Rapid and reliable identification of multivariate geochemical anomalies is critical for delineating prospective mineralized zones and reducing uncertainty in mineral exploration targeting. Extended isolation forest (EIF) is a powerful unsupervised ensemble learning algorithm that efficiently isolates anomalies from high-dimensional geochemical datasets using randomly oriented hyperplane partitions. Previous studies have demonstrated the effectiveness of EIF in multivariate geochemical anomaly detection and mineral potential modeling. However, its performance can be significantly affected by stochastic variability arising from random partitioning and random subsampling during isolation tree construction, which may result in unstable anomaly patterns and inconsistent exploration targets in complex geological environments. To mitigate this limitation, we developed a robust unsupervised framework for the identification of multivariate geochemical anomalies associated with gold mineralization in the Southwestern Yilgarn Craton, Australia. The proposed framework integrates robust factor analysis (RFA), a Jaccard-based stability index and EIF to enhance the reliability and reproducibility of anomaly detection. RFA was first applied to compositional soil geochemical data to identify the most significant pathfinder elements associated with gold mineralization, which were subsequently used as input variables for the EIF model. The model was then optimized using a Jaccard-based stability criterion to ensure consistent anomaly detection across repeated independent runs. Model performance was assessed using area under the receiver operating characteristic curve (AUC). The obtained AUC value of 0.82 indicates strong predictive capacity, confirming that the generated anomaly map effectively delineates mineralization-related geochemical patterns and provides a reliable proxy for mineral prospectivity mapping. Overall, the proposed framework offers a robust and reproducible unsupervised approach for multivariate geochemical anomaly detection with strong applicability in both greenfield and brownfield mineral exploration settings.
BACKGROUND:Androgen deprivation therapy (ADT) for prostate cancer causes substantial adverse effects. Despite consistent national and international guideline recommendations, supervised exercise is rarely integrated into care. We aimed to determine whether the STAMINA lifestyle intervention, embedded into cancer care, would improve cancer-specific quality of life and fatigue versus behaviourally Optimised Usual Care in men with prostate cancer in England. METHODS:STAMINA was a multicentre, randomised trial done across 15 UK National Health Service (NHS) trusts in England. Men on ADT for prostate cancer were eligible. Participants were randomly assigned (5:4) via computer-generated minimisation, stratified by age, ADT duration, chemotherapy or androgen receptor pathway inhibitor therapy, and radiotherapy, to the STAMINA lifestyle intervention or to Optimised Usual Care. Participants were aware of treatment allocation. The STAMINA lifestyle intervention comprised supervised aerobic and resistance exercise for 12 months, dietary advice, behavioural support, and complimentary gym membership. Optimised Usual Care comprised clinician training, educational materials, behavioural prompts, and safety-to-exercise checks. Primary outcomes were the Functional Assessment of Cancer Therapy-prostate (FACT-P) and the Functional Assessment of Chronic Illness Therapy-fatigue (FACIT-F) subscale at 12 months, analysed by intention to treat (according to randomised treatment). This trial is registered with ISRCTN (ISRCTN46385239), and recruitment is complete. FINDINGS:Between Jan 20, 2022, and June 12, 2023, 700 men were randomly assigned to STAMINA lifestyle intervention (n=389) or Optimised Usual Care (n=311). Median age was 71·6 years (IQR 66·3-76·0), and 680 (97%) of 700 participants were White. Primary outcome data were available for 345 (89%) of 389 participants in the STAMINA lifestyle intervention group and 251 (81%) of 311 in the Optimised Usual Care group. The STAMINA lifestyle intervention was superior to Optimised Usual Care in terms of FACT-P score (adjusted mean difference 4·5, 97·232% CI 1·7-7·2; p=0·0004) and FACIT-F score (1·9, 0·4-3·4; p=0·0068). Three intervention-related serious adverse events occurred in the STAMINA lifestyle intervention group (transient loss of consciousness, leg pain or weakness, and back pain); all participants recovered. No treatment-related deaths occurred. INTERPRETATION:The STAMINA lifestyle intervention meets best practice guidelines, can be implemented in NHS trusts in England, and offers clinicians a clear basis for identification and prescription of a supervised exercise and dietary advice intervention to mitigate negative effects associated with ADT. FUNDING:National Institute for Health Research.
Water conservancy and hydropower projects enhance regional climate resilience and watershed water security yet inevitably trigger large-scale involuntary reservoir resettlement. As representative involuntarily displaced populations, reservoir resettlees' social identity directly impacts local social stability and regional sustainable socioeconomic development. Based on a ten-year longitudinal qualitative investigation including in-depth interviews and participant observation in Village Y of Wuxikou Reservoir, Jiangxi Province, this paper divides the entire resettlement process into three stages: relocation, stabilization and development. From the dual perspectives of host community identity and out-groups identity, this study explores the dynamic evolutionary rules of resettlees' social identity. The results indicate that resettlees sequentially develop alienated identity, superficial adaptive identity and segregated identity across different phases. On this basis, the core concept of differential identity is proposed, which features a dual structure of vertical temporal differentiation and horizontal spatial differentiation. This paper expands the applicable scope and explanatory power of the “differential mode of association” and social identity theory in involuntary resettlement contexts. Grounding on the differential identity framework, this paper puts forward targeted integrated governance solutions to break intergroup segregation, facilitate cross-group integration and build resilient resettlement communities consistent with Sustainable Development Goals (SDGs) 11 and 13.
The discrimination of ore deposit types is primarily based on geological, geochemical, and isotopic characteristics. Conventionally, these types are identified using specific element diagrams. However, traditional geochemical methods often fail to determine scheelite deposit types of the complex Xuefengshan Sb-Au-W metallogenic belt in China, where mineralization resulted from the superposition of multiphase geological events. Machine learning (ML) methods, have been increasingly applied to identify deposit genesis by establishing relationships between deposit characteristics and genetic types using extensive datasets. However, inaccurate data labels, the limitations of single models, and poor model interpretability lead to decreased accuracy. This study proposes a ML framework based on interpretable ensemble learning. We collects geochemical element data from typical orogenic and magmatic-hydrothermal scheelite deposits globally. Deep clustering is used to filter data and overcome the subjectivity of original data labels. An ensemble learning model is used to construct a classifier to improve the model's robustness and generalization ability. An interpretable model is introduced to analyze the contribution of individual feature elements, revealing the metallogenic genesis. This method demonstrates high accuracy on the test set. According to this method, the scheelite deposit type of the Xuefengshan metallogenic belt is primarily magmatic-hydrothermal in origin, with orogenic superposition. This helps resolve a long-standing controversy in the region and establishes a repeatable and interpretable new paradigm for ML-based discrimination of ore deposit genetic types.
Though volcanogenic massive sulfide (VMS) deposits are major global sources of indium (In), the physicochemical mechanisms and key factors controlling its significant enrichment remain poorly understood. To address the issue, this study investigates the Tiemurt VMS Pb-Zn-Cu deposit, utilizing detailed petrography, in-situ LA-ICP-MS analysis, and thermodynamic modeling to reveal the In enrichment mechanisms in VMS deposits. Petrographic observations identified two distinct generations of sphalerite corresponding to different mineralization stages. The early-stage sphalerite (Sp1) is euhedral-subhedral, associated with pyrite, and displays darker colors (red to brown), whereas the late-stage sphalerite (Sp2) is anhedral, intimately intergrown with chalcopyrite, and shows lighter colors (mainly yellow). The trace element results demonstrate that Sp1 has a significantly higher In content (average 317 ppm) than Sp2 (average 220 ppm). Additionally, In concentrations positively correlate with Fe contents. Because Fe is the primary chromophore that darkens sphalerite, this strong coupled enrichment mechanism allows macroscopic sphalerite color (red > brown > yellow) to serve as a reliable indicator for In concentration. Crystallization temperatures calculated using the GGIMFis thermometer range from 344 to 382 °C for Sp1 and 312 to 355 °C for Sp2, indicating a cooling trend during fluid evolution. Thermodynamic modeling data showed that in the early-stage hydrothermal fluids (≥360 °C), Zn2+ preferentially complexes with Cl−, leaving InCl2+ or In3+ as unstable species, and In efficiently precipitates into Sp1 under the environment of log fO2 = −32 to −26 and pH = 6–8. As the fluids cool at ~340 °C, weakened Zn2+ competition allows In3+ to form stable InCl3, and In precipitates into Sp2 under the conditions of log fO2 = −42 to −32 and pH = 5.5–11. We therefore conclude that the key factor controlling the difference in In content between Sp1 and Sp2 is the precipitation mechanism rather than migration capacity. This may be different from the In enrichment mechanism associated with magmatic hydrothermal systems, where In is mainly present as InCl3 complexes with strong migration capacity. These new findings enable us to understand how the physicochemical conditions of fluids control the enrichment of In in VMS deposits, and also highlight that the color of sphalerite can be used to target potential In resources in PbZn deposits.
BACKGROUND:Stromal tumour-infiltrating lymphocytes (sTILs) are prognostic in early-stage HER2-positive breast cancer, but their role in the context of dual HER2 blockade remains undefined. We evaluated manual, digital, and artificial intelligence (AI)-based sTIL quantification, together with AI-derived spatial metrics, for prognostic and treatment-benefit stratification using tumour samples from the phase 3 APHINITY trial. METHODS:In the APHINITY trial, 4805 patients were randomly assigned to receive chemotherapy plus trastuzumab with pertuzumab or chemotherapy plus trastuzumab with placebo. Median follow-up was 74·1 months (IQR 68·3-75·4). We analysed 4262 haematoxylin and eosin-stained images using manual assessment, an automated digital approach, AI-based lymphocyte quantification (AI percentage lymphocytes), and two AI-derived spatial features (AI-TIL and immune hotspot). Interobserver reproducibility was assessed in 262 randomly chosen tumour samples scored independently by five pathologists. Multivariable Cox models were used to assess associations between TIL levels and invasive disease-free survival (primary outcome in APHINITY), distant recurrence-free interval, and overall survival. The heterogeneity of pertuzumab benefit was evaluated using subgroup analyses, subpopulation treatment effect pattern plot analyses, and nested Cox models with treatment-by-biomarker interaction terms. FINDINGS:Manual scoring showed high interobserver reproducibility (intraclass correlation coefficient 0·84 [95% CI 0·79-0·88]). Concordance between manual and automated methods was modest. AI-based scoring (AI percentage lymphocytes) reclassified 120 (11·6%) of 1035 node-positive tumours from immune-low (by manual scoring) to immune-high; this subgroup of patients showed greater separation of 5-year invasive disease-free survival curves between pertuzumab and placebo groups compared with patients whose tumours were concordantly classified as immune-low by both manual and AI-based approaches. Higher levels of TILs were associated with improved invasive disease-free survival for all sTIL measurement approaches and spatial measurements (hazard ratios [HRs] 0·41-0·93). Pertuzumab was associated with improved invasive disease-free survival at higher sTIL levels across all measurement approaches (HRs 0·36-0·48), but was not associated with higher values of spatial measures. The largest 6-year absolute improvements with pertuzumab were observed in patients with node-positive disease whose tumours scored in the highest level of immune infiltration of manual sTIL scoring (≥70·0%; mean absolute improvement 12·1 percentage points [SD 2·8]). In nested prognostic and predictive models, AI-based immune hotspot scores provided the most consistent additional information when combined with any sTIL measurement (all p<0·010). INTERPRETATION:Standardised manual sTIL scoring was reproducible, and digital and AI-based methods showed consistent prognostic stratification and potential for treatment-benefit stratification despite only modest correlation between platforms. AI spatial metrics provided complementary information beyond sTIL density and could support more scalable immune assessment. Future studies are needed to validate these approaches in independent cohorts and to clarify their clinical utility for stratifying contemporary HER2-directed therapies. FUNDING:None.
BACKGROUND:Ifebemtinib is a potent oral focal adhesion kinase inhibitor. Preclinical evidence supports combining ifebemtinib with the KRASG12C inhibitor garsorasib. This study aimed to evaluate this combination in KRASG12C-mutated solid tumours. METHODS:This multicentre, phase 1b/2 study had a phase 1b component to establish the recommended phase 2 dose and a phase 2 multitumour expansion component. In phase 1b, the safety and tolerability of ifebemtinib combined with garsorasib was assessed using a 3 + 3 design in KRASG12C-mutated solid tumours. No dose-limiting toxic effects were observed, and the recommended phase 2 dose was established as ifebemtinib 100 mg orally once daily plus garsorasib 600 mg orally twice daily. Here, we report the results of the cohort of previously treated KRASG12C-mutated metastatic colorectal cancer from phase 2 expansion. Eligible patients (aged ≥18 years) who had histologically confirmed locally advanced or metastatic colorectal cancer harbouring the KRASG12C mutation, an Eastern Cooperative Oncology Group performance-status score of 0 or 1, and had disease progression after previous irinotecan-based or oxaliplatin-based combination therapy, were recruited from seven of nine participating tertiary hospitals in China. On the basis of the recommended phase 2 dose, phase 2 comprised a single-arm study to evaluate the safety and efficacy of ifebemtinib combined with garsorasib and an open-label, randomised study in which patients were randomly assigned (1:1) to receive ifebemtinib plus garsorasib or garsorasib alone, by use of centralised computer-generated block randomisation with no stratification. Investigators were masked to the block size. The primary efficacy endpoint of phase 2 was investigator-assessed objective response rate (Response Evaluation Criteria in Solid Tumours, version 1.1), assessed in the safety analysis set in the single-arm study and in all randomly assigned patients (intention-to-treat population) in the randomised study. At least six objective responses (safety analysis set) were required in the single-arm study to proceed to the randomised study. This study is registered with ClinicalTrials.gov, NCT06166836 and NCT05379946, and is active but not recruiting. FINDINGS:Between April 7, 2023 and Dec 13, 2024, 51 patients were enrolled in phase 2 (15 in the single-arm study and 36 in the randomised study). In the single-arm study, the median age was 53 years (IQR 39 to 63), nine (60%) patients were female, six (40%) were male, and all were Asian. In the randomised study, the median age was 51 years (IQR 42 to 59) in the combination group and 63 years (IQR 54 to 66) in the monotherapy group, 24 (67%) were female, 12 (33%) were male, and all patients were Asian. In the single-arm part, the confirmed objective response rate was 46·7% (95% CI 21·3 to 73·4). Seven patients had partial responses, triggering progression to the randomised study. In the randomised study, the confirmed objective response rate was 38·9% (95% CI 17·3 to 64·3) with the combination therapy versus 16·7% (95% CI 3·6 to 41·4) with garsorasib alone (between-group difference 22·2%, 95% CI -7·7 to 49·1; one-sided p=0·068). In the single-arm study, grade 3 treatment-related adverse events occurred in four (27%) of 15 patients, and in the randomised study, grade 3 treatment-related adverse events occurred in six (33%) of 18 patients in the combination group and five (28%) of 18 in the garsorasib group. Grade 3 treatment-related adverse events occurring in at least two patients were diarrhoea (six [18%]), proteinuria (two [6%]), and intestinal obstruction (two [6%]) in patients treated with combination therapy (combined), and increased alanine aminotransferase and γ-glutamyltransferase (two [11%] each) in patients treated with garsorasib alone. Serious adverse events occurred in ten (30%) patients in the combination group and in four (22%) patients in the monotherapy group. One patient in the garsorasib monotherapy group died due to the underlying malignancy within 30 days after completing study treatment, which was reported as a serious adverse event. The death was assessed by the investigators as not related to garsorasib. No grade 4 treatment-related adverse events or treatment-related deaths were reported across all cohorts. INTERPRETATION:The combination of ifebemtinib and garsorasib showed promising anticancer activity and manageable safety profile in previously treated patients with KRASG12C-mutated metastatic colorectal cancer. Although the improvement in response rate did not reach statistical significance in the randomised study, these findings support further evaluation of ifebemtinib plus garsorasib in this population. FUNDING:InxMed, InventisBio, National Natural Science Foundation of China, the Jian Bing Ling Yan + X Research and Development Program of Zhejiang Province, and the Zhejiang Province Medical and Health Science and Technology Plan Project.
BACKGROUND:Transarterial chemoembolisation (TACE), a standard treatment for embolisation-eligible hepatocellular carcinoma (HCC), induces tumour immune responses. Single tremelimumab regular interval durvalumab (STRIDE) is a standard treatment in advanced HCC. In this phase 3 trial, we assessed the efficacy and safety of STRIDE, with or without lenvatinib, plus TACE, in participants with embolisation-eligible HCC. METHODS:EMERALD-3 is a phase 3, randomised, open-label, sponsor-blinded study, conducted at 177 medical sites in 21 countries. Eligible participants were 18 years or older (aged ≥21 years in Egypt or Singapore) at screening and had confirmed HCC (by imaging or histopathologically from biopsy specimen, surgery, or both) not amenable to curative surgery, curative ablation, or transplantation but amenable to TACE. Participants had Child-Pugh class A liver function, an Eastern Cooperative Oncology Group performance status of 0-1, and at least one measurable target intrahepatic lesion per modified Response Evaluation Criteria in Solid Tumours. Participants were randomly allocated in a 1:1:1 ratio to receive STRIDE plus lenvatinib plus TACE, STRIDE plus TACE, or TACE until each group reached its preplanned enrolment target of 175 participants. After the STRIDE plus TACE group reached its enrolment target, randomisation was adjusted to continue in a 1:1 ratio between the STRIDE plus lenvatinib plus TACE group and TACE group until approximately 275 participants were enrolled in each of these two groups. Randomisation used a centrally assigned interactive response technology system, stratified by region, baseline tumour burden, and previous palliative embolisation. In the STRIDE plus lenvatinib plus TACE group, on the first day, participants were given 300 mg tremelimumab intravenously, followed by 1500 mg durvalumab plus oral lenvatinib (8 mg for <60 kg bodyweight or 12 mg for ≥60 kg bodyweight); participants then received 1500 mg durvalumab every 4 weeks plus once-daily lenvatinib for up to 36 cycles. In the STRIDE plus TACE group, participants were given 300 mg tremelimumab and 1500 mg durvalumab intravenously on the first day, followed by 1500 mg durvalumab every 4 weeks. The technique and number of TACE procedures were at the investigators' discretion, with the first procedure administered at least 7 days after the first dose of durvalumab in the two investigation treatment groups and within 7 days of random allocation in the TACE group. The primary endpoint was progression-free survival for STRIDE plus lenvatinib plus TACE versus TACE. Key secondary endpoints were overall survival for STRIDE plus lenvatinib plus TACE versus TACE and progression-free survival and overall survival for STRIDE plus TACE versus TACE. This study was registered with ClinicalTrials.gov (NCT05301842), with enrolment completed. FINDINGS:From March 28, 2022, to Nov 20, 2024, 1124 participants were screened. The full analysis set comprised 760 participants, who were randomly allocated to STRIDE plus lenvatinib plus TACE (n=293), STRIDE plus TACE (n=175), or TACE (n=292). 633 (83%) participants were male and 127 (17%) were female; 548 (72%) were Asian. At the first data cutoff (Sept 2, 2025); the overall median follow-up for progression-free survival was 10·0 months (IQR 4·6-17·2); median follow-up for progression-free survival was 11·0 months (IQR 4·8-18·4) for STRIDE plus lenvatinib plus TACE and 8·3 months (4·1-15·5) for TACE. Median progression-free survival was 13·0 months (95% CI 12·2-16·7) for STRIDE plus lenvatinib plus TACE versus 9·8 months (8·0-11·4) for TACE (HR 0·70 [95% CI 0·57-0·86]; p=0·0007). At the second data cutoff (Feb 23, 2026) and a median follow-up for overall survival of 24·6 months (IQR 16·5-31·5) for STRIDE plus lenvatinib plus TACE and 22·9 months (14·9-30·2) for TACE, median overall survival was 39·5 months (95% CI 34·1-not reached) for STRIDE plus lenvatinib plus TACE and 34·7 months (28·8-not reached) for TACE (HR 0·84 [95% CI 0·65-1·09]; p=0·18). At this data cutoff, median progression-free survival was 12·9 months (95% CI 10·2-15·9) for STRIDE plus TACE and 8·1 months (6·5-10·2) for the first 175 participants randomised to TACE (HR 0·71 [95% CI 0·56-0·91]), with median follow-up of 10·3 months (IQR 4·6-23·7) for STRIDE plus TACE and 7·7 months (3·0-18·5) for the first 175 participants randomly allocated to TACE. The most common adverse events of maximum grade 3 or 4 were hypertension (34 [12%] of 287) for STRIDE plus lenvatinib plus TACE, post-embolisation syndrome and anaemia (ten [6%] of 175 each) for STRIDE plus TACE, and post-embolisation (17 [6%] of 290) for TACE. 184 (64%) participants receiving STRIDE plus lenvatinib plus TACE, 89 (51%) receiving STRIDE plus TACE, and 68 (23%) receiving TACE had serious adverse events. Treatment-related adverse events with an outcome of death during the treatment-emergent period occurred in seven (2%) of 287 participants who received STRIDE plus lenvatinib plus TACE (two for myocarditis; and one each for hepatic failure, haemophagocytic lymphohistiocytosis, septic shock, cardiac failure, and unknown cause), none of 175 participants who received STRIDE plus TACE, and two (1%) of 290 participants who received TACE (one each for acute myocardial infarction and unknown cause). INTERPRETATION:STRIDE plus lenvatinib plus TACE showed a statistically significant progression-free survival improvement versus TACE. These findings support a STRIDE-based regimen as a potential new treatment option for people with embolisation-eligible HCC; additional follow-up is being conducted for final analysis of overall survival across treatment groups. FUNDING:AstraZeneca.
Tumour-infiltrating lymphocytes (TILs) are prognostic and predictive biomarkers in breast cancer. High pre-treatment TILs are associated with a favourable prognosis and improved response to systemic therapies. However, the role of TILs in mediating response to radiotherapy in breast cancer remains underexplored, with scarce clinical evidence to date. In this Review, we present an overview of current evidence and potential mechanisms, highlight opportunities for integrating TILs into radiation oncology trials and clinical practice, and call for standardised TIL reporting to accelerate biomarker-driven individualisation of radiotherapy in breast cancer.
BACKGROUND:SHR-A2102 is a new antibody-drug conjugate consisting of a fully human nectin-4-directed monoclonal antibody bound to a topoisomerase I inhibitor payload via a cleavable linker. We did a phase 1 trial to evaluate the safety, preliminary activity, and pharmacokinetics of SHR-A2102 in advanced solid tumours. METHODS:This multicentre, single-arm, phase 1 trial was done at 39 hospitals in China and included dose-escalation (Bayesian Optimal Interval design), pharmacokinetic-expansion, and efficacy-expansion stages. Eligible patients were aged at least 18 years, had unresectable, locally advanced or metastatic solid tumours that had progressed after, were intolerant to, or had no available standard therapy, and had an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients received SHR-A2102 intravenously at doses of 2-10 mg/kg once every 3 weeks. The primary endpoints were safety, dose-limiting toxicity, maximum tolerated dose, and recommended phase 2 dose. All patients who received at least one dose of SHR-A2102 were included in the safety and activity analyses. This trial is registered at ClinicalTrials.gov (NCT05701709) and is ongoing. FINDINGS:Between April 17, 2023 and Feb 20, 2025, 395 patients (median age 59 years [IQR 53-66]; 239 [61%] male and 156 [39%] female; 395 [100%] Chinese) were enrolled and treated across study stages, including 197 with non-small cell lung cancer, 32 with hormone receptor-positive, HER2-negative breast cancer, 36 with triple-negative breast cancer, 77 with oesophageal squamous cell carcinoma, 26 with head-and-neck squamous-cell carcinoma, and 27 with other solid tumours. As of data cutoff (June 20, 2025), the median follow-up was 7·2 months (IQR 4·7-9·7). Based on data from the dose-escalation stage, 6 mg/kg (n=10) and 8 mg/kg (n=11) were selected for pharmacokinetic expansion. During dose escalation, one dose-limiting toxicity was reported at 10 mg/kg (grade 4 decreased platelet count); maximum tolerated dose was not reached. Grade 3-4 treatment-related adverse events were reported in 212 (54%) of 395 patients, with the most common being decreased neutrophil count (118 [30%]), decreased white-blood-cell count (75 [19%]), and anaemia (69 [17%]). Treatment-related serious adverse events were reported in 98 (25%) patients with the most common being pneumonia (21 [5%]). Treatment-related deaths occurred in two (<1%) patients (pulmonary embolism and pneumonia). INTERPRETATION:SHR-A2102 demonstrated a safety profile consistent with its topoisomerase I inhibitor payload and showed promising activity in patients with various advanced solid tumours who had previously received anti-cancer treatment. A range of active dose was identified in various tumour types. Several trials are ongoing to evaluate SHR-A2102, either as monotherapy or in combination, in advanced solid tumours. FUNDING:Jiangsu Hengrui Pharmaceuticals.
BACKGROUND:Tumour-infiltrating lymphocytes (TILs) are a robust prognostic marker in patients with triple-negative breast cancer. Artificial intelligence (AI)-derived computational tools assessing TILs could improve efficiency, but require independent validation against clinical outcomes. We aimed to compare the prognostic performance of AI-derived TIL scores with pathologist-scored TILs in a large, prospectively collected dataset pooled from randomised controlled trials. METHODS:CATALINA was an independent, external validation study using prospectively collected long-term clinical outcome data pooled from seven randomised clinical trials conducted at multiple sites. We independently evaluated two previously validated AI pipelines that generate five computationally assessed tumour-infiltrating lymphocyte (cTIL) scores by masked, independent deployment of locked models. cTIL scores were correlated with the mean of the pathologist-scored stromal TILs (sTILs) in 220 digitised haematoxylin and eosin whole slide images in a cohort of patients with early-stage triple-negative or HER-2 positive breast cancer, previously scored by trained pathologists in a TIL-reproducibility study. Prognostic performance was assessed in a separate cohort of patients with early triple-negative breast cancer pooled from seven prospective, randomised adjuvant trials. Multivariable Cox regression models adjusted for clinicopathological factors and study heterogeneity assessed associations of cTIL score and sTIL score with invasive disease-free survival, distant disease-free survival, and overall survival. 5-year discrimination was estimated using time-dependent area under the receiver operating characteristic curve (AUC). FINDINGS:Individual data were collated from 1759 patients, of whom 1356 had complete clinicopathological data, pathologist sTIL scores, and cTIL scores available. Modest correlation (r 0·375-0·473) was observed between cTIL scores and the mean pathologist sTIL score. Both sTIL and cTIL were independently associated with 5-year invasive disease-free survival, distant disease-free survival, and overall survival after adjustment for clinicopathological factors (hazard ratio for invasive disease-free survival was 0·73 [95% CI 0·66-0·82]; q<0·0001, distant disease-free survival was 0·70 [0·61-0·79]; q<0·0001, and overall survival was 0·72 [0·63-0·82]; q<0·0001 for sTIL scores and 0·80 [0·73-0·89]; q<0·0001, 0·77 [0·69-0·86]; q<0·0001, and 0·79 [0·70-0·88]; q=0·0002, respectively, for percentage_lymphocyte scores). In models adjusted for clinicopathological variables and sTIL score, cTIL score did not maintain a statistically significant prognostic association. Both sTIL and cTIL scores improved the 5-year AUC over clinicopathological variables alone, while cTIL score did not significantly further improve AUC when combined with clinicopathological variables and sTIL score. INTERPRETATION:Two cTIL models deployed entirely without retraining or modification provided statistically significant prognostic information and improved risk discrimination compared with clinicopathological variables alone in this large, platform-based, independent validation study. Although cTIL score did not incrementally improve prognostication compared with models combining clinicopathological variables with sTIL score, these findings support the application of cTILs as a reproducible prognostic biomarker, particularly in settings where routine or widespread pathologist assessment is unavailable. FUNDING:Breast Cancer Research Foundation (USA).
BACKGROUND:For patients with high-risk prostate cancer, the role of dose-escalated radiotherapy in combination with long-term androgen deprivation treatment (ADT) is controversial, without any demonstrated benefit on cancer-specific or overall survival. We aimed to evaluate the effect of a 10 Gy dose increase, from 70 Gy to 80 Gy, on progression-free survival in men with high-risk prostate cancer. METHODS:In this multicentre, open-label, randomised, phase 3 trial, we enrolled patients with high-risk prostate cancer, defined as prostate-specific antigen of 20 ng/mL or more, Gleason score of at least 8, or clinical stage T3-T4, from 25 centres in France. Participants were randomly assigned (1:1) by minimisation, stratified by centre and previous pelvic lymph node dissection, to receive prostate-targeted dose-escalated external beam radiotherapy (80 Gy; 2 Gy per fraction for 8 weeks) or standard-dose external beam radiotherapy (70 Gy; 2 Gy per fraction for 7 weeks), combined with long-term ADT. Neither the participants nor the investigators were masked to the allocated treatment. The primary endpoint was 5-year progression-free survival defined as the time from randomisation to first biochemical (defined as prostate-specific antigen >nadir plus 2 ng/mL) or clinical (ie, local, regional, or metastatic) disease progression, analysed in the intention-to-treat population, with 197 events required. 5-year progression-free survival was the prespecified endpoint, and 10-year progression-free survival was additionally reported (post hoc) in view of the low number of events at 5 years. The trial is registered at ClinicalTrials.gov, NCT00967863, and is complete. FINDINGS:Between April 6, 2009, and Jan 24, 2013, 505 patients with high-risk prostate cancer were enrolled; 250 were assigned to receive dose-escalated radiotherapy (80 Gy) and 255 to receive standard dose radiotherapy (70 Gy). All participants were male and ethnicity data were not collected. At a median follow-up of 9·5 years (IQR 8·5-10·3), 5-year progression-free survival was 91·4% (95% CI 87·0-94·4) in the dose-escalation group versus 88·1% (83·2-91·6) in the control group, and 10-year progression-free survival was 83·6% (77·8-88·0) versus 72·2% (65·3-78·0; stratified HR 0·56, 95% CI 0·40-0·78, p<0·0001). Grade 3 or worse adverse events assessed at 6 months (acute toxicity) were observed in 60 (24%) of patients in the dose-escalation group and 62 (25%) in the control group. The most frequent grade 3 or worse adverse events were sexual disorders (28 [11%] in the dose-escalation group vs 20 [8%] in the control group) and bladder or urethra disorders (12 [5%] vs 19 [8%]). Adverse events assessed at 5 years (late toxicity) occurred in 118 (70%) of 168 in the dose-escalation group and 122 (73%) of 168 in the control group; grade 3 or worse late toxicities occurred in 19 (8%) participants in the dose-escalated radiotherapy group versus 17 (7%) participants in the control group. The most common late grade 3 adverse event was bladder or urethra disorders (seven [4%] vs three [2%], respectively). Serious adverse events occurred in nine (4%) patients in the dose escalation group and nine (4%) in the control group; none were considered to be treatment related. There were no treatment-related deaths. INTERPRETATION:For patients with high-risk prostate cancer, radiotherapy at a total dose of 80 Gy, in combination with long-term ADT, improved progression-free survival and could be a potential option in this situation. However, given the low number of events, further research is needed to consolidate and confirm the benefit in dose-escalation in prostate cancer-specific survival and overall survival. FUNDING:French National Cancer Institute and AstraZeneca.
BACKGROUND:Ivonescimab has shown clinical efficacy in non-small-cell lung cancer (NSCLC). We aimed to assess the efficacy and safety of ivonescimab plus chemotherapy versus placebo plus chemotherapy in patients with advanced EGFR-mutated NSCLC whose disease progressed after third-generation EGFR tyrosine kinase inhibitor (TKI) therapy. METHODS:HARMONi is a randomised, placebo-controlled, double-blind, phase 3 trial done at 114 cancer centres and hospitals across Asia, Europe, and North America. Eligible patients were aged at least 18 years (upper limit: 75 years in Asia) with stage IIIB/IIIC or IV non-squamous EGFR-mutated NSCLC, disease progression after treatment with a third-generation EGFR-TKI, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) via a centralised interactive voice response system or interactive web response system to receive ivonescimab (20 mg/kg) or placebo plus pemetrexed (500 mg/m2) and carboplatin (target area under the curve 5 mg/mL per min) intravenously every 3 weeks. Randomisation was stratified by brain metastases status at enrolment and geographical region. The primary endpoints were progression-free survival by blinded independent radiology review committee and overall survival in the intention-to-treat population. Safety was assessed in patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov (NCT06396065), has completed enrolment, and is ongoing for treatment and follow-up. FINDINGS:From Jan 25, 2022, to Oct 1, 2024, 660 individuals were screened for eligibility; of these, 438 were enrolled and randomly assigned to receive ivonescimab plus chemotherapy or placebo plus chemotherapy (219 per group). Of enrolled patients, 257 (59%) were female and 181 (41%) were male; 306 (70%) reported race as Asian, and 105 (24%) as White. At a median follow-up of 22·3 months (95% CI 21·5-23·0), 275 progression or death events had occurred in 345 patients (129 events among 172 patients in the ivonescimab plus chemotherapy group and 146 events among 173 patients in the placebo plus chemotherapy group). Median progression-free survival was 6·8 months (95% CI 5·7-7·1) in the ivonescimab plus chemotherapy group versus 4·4 months (4·1-5·5) in the placebo plus chemotherapy group (hazard ratio [HR] 0·52; 95% CI 0·41-0·66; p<0·0001). At a median follow-up of 29·7 months (95% CI 27·7-31·0), 262 deaths occurred in 438 patients (122 in the ivonescimab plus chemotherapy group and 140 in the placebo plus chemotherapy group). Median overall survival was 16·8 months (14·3-19·0) in the ivonescimab plus chemotherapy group versus 14·0 months (12·8-15·7) in the placebo plus chemotherapy group (HR 0·79; 0·62-1·01). The most common grade 3-4 treatment-related adverse events in the ivonescimab plus chemotherapy versus the placebo plus chemotherapy group were decreased neutrophil count (42 [19%] of 218 vs 36 [17%] of 218), decreased white blood cell count (28 [13%] vs 24 [11%]), decreased platelet count (27 [12%] vs 14 [6%]), and anaemia (22 [10%] vs 27 [12%]). Serious treatment-related adverse events occurred in 61 (28%) patients in the ivonescimab plus chemotherapy group and 33 (15%) patients in the placebo plus chemotherapy group. Treatment-related adverse events led to death in four patients (disease progression, multiple organ dysfunction syndrome, and hepatic failure, each in one patient; gastrointestinal haemorrhage and pulmonary embolism in one patient) in the ivonescimab plus chemotherapy group and five patients (pneumonitis, myocardial infarction, cerebrovascular accident, cognitive disorder, and embolic stroke, each in one patient) in the placebo plus chemotherapy group. INTERPRETATION:Ivonescimab plus chemotherapy showed a clinically meaningful and statistically significant progression-free survival benefit in patients with EGFR-mutated NSCLC after progression on EGFR-TKI therapy. The clinical benefit and lack of new safety signals of ivonescimab with chemotherapy support the potential for the combination as a new treatment option in this patient population. FUNDING:Summit Therapeutics.
The oligometastatic disease classification system, developed within the European Society for Radiotherapy and Oncology (ESTRO)-European Organisation for Research and Treatment of Cancer (EORTC) OligoCare project, has been proposed for prognostic stratification and clinical trial design across solid tumours. Its application to ovarian cancer, however, is challenged by two disease-specific features: early and often diffuse peritoneal spread and the difficulty of lesion enumeration when peritoneal deposits are not discretely measurable. Historically, radiotherapy has had a restricted role in ovarian cancer, largely because effective doses cannot be safely delivered to diffuse peritoneal disease in a condition that is typically systemic at diagnosis. With the advent of more effective systemic therapies, stereotactic radiotherapy has emerged as a strategy to reach durable local control in selected patients with minimal metastatic burden. Adapting the ESTRO-EORTC oligometastatic disease classification system to this setting could improve patient stratification and therapeutic planning. We therefore advocate for a joint ESTRO-EORTC-European Society of Gynaecological Oncology initiative, in collaboration with the EORTC Gynecological Cancer Group, to define ovarian-specific rules for peritoneal disease, refine patient selection, and harmonise clinical practice and trial eligibility within a multidisciplinary framework.
