Annals of Oncology最新文献

Background: Global inequities in access to cancer diagnostics and treatment contribute to wide variation in cancer mortality-to-incidence ratios (MIRs), a proxy for survival. We aimed to develop an interpretable machine learning framework to quantify country-specific health system contributors to MIR and inform policy prioritization.

Materials and methods: We assembled national MIRs from GLOBOCAN 2022 for 185 countries and health system indicators from multilateral sources, including gross domestic product (GDP) per capita, universal health coverage (UHC) index, radiotherapy centers per population, health spending (%GDP), out-of-pocket expenditure, work force densities (physicians; nurses/midwives; surgical work force), pathology availability, Human Development Index, and gender inequality index. A CatBoost gradient-boosting model was trained with repeated leave-one-country-out cross-validation (10 repeats; 1850 predictions). Nested hyperparameter optimization and strict leakage control were used. Model interpretability employed SHapley Additive exPlanations (SHAP; TreeExplainer) to generate global and country-level feature attributions. SHAP values, model-derived metrics quantifying each factor's contribution to cancer outcomes, were generated. Performance metrics included R², root mean squared error (RMSE), mean absolute error, and Pearson correlation; uncertainty was estimated by bootstrap resampling.

Results: The model showed strong out-of-sample performance [R² = 0.852, 95% confidence interval (CI) 0.801-0.891; RMSE 0.057, 95% CI 0.050-0.064]; correlation between predicted and observed MIRs was r = 0.923 (P = 8.30 × 10^-78). Global SHAP contributions ranked GDP per capita (22.5%), radiotherapy centers per population (15.4%), and UHC index (12.9%) as the leading determinants. Country-specific SHAP profiles revealed substantial heterogeneity in dominant drivers across settings, enabling tailored policy levers (e.g. infrastructure, coverage expansion, or financial protection). An accompanying web interface provides country-level SHAP summaries for decision support.

Conclusions: An explainable machine learning approach accurately predicts national MIRs and decomposes predictions into country-specific health system attributions. While ecological and noncausal by design, the SHAP profiles translate population-level associations into actionable hypotheses for prioritizing investments-highlighting, across many contexts, radiotherapy capacity and UHC expansion as recurrent levers, and underscoring that higher total health spending alone may be insufficient without strategic allocation. Prospective, country-specific evaluations are warranted to test whether targeting model-identified drivers improve cancer outcomes.

Background: At the primary progression-free survival (PFS) analysis, the phase III EMBER-3 trial in endocrine therapy-pretreated patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) demonstrated significant PFS benefit with imlunestrant versus standard of care (SOC: fulvestrant or exemestane) in patients with ESR1 mutations (ESR1m) and with imlunestrant-abemaciclib versus imlunestrant in all patients, regardless of ESR1m. In this article, we report updated efficacy from a prespecified interim overall survival (OS) analysis.

Patients and methods: Patients with ER-positive, HER2-negative ABC previously treated with aromatase inhibitors ± cyclin-dependent kinase 4 and 6 inhibitors were randomly assigned (1 : 1 : 1) to receive imlunestrant, SOC, and imlunestrant-abemaciclib. Primary endpoints were PFS in imlunestrant versus SOC in patients with ESR1m and all patients, and versus imlunestrant-abemaciclib in all concurrently randomized patients. OS was a key secondary endpoint (tested if the corresponding PFS was statistically significant). Due to only two of three PFS endpoints being met, a limited significance level was passed to the OS comparisons. Exploratory endpoints included time to chemotherapy, chemotherapy-free survival, and PFS2.

Results: A total of 874 patients were randomized (imlunestrant, n = 331; SOC, n = 330; imlunestrant-abemaciclib, n = 213). Median follow-up was 28.5 months; 10.1% of patients remained on treatment (data cut-off: 18 August 2025).In patients with ESR1m, median OS (mOS) was 34.5 months for imlunestrant versus 23.1 months for SOC [hazard ratio (HR) 0.60, 95% confidence interval (CI) 0.43-0.86, P = 0.0043, boundary for significance not reached]. In all patients regardless of ESR1m, mOS was not reached with imlunestrant-abemaciclib versus 34.4 months with imlunestrant (HR 0.82, 95% CI 0.59-1.16, P = 0.2622). Updated PFS demonstrated sustained benefit. Notably, in all patients regardless of ESR1m, the median PFS of imlunestrant-abemaciclib versus imlunestrant was 10.9 versus 5.5 months (HR 0.59, 95% CI 0.47-0.74, nominal P < 0.0001). All prespecified exploratory endpoints favored imlunestrant-based regimens. Safety remains consistent with prior reports.

Conclusions: These findings reinforce the clinical benefit of imlunestrant-based regimens as a potential all-oral, chemotherapy-free treatment option for endocrine-pretreated patients with ER-positive, HER2-negative ABC.

Background: Despite treatment advances in newly diagnosed advanced-stage ovarian cancer (aOC), improved outcomes are needed.

Patients and methods: DUO-O (NCT03737643), a phase III placebo-controlled trial, enrolled patients with newly diagnosed aOC. Following one cycle of carboplatin/paclitaxel ± bevacizumab, patients without a tumor BRCA mutation (non-tBRCAm) were randomly assigned (1 : 1 : 1) at cycle 2 to carboplatin/paclitaxel plus bevacizumab followed by bevacizumab (control); carboplatin/paclitaxel, bevacizumab plus durvalumab followed by bevacizumab plus durvalumab (durvalumab arm); or carboplatin/paclitaxel, bevacizumab plus durvalumab followed by bevacizumab, durvalumab plus olaparib (durvalumab + olaparib arm). Investigator-assessed progression-free survival (PFS; primary endpoint) was tested for the durvalumab + olaparib arm versus control in the non-tBRCAm homologous recombination deficiency (HRD)-positive and non-tBRCAm intention-to-treat (ITT) populations.

Results: One thousand one hundred and thirty patients were randomly allocated to the study. The prespecified interim PFS analysis [data cut-off (DCO): 5 December 2022] qualified as the primary analysis; PFS hazard ratio (HR) for the durvalumab + olaparib arm versus control was 0.49 [95% confidence interval (CI) 0.34-0.69, P < 0.0001; median (m) PFS 37.3 versus 23.0 months] in the non-tBRCAm HRD-positive and 0.63 (95% CI 0.52-0.76, P < 0.0001; mPFS 24.2 versus 19.3 months) in the non-tBRCAm ITT population. For the durvalumab arm versus control, PFS HR was 0.87 (95% CI 0.73-1.04, P = 0.13; mPFS 20.6 versus 19.3 months) in the non-tBRCAm ITT population. At final PFS and interim overall survival (OS) analysis (DCO: 18 September 2023), PFS results were consistent with primary analysis; interim OS HR for the durvalumab + olaparib arm versus control was 0.95 (95% CI 0.76-1.20, P = 0.68; 39.0% maturity) in the non-tBRCAm ITT population. Safety was generally consistent with the profiles of the individual agents.

Conclusions: DUO-O met its primary PFS endpoints for first-line durvalumab plus carboplatin/paclitaxel and bevacizumab followed by durvalumab, bevacizumab plus olaparib maintenance versus carboplatin/paclitaxel and bevacizumab followed by bevacizumab in the non-tBRCAm HRD-positive and non-tBRCAm ITT populations. Further insight into long-term benefit is anticipated with additional follow-up.

Twenty years after its initial approval, trastuzumab remains a cornerstone in the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (eBC). Long-term follow-up from pivotal adjuvant trials has consistently demonstrated significant and durable improvements in survival outcomes across various risk groups and chemotherapy backbones. In parallel, trastuzumab-induced cardiotoxicity (TIC) remains overall infrequent, particularly in patients without prior exposure to anthracycline and appears comparable to the incidence observed in the general population after treatment completion. While real-world data further support the long-term efficacy and safety of trastuzumab, advancements such as more convenient subcutaneous formulations and the widespread availability of more accessible cost-effective biosimilars solidify its ongoing relevance in clinical practice. Conversely, despite two decades of clinical and translational research, no predictive biomarker beyond HER2 overexpression or amplification has yet been validated to guide trastuzumab use. Emerging candidates, including stromal tumor-infiltrating lymphocytes, circulating tumor DNA, and the HER2DX genomic assay, are not yet validated for use in clinical practice, although prospective studies are ongoing. Similarly, while clinical factors and imaging tools may help identify early on patients at higher risk of experiencing TIC, no cardioprotective strategy has yet demonstrated robust and conclusive benefit. Despite the emergence of newer anti-HER2 agents and evolving treatment paradigms, trastuzumab will probably continue to serve as a key therapeutic backbone, especially for patients with lower-risk HER2-positive eBC.