patients remained modest (AUC 0.71, p<0.001). ConclusionsThe high initial attrition of approximately 25% in NSCLC could improve with availability of monoimmunotherapy, but requires optimized, faster patient workflows for better mitigation. Adoption of the SmPC criteria could support a priori identification of patients at risk for mBSC or platinum overtreatment to enhance utilization of monoimmunotherapy and other novel platinum-free first-line options in the future. HighlightsO_LIA high initial attrition of approximately 25% is caused by deterioration after histologic diagnosis in advanced NSCLC. C_LIO_LIMonoimmunotherapy and optimized workflows may facilitate treatment for ca. 15% additional stage IV NSCLC patients. C_LIO_LISmPC criteria indicate cases at higher risk for BSC (>3x) or platinum overtreatment (i.e. platinum dose ratio [&le;]60%). C_LIO_LISmPC patients receiving platinum have higher toxicity and shorter survival than non-SmPC patients. C_LIO_LIImproved therapeutic allocation will be essential for utilization of any novel platinum-free option in the future. C_LI

BackgroundIn immune checkpoint inhibitor (ICI) trials, overall survival (OS) benefits are well established, yet improvements in quality of life (QoL) are often inconsistent or absent in conventional analyses. This apparent discordance raises important questions: are QoL outcomes truly unrelated to survival, and how can QoL results be better utilized and interpreted? MethodsA model-based meta-analysis (MBMA) of longitudinal EORTC QLQ-C30 global health status/quality of life data from randomized ICI trials was conducted. Longitudinal QoL trajectories were analyzed using a nonlinear mixed-effects model to estimate treatment-related toxicity and long-term QoL improvement. Associations between QoL trajectory parameters and OS were assessed using spearman rank correlation tests and Cox proportional hazards models. ResultsTwenty-seven studies (8,149 ICI and 5,593 control patients) contributed longitudinal QoL data, and 18 studies provided matched OS data. Raw QoL trajectories showed overlap between treatment arms, while OS consistently favored ICIs. MBMA revealed that ICIs had similar toxicity but significantly faster QoL improvement than control therapies (p < 0.0001). Baseline QoL, toxicity, and QoL improvement rate were all significantly associated with OS (p < 0.001). MBMA-based QoL comparisons were more sensitive in detecting associations with survival than raw QoL data, with the strongest association observed at Week 24 (R = -0.37, p = 0.067). ConclusionsConventional analyses comparing QoL at a single time point may obscure meaningful patient-reported benefits. By capturing longitudinal QoL trajectories across trials, MBMA reveals how patient experience evolves alongside survival outcomes and supports improved interpretation and utilization of QoL data in treatment evaluation.

BackgroundCapecitabine monotherapy is frequently employed as second/third-line treatment for metastatic gastrointestinal malignancies. Standard dosing often produces severe toxicities incompatible with palliative care principles. This study compared continuous low-dose (CLD) versus standard-dose (StD) capecitabine in the palliative setting. MethodsAfter at least one prior line of chemotherapy, 33 and 45 patients received StD (1.0-1.25 g/m2 bid on days 1-14 of a 21-day cycle) and CLD (500 mg bid daily without interruption) capecitabine, respectively, between March 2013 and August 2016 for metastatic gall bladder (n=51), pancreatic (n=14), and gastric (n=13) cancers. Toxicity and treatment discontinuation rates were compared using Fishers Exact Test. Progression-free survival (PFS) and overall survival (OS) were compared using the Mann-Whitney U test. ResultsGrade [&ge;]3 toxicity was significantly higher in StD versus CLD (57.6% vs 4.4%; p<0.001). Treatment discontinuation due to toxicity was higher in StD versus CLD (66.7% vs 2.2%; p<0.001). Grade 5 toxicity occurred in 3 patients (9.1%) in the StD arm versus 0 in the CLD arm. Median PFS was 90 days (StD) versus 119 days (CLD; p=0.018). Median OS was 160 days (StD) versus 181 days (CLD; p=0.085). Disease stabilization was more common in CLD (51.1% vs 54.5%), while progression-free survival was prolonged. ConclusionsWhile lower toxicities and discontinuation rates were expected in the CLD arm, the superior PFS and comparable OS with substantially reduced toxicity were striking. The metronomic low-dose approach provides a more favorable balance between disease control and tolerability in palliative gastrointestinal cancer therapy. Further prospective randomized trials are warranted.

Allogeneic hematopoietic cell transplantation is the only curative option for many patients with acute myeloid leukemia (AML). In the current study, we designed and implemented a personalized assay, called v96, incorporating up to 96 mutations in 30 AML patients undergoing transplantation. The assay was performed on DNA derived in cells from the bone marrow as well as in cell-free plasma. All 30 (100%) of patients harbored molecular evidence of residual leukemia during remission that was detectable by the v96 assay, while only 6 (20%) had evidence of disease as assessed by conventional clinical assays. Furthermore, cell-free DNA from plasma proved to be more sensitive than DNA from cells of the bone marrow for identifying residual leukemia. The median number of mutants was 352-fold higher in plasma taken prior to transplantation for patients who relapsed compared to those who did not relapse. At two months post-transplantation, 27 of the 30 patients still harbored detectable leukemia as assessed by the v96 assay. Twenty-two of these patients had a subsequent decrease in leukemic burden assessed by the v96 assay, usually only after immunosuppression was discontinued and supporting a graft-versus-leukemia effect. These results document the feasibility of using a relatively large panel of carefully chosen mutations and a highly specific assay as non-invasive markers of therapeutic response in AML patients, minimizing the need for multiple bone marrow biopsies. STATEMENT OF SIGNIFICANCEWe report a blood test that tracks up to 96 patient-specific mutations and applied it to patients with AML who had undergone bone marrow transplantation. Using this test to evaluate cell-free plasma DNA, we found evidence of residual leukemia cells both during remission (prior to transplantation) in all patients, and two months following transplantation in 90% of patients. This test can mitigate the need for invasive bone marrow biopsies to follow patients with leukemia. Moreover, the test appears to be more accurate than standard assays for detecting residual leukemia, and has the potential to guide the timing of transplantation and subsequent therapeutic measures, thereby laying the foundation for future prospective studies.

The relationship between red blood cell (RBC) storage duration and cancer recurrence remains controversial, with the "storage lesion" potentially amplifying transfusion-related immunomodulation effects. This retrospective cohort study examined whether RBC storage duration is independently associated with biochemical recurrence following radical prostatectomy for prostate cancer. We analyzed 316 men who underwent radical prostatectomy with perioperative allogeneic RBC transfusion at Cleveland Clinic (1998-2007). Patients were stratified by RBC storage duration: younger ([&le;]13 days, n=106), middle (13-18 days, n=103), and older ([&ge;]18 days, n=107). Primary outcome was biochemical recurrence (PSA [&ge;]0.4 ng/mL). We employed Kaplan-Meier survival analysis, Cox proportional hazards regression, and multivariable logistic regression with comprehensive diagnostics. Missing data (10.8%) were handled using multiple imputation by chained equations (MICE). Over median follow-up of 36.2 months, 54 patients (17.1%) experienced biochemical recurrence. RBC storage groups demonstrated exceptional baseline balance (all p>0.05). Kaplan-Meier analysis showed virtually identical survival curves (log-rank p=0.98). In fully adjusted Cox regression, neither middle (HR=1.01, 95% CI: 0.47-2.18, p=0.987) nor older (HR=0.82, 95% CI: 0.38-1.76, p=0.569) RBC storage was associated with recurrence. Logistic regression yielded consistent results (middle: OR=0.85, p=0.692; older: OR=0.93, p=0.854). Effect estimates remained stable across progressive covariate adjustment. In contrast, tumor biology factors demonstrated powerful associations: Gleason 8-10 (OR=5.72, p=0.001), log(PSA) (OR=2.24, p=0.007), and organ confinement (OR=0.48, p=0.047). Model discrimination was excellent (C-index=0.798, AUC=0.805), driven entirely by tumor characteristics. RBC storage alone provided zero discriminative ability (AUC=0.511). RBC storage duration (10-25 days) is not associated with biochemical recurrence after radical prostatectomy. This null finding is consistent across three complementary analytical methods. Tumor biology dominates prognosis with effect sizes far exceeding any potential transfusion effects. Current blood banking practices appear oncologically safe within typical storage windows.

ObjectivePopulation-based information regarding adherence to first-line chemotherapy in epithelial ovarian cancer is scarce. This study aimed to evaluate chemotherapy adherence, reasons for chemotherapy modifications, and associations with overall survival. MethodsAdvanced-stage epithelial ovarian cancer patients diagnosed between January 2015 and December 2021 were identified from the Netherlands Cancer Registry. Patients who underwent cytoreductive surgery combined with platinum- and taxane-based chemotherapy were included. Patients were categorized into two groups: adherent (patients without modifications) and non-adherent (patients with modifications: dose reduction, chemotherapy interruption, and/or reduction in chemotherapy cycles). Reasons for modifications were assessed. Kaplan-Meier survival curves and Cox proportional hazards models were used to analyze overall survival. ResultsAmong the cohort (N = 3,687), 54% of patients underwent chemotherapy modifications. Dose reduction (38%) was the most common, followed by interruption (24%) and reduction in chemotherapy cycles (9%). Non-adherence was associated with poorer performance scores, higher comorbidity indices, and undergoing primary cytoreductive surgery. Neurotoxicity and hematologic toxicity were the primary reasons for modifications in platinum (33% and 37%) and taxane (47% and 35%) agents. No association with survival was found for dose reduction and interruption. However, reduction in chemotherapy cycles was associated with lower 5-year overall survival (32% (95% CI 26%-38%) vs. 36% (95% CI 34%-38%)), remaining significant after multivariable adjustment (hazard ratio 1.36; 95% CI 1.17-1.59). ConclusionA significant proportion of Dutch advanced-stage epithelial ovarian cancer patients undergo chemotherapy modifications. No impact on overall survival was found for dose reduction or chemotherapy interruption, warranting prospective studies. Reduction in chemotherapy cycles was negatively associated with overall survival, possibly reflecting underlying treatment ineffectiveness. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSGuideline-recommended chemotherapy for advanced epithelial ovarian cancer is often difficult to deliver in routine practice, and real-world data on adherence and its impact on survival are limited. What this study addsIn this nationwide retrospective cohort, over half of patients experienced chemotherapy modifications; dose reductions and interruptions were not associated with poorer overall survival, whereas a reduction in the number of cycles showed an association with worse outcomes, although this may partly reflect underlying disease severity or treatment response. How this study might affect research, practice or policyOur findings suggest that standard dosing and treatment duration of six cycles may not always be necessary, emphasizing the need to tailor treatment plans to optimize both efficacy and tolerability in advanced-stage epithelial ovarian cancer patients

BackgroundOnce the treatment starts, early prediction of treatment benefit and its correlation with overall survival (OS) remains challenging in metastatic castration-resistant prostate cancer (mCRPC). Existing prognostic models require long-term follow-up, limiting their ability to inform timely treatment decisions. To address this gap, we evaluated tumor growth rate (g-rate)-based survival models across multiple treatment lines to assess their ability to predict OS and support early clinical decision-making. MethodsWe developed GxSurv, a Random Survival Forest (RSF)-based framework that incorporates baseline clinical variables and g-rate calculated from serial on-treatment PSA, to construct line-specific prediction models of OS, a direct measure of treatment outcome. Three variants were developed: G3Surv, using the 3-month g-rate; G6Surv, using the 6-month g-rate; and GfSurv, using the final observed g-rate. Model performance was evaluated using Harrells C-index, Unos C-index, Integrated Brier Score (IBS), time-dependent area under the curve (tAUC). Model interpretability was assessed using permutation importance to quantify predictor contributions within the GxSurv framework. FindingsThe study included 15912 treatment records from 11014 patients with mCPRC across four lines of therapy. We found that incorporation of g-rate consistently improved model performance across all treatment lines, with all GxSurv models outperforming Cox proportional hazards (CoxPH). As the earliest prognostic model, our G3Surv demonstrated strong early predictive performance, with Harrells C-index values ranging from 0{middle dot}700 to 0{middle dot}746 and tAUC values of 0{middle dot}766 to 0{middle dot}822 across all lines, representing 5-8% and 4-5% improvements over CoxPH, respectively. These results indicate that G3Surv accurately predicts individual treatment outcomes at 3 months after treatment initiation. Feature importance analyses consistently identified g-rate as a top predictor, followed by baseline PSA and hemoglobin, with relative variation across treatment lines. InterpretationIntegrating g-rate calculated from on-treatment PSA values enables accurate, line-specific prediction of treatment outcomes in mCRPC, with the 3-month g-rate providing robust early prognostic information to support timely, personalized clinical decision-making. FundingU.S. National Science Foundation, National Institutes of Health, American Cancer Society.

PurposeSquamous non-small cell lung cancer (sq-NSCLC) is a distinct subtype of NSCLC. This exploratory, phase II study investigated the feasibility and efficacy of a four-cycle perioperative regimen combining serplulimab with a taxane (paclitaxel or nab-paclitaxel) and carboplatin in patients with resectable stage II-IIIA sq-NSCLC. MethodsThis investigator-initiated, single-arm, phase II exploratory trial (NCT05775796) enrolled patients with histologically confirmed, resectable clinical stage II-IIIA squamous NSCLC. Patients received 2-3 cycles of neoadjuvant serplulimab plus taxane-carboplatin, followed by curative-intent surgery and 1-2 cycles of adjuvant treatment. The primary endpoint was major pathological response (MPR). Secondary endpoints included pathological complete response (pCR), R0 resection rate, overall response rate (ORR), safety, event-free survival (EFS), and overall survival (OS). ResultsA total of 30 patients without actionable driver mutations were enrolled and 29 underwent surgery. The median age was 65 years, and most were male smokers (n=28, 93.33%). An R0 resection was achieved in 28 patients (93.33%), and the MPR and pCR rates were 76.67% and 50.00%, respectively. Based on radiological assessments during the neoadjuvant phase, the ORR was 73.33% (95% CI: 54.11-87.72). Grade 3 and more treatment-related adverse events were predominantly hematologic and were generally manageable. Long-term EFS and OS data are not yet mature. Additionally, exploratory minimal residual disease analysis using circulating tumor DNA (ctDNA) in 27 patients showed a strong correlation between ctDNA clearance and pCR (p=0.004), suggesting ctDNA as a promising biomarker for immunochemotherapy response. ConclusionsA four-cycle perioperative regimen of serplulimab combined with taxane-carboplatin demonstrated promising MPR and pCR rates with an acceptable safety profile in resectable sq-NSCLC patients. Long-term follow-up and future phase III trials are warranted to confirm survival benefits.

IntroductionBRCA1/2 alterations are increasingly recognized as biologically and clinically relevant features in prostate cancer, yet the prognostic and therapeutic significance of zygosity status remains uncertain. Understanding differences between monoallelic and biallelic inactivation may refine risk stratification and guide therapeutic decision-making. Materials and MethodsA retrospective, desk-based observational analysis was performed using publicly accessible datasets from TCGA-PRAD (primary disease) and SU2C/PCF (metastatic disease). BRCA1/2 status was categorized as wild-type, monoallelic, or biallelic based on mutation, copy-number, and loss-of-heterozygosity profiles. Overall survival was evaluated using Kaplan-Meier estimates and Cox models. Systemic therapy outcomes were assessed by treatment class, incorporating exploratory interaction tests. ResultsIn TCGA-PRAD (n=300), OS did not significantly differ by zygosity (global log-rank p=0.45), with median OS of 80.0 months (wild-type), 78.0 months (monoallelic), and 55.0 months (biallelic). In SU2C/PCF (n=200), zygosity stratified outcomes significantly (global log-rank p=0.04): median OS was 22.0 months (wild-type), 14.0 months (monoallelic), and 16.0 months (biallelic). Treatment analyses showed ARSI exposure improved OS in wild-type disease (HR 0.60; 95% CI 0.38-0.95), while interaction testing suggested potential heterogeneity without statistical confirmation (interaction p=0.092). PARP inhibitor exposure showed directionally favorable HRs in wild-type and monoallelic groups but no significant interaction (interaction p=0.757). No therapy class demonstrated consistent effect modification by zygosity. ConclusionBRCA1/2 zygosity shows prognostic relevance in metastatic prostate cancer but not clearly in primary disease. While zygosity did not consistently modify systemic therapy associations in this dataset, findings support zygosity-aware reporting as a practical tool for molecular stratification and future research design.

PurposePrognosis in metastatic non-seminomatous germ cell tumors (mNSGCT) is currently guided by the IGCCCG classification, which incorporates tumor markers, organs involved with metastatic disease, and primary site but not histologic subtype. We aimed to evaluate whether specific histological components provide additional prognostic information in a large international mNSGCT cohort. Patient and MethodsWe analyzed clinical, pathologic, and outcome data from 662 patients with mNSGCT across multiple international centers. Cox regression and multivariable stepwise models were used to evaluate the impact of age, tumor histology, serum markers, primary site of disease, chemotherapy, IGCCCG, and post-chemotherapy surgery on overall survival. Analyses were performed using both complete-case and imputed datasets to account for missing values. ResultsThe presence of any percentage of embryonal carcinoma (EC) was independently associated with improved overall survival HR 0.603 (95% CI: 0.37-0.98, p=0.040), whereas yolk sac tumor (YST) predicted worse prognosis in complete-case analysis HR 2.27 (95% CI: 1.43 - 3.61 p = 0.001). Choriocarcinoma was also associated with a HR 1.58 (95% CI: 1.08 - 2.32 p= 0.019) adverse outcomes. IGCCCG risk classification remained a strong predictor of mortality HR up to 8.9 for Poor vs Good risk, (95% CI: 4.63 - 17.09 p < 0.001), but histologic components added significant independent prognostic value. Post-chemotherapy retroperitoneal lymph node dissection (RPLND) conferred a substantial survival benefit HR 0.44 (95% CI: 0.258 - 0.754 p=0.003). Interestingly, teratoma was not associated with mortality but was linked to younger age, testicular primaries, and higher likelihood of residual disease requiring surgery. ConclusionsHistological composition, particularly the presence of EC or YST, has a significant and independent impact on survival in mNSGCT, beyond established risk classifications. Integration of histological subtypes may enhance prognostic accuracy and guide individualized treatment strategies in advanced germ cell tumors.

BackgroundResearch infra-structure is essential for conducting phase III cancer clinical trials as its lack precludes trial availability and its maturity may influence the portfolio of available options. Several studies have highlighted global disparities, but none has ever mapped the worldwide network of research facilities conducting such trials. MethodsWe extracted all research sites within recruiting phase III cancer interventional trials from the ClinicalTrials.gov database on July 23, 2024. Address components were combined and queried through the Google Maps API for standardized identification. Matched pairs were subsequently screened for inconsistencies, and Google Maps entries within 1,000 meters were grouped if they represent the same facility. We compared research facilities number, density (per 1M inhabitants), size, and portfolio of available trials across World Development Index regions, and modelled the number of available trials and research facilities per country with log-log linear models (elasticity coefficient [{beta}] estimand). FindingsOf 77,625 listed sites from 1,287 trials, 65,736 (84.7%) were mapped to 6,634 unique research facilities across 84 countries. We found a strong correlation between the number of research facilities and trials by country (R2=0.86, p-value<0.001, {beta}=0.95, 95%CI 0.87-1.04). The United States and China had the largest number of facilities (2,626, 39.6%) and available trials (624, 48.5%) respectively. All the 100 largest research facilities in size were from high-income countries or China, and 16 of the top 20 countries by density were located in Europe and Central Asia. Latin America and Caribbean, South Asia Region, and Sub-Saharan Africa had the highest proportion of facilities running only multiregional (>93%, p-value<0.001), industry-sponsored (>90%, p-value<0.001), and systemic therapy trials (>80%, p-value<0.001). InterpretationPhase III cancer trials are directly limited and responsive to physical institutional growth. Outside high-income countries, research capacity remains substantially constrained, largely focused on systemic therapies and frequently reliant on industry-sponsored, multiregional trials. FundingNone RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched the Pubmed/EMBASE database for studies investigating cancer clinical trials and research facilities distribution worldwide using the search terms "trials OR clinical trials", "cancer", "distribution OR barriers OR access OR inequalit*" between inception to November 1st, 2025. Several studies have consistently shown a higher concentration and availability of cancer clinical trials in high-income countries (HIC) compared to lower-income regions. In addition, cancer clinical trials in lower middle-income countries (LMIC) are predominantly phase III, industry-sponsored, and led by HIC. However, most of this evidence is derived from country-level aggregate data, which collapse heterogeneous research infrastructures within countries into single summary measures and therefore lack the resolution needed to describe, and ultimately explain the underlying drivers of these disparities. Only a small number of studies have examined cancer trial distribution at finer geographic scales, and these have generally been limited to city or county-level analyses or to single-country settings. Therefore, there remains no comprehensive mapping of the research infrastructure responsible for conducting cancer clinical trials, even though this infrastructure is a key determinant of national trial availability and study profiles. Added value of this studyThis is the first study to map and profile research facilities conducting phase III cancer clinical trials worldwide. We show that the availability of phase III cancer clinical trials is linearly correlated with the absolute number of research facilities on a log-log scale, such that a 1% increase in research facilities is associated with a 0.95% (95%CI, 0.87-1.04) increase in phase III trial availability within countries. The United States had the largest share of research facilities (N=2,626, 39%) while China had the highest number of available phase III clinical trials (N=624), driven by a high number of single-center studies (N=398). Of the largest 100 research facilities in size (median [IQR] number of phase III cancer trials 62 [57-73.25]), all were from HIC or China. Of the top 20 countries by density (per million people), 80% were located in Europe and Central Asia (ECA). In Latin America and Caribbean (LAC), South Asia Region (SAR) and Sub-Saharan Africa (SSA), research facilities are found in fewer numbers and smaller sizes, and are predominantly running only multiregional (>93%), industry-sponsored (>90%), and systemic therapy trials (>80%). Implications of all the available evidenceGlobal disparities in cancer clinical trials are perpetuated by constrained research infrastructure in less developed regions, reflected not only in the limited number of research facilities but also in their profiles, which often have little experience beyond industry-sponsored trials, as we have shown. While investments in research facilities are crucial and are associated with increased trial availability, particularly during the early stages of infrastructure development, they are not sufficient on their own. Complementary strategies are needed, including financial incentives to support locally designed trials (i.e., investigator-initiated grants) and sustained investment in human resources to design and conduct them. Aligning infrastructure expansion with workforce development is essential to improve both the quantity and the profile of available cancer clinical trials, enhance local leadership, and ensure that research is relevant and generalisable to diverse populations.

PurposeTumor comprehensive genomic profiling (CGP) has revolutionized cancer care and identifies patients for biomarker-specific therapy. In metastatic hormone-sensitive prostate cancer (mHSPC), CGP is not currently prognostic and no DNA-based genomic classification exists that accounts for combinations of alterations. We developed a DNA-based CGP classification that is prognostic for overall survival (OS) and could inform treatment. MethodsRetrospective cross-sectional study using multivariable models to develop a clinico-genomic prognostic risk classification in U.S. Veterans diagnosed with synchronous mHSPC. Primary outcome was overall survival (OS) from time of metastatic diagnosis. Results7201 Veterans with metastatic prostate cancer who underwent CGP were identified. There were 2484 Veterans (median [IQR] age 72 [67-77] years) with synchronous mHSPC and tissue CGP, which were divided into training and testing datasets. 16 genes associated with survival were identified and favorable, intermediate, and unfavorable genomic prognostication groups were created based upon mortality risk to generate the STRATOS-P classification. In a multivariable model, classification into intermediate and unfavorable groups was associated with increased mortality relative to the favorable group (aHR 1.54 [95% CI 1.33-1.78]; aHR 2.37 [95% CI 1.97-2.485], respectively), demonstrating an average AUC of 0.83. In an external validation cohort of non-Veterans, intermediate and unfavorable classifications were associated with increased mortality (aHR 2.45 [95% CI 1.87-3.21]; aHR 4.37 [95% CI 3.06-6.22], respectively) with an AUC of 0.79. The intermediate and unfavorable genomic prognostication groups were also associated with increased mortality across multiple disease states including synchronous and metachronous diagnoses, castration-resistance, and analyte type. ConclusionsIn metastatic prostate cancer, tumor DNA genomic alterations are prognostic for OS. The STRATOS-P classification is a validated prognostic tool that has the potential to guide decision-making in mHSPC.

Chronic myelomonocytic leukemia (CMML) is a clonal myelodysplastic/myeloproliferative neoplasm characterized by persistent monocytosis and heterogeneous risk of progression to acute leukemia. Mutations within the RAS/MAPK signaling pathway, particularly involving KRAS, are linked to a proliferative disease phenotype and adverse prognosis. We report the first Colombian CMML case harboring two concurrent activating KRAS mutations (p.G12S and p.G13D). Both variants were detected at variant allele frequencies of 17% and 21% in a female patient in her late 50s presenting with marked leukocytosis, anemia, and thrombocytopenia. The coexistence of these mutations suggests synergistic hyperactivation of the RAS/MAPK pathway, likely driving clinical aggressiveness and therapeutic resistance. This case delineates a rare molecular subgroup within CMML and highlights the critical role of comprehensive genomic profiling to improve prognostic accuracy and inform precision medicine approaches.

BackgroundGlyphosate-based herbicides are among the most widely used agricultural chemicals globally. Concerns regarding their carcinogenic potential, particularly in relation to non-Hodgkins lymphoma (NHL), persist despite multiple prior systematic reviews and meta-analyses. However, these reviews have demonstrated important methodological limitations and inconsistent analytic decisions, limiting confidence in their conclusions. ObjectiveTo conduct a rigorous, up-to-date systematic review and meta-analysis of observational studies examining the association between glyphosate-based herbicide exposure and risk of NHL and its subtypes, while addressing methodological and analytic shortcomings of prior syntheses. MethodsWe searched MEDLINE (1970-February 26, 2026) and EMBASE (inception-February 26, 2026), supplemented by reference list review. Eligible studies included cohort, case-control, and pooled analyses reporting effect estimates (or sufficient data) for glyphosate exposure and NHL incidence. Two reviewers independently assessed risk of bias using the Newcastle-Ottawa Scale (for primary studies) and structured criteria for pooled analyses. Random- and fixed-effects meta-analyses were conducted using inverse-variance methods. Heterogeneity was evaluated using Cochrans Q and I{superscript 2} statistics. Publication bias was assessed using standard and contour-enhanced funnel plots. Sensitivity analyses addressed overlapping cohorts, hazard ratio inclusion, exposure definitions, and model overfitting (events-per-variable considerations). Certainty of evidence was graded using GRADE. ResultsSeventeen publications were identified, representing 20 unique study populations; after accounting for overlap, 10 primary datasets were included in quantitative synthesis. Five studies were assessed as low risk of bias, four as moderate risk, and one as high risk. For ever exposure, the random-effects model across all eligible datasets yielded an odds ratio (OR) of 1.11 (95% CI: 0.98-1.27), with moderate heterogeneity (I{superscript 2}{approx}53%). In sensitivity analyses excluding hazard ratio-only studies and overlapping cohorts, pooled ORs ranged from 1.19 to 1.23, with estimates approaching or reaching statistical significance depending on modeling assumptions. For the highest exposure categories, the random-effects model demonstrated a statistically significant association (OR{approx}1.38; 95% CI: 1.00-1.90), with moderate heterogeneity (I{superscript 2}{approx}61%). Sensitivity analyses excluding selected pooled cohort estimates strengthened the association (OR{approx}1.47; 95% CI: 1.04-2.06). Analyses incorporating alternative cumulative exposure metrics yielded similar significant associations (OR{approx}1.33-1.45) with low or absent residual heterogeneity. Subtype analyses suggested elevated risks particularly for diffuse large B-cell lymphoma and follicular lymphoma in certain datasets. Publication bias assessments revealed evidence of small-study effects in some models, though contour-enhanced analyses suggested that not all asymmetry was attributable to selective publication. Overall certainty of evidence was graded as moderate for highest exposure analyses and low-to-moderate for ever-exposure analyses due to residual heterogeneity and observational design limitations. ConclusionsThis updated synthesis indicates that while associations with ever exposure to glyphosate are modest and sensitive to analytic decisions, higher levels of exposure are consistently associated with increased odds of NHL. Findings are robust across multiple sensitivity analyses addressing overlapping data, exposure classification, and model overfitting. These results support a dose-related association between glyphosate-based herbicide exposure and NHL risk and underscore the need for continued surveillance, improved exposure characterization, and prospective cohort analyses with minimized loss to follow-up and transparent analytic reporting.

Post-treatment measurable residual disease (MRD) in acute myeloid leukemia (AML) patients is associated with adverse clinical outcomes. Validated molecular methods for AML MRD are preferable to flow cytometry assays but are not available for all patients. The limit of detection (LOD) of next-generation sequencing (NGS) assays for single nucleotide variants is restricted by technical error rates. Structural alterations are common genetic features of AML, but MRD approaches for detecting this class of variants have primarily relied on RNA. However, RNA has suboptimal stability, not all structural alterations are expressed as transcripts, and the impact of anti-leukemic therapy on transcription may make leukemic disease burden quantification inaccurate. In this study, we demonstrate a whole genome sequencing (WGS)-based approach to identify genomic DNA breakpoints of chromosomal rearrangements that allowed design of highly sensitive patient-personalized digital droplet PCR (ddPCR) MRD assays. Acute myeloid leukemia (AML) is an aggressive malignancy of the hematopoietic precursor cells that predominantly affects older individuals. Oncogenic transformation occurring through the acquisition of structural chromosomal aberrations is noted in 35% of AML cases, and can result in the formation of fusion proteins that confer proliferation and survival advantages (1). When compared to classical cytogenetics for the identification of structural variants at diagnosis, newer techniques such as optical genome mapping can identify clinically pertinent aberrations that may be cryptic or smaller than the resolution of conventional karyotyping and FISH (2). Similarly, short-read whole genome sequencing (WGS) has been shown to increase diagnostic yield and better refine risk stratification when compared to traditional cytogenetic testing in myeloid malignancies (3). Additionally, WGS can be utilized to identify genomic breakpoints of chromosomal rearrangements at a basepair (bp) resolution.

BackgroundA retrospective study in Nature recently reported improved overall survival (OS) when COVID-19 mRNA vaccination was administered around initiation of immune checkpoint inhibitor (ICI) therapy. Whether this association depends on vaccination timing relative to ICI treatment remains unclear. MethodsWe conducted a single-centre retrospective cohort study of patients receiving palliative-intent ICI therapy at a UK tertiary cancer centre (October 2014-December 2025). Two vaccination exposure definitions were evaluated: (1) vaccination within 100 days of the first ICI cycle (initial window); and (2) vaccination from 100 days before the first ICI cycle to 100 days after the final ICI cycle (extended window). OS was analysed using Kaplan-Meier methods and Cox models relative to unvaccinated patients. ResultsAmong 2109 patients, 515 (24.4%) received [&ge;]1 COVID-19 vaccine dose. Under the initial window, mRNA vaccination was associated with a longer OS in the all-tumours cohort only (HR 0.76; 95% CI 0.58-0.99; p=0.04). Under the extended window, mRNA vaccination was associated with longer OS in the all-tumours cohort (HR 0.58; 95% CI 0.46-0.75; p<0.0001), including melanoma (HR 0.35; 95% CI 0.18-0.69; p=0.002) and kidney cancer (HR 0.47; 95% CI 0.28-0.79; p=0.004), but not NSCLC. In an era-restricted analysis limited to patients receiving ICI therapy from 2020 onwards, the all-tumours association persisted (HR 0.76; 95% CI 0.59-0.98; p=0.04) with no significant tumour-specific associations. ConclusionsCOVID-19 mRNA vaccination was associated with improved OS, with magnitude and tumour specificity dependent on vaccination exposure definition. Prospective studies are required to assess causality and tumour-specific effects.

Lung cancer remains the leading cause of cancer mortality worldwide. Immune checkpoint inhibitors targeting PD-1/PD-L1 have significantly improved outcomes in a subset of patients. OncoPrism, a clinical test employing a multidimensional predictive RNA-based immune biomarker, was evaluated for predicting immune checkpoint inhibitor (ICI) benefit in non-small cell lung cancer (NSCLC) patients. This study included data from 1,487 patients and evaluated OncoPrism across four NSCLC cohorts: one PD-L1 inhibitor cohort (n=195), one PD-1 inhibitor cohort (n=89), and two non-ICI cohorts (n=193 and n=1,010, respectively). In the PD-L1 inhibitor cohort, OncoPrism predicted progression-free survival (p<0.0001) and overall survival (p=0.043). In the PD-1 inhibitor cohort, an observational clinical trial, PREDAPT (NCT04510129) enrolling patients from 17 healthcare systems, OncoPrism predicted overall response rate (p=0.008), progression-free survival (p=0.004), and overall survival (p=0.011). PD-L1 Tumor Proportion Score (TPS) was not predictive of response, progression-free survival, or overall survival. OncoPrism did not predict overall survival across two non-ICI NSCLC cohorts (p=0.54, p=0.73), suggesting the test is specifically predictive of ICI benefit rather than being prognostic with more limited clinical utility. Overall, the data show OncoPrism high patients are likely to benefit from a two to three-fold increase in overall response rate, progression-free survival, and overall survival compared to those in other OncoPrism groups. These results underscore the impact of OncoPrism to address the current unmet need for ICI response prediction in NSCLC.