Oligometastatic cancer is characterised by a low volume of metastases to a small number of anatomical sites. However, evaluating the impact of metastases-directed therapies (MDTs) on overall survival or quality of life i...Oligometastatic cancer is characterised by a low volume of metastases to a small number of anatomical sites. However, evaluating the impact of metastases-directed therapies (MDTs) on overall survival or quality of life is often challenging. Current clinical trials use a wide range of primary endpoints that might not be validated or suited to MDT. To address this issue, we did a systematic review of international trial registries, alongside a Delphi consensus process involving 30 experts and five patient representatives. The aim was to identify preferred primary endpoints for MDT trials in oligometastatic disease, regardless of tumour type. Overall survival and progression-free survival were the most frequently used endpoints across the 121 comparative trials reviewed. Over four Delphi consensus rounds, overall survival had the highest level of agreement, although its limitations as a sole endpoint were emphasised. In addition to the widely used progression-free survival endpoint, polymetastatic progression-free survival and start-or-switch of systemic therapy-free survival also reached consensus, particularly for trials integrating systemic therapies. Both polymetastatic progression-free survival and systemic therapy-free survival permit repeat MDT without classifying it as treatment failure. Patient representatives highlighted the importance of time-to-deterioration of quality of life. This consensus supports overall survival as a primary endpoint and, in addition to progression-free survival, recommends polymetastatic progression-free survival and systemic therapy-free survival, especially in combination with systemic therapies. Adopting these endpoints will make MDT trials more relevant, comparable, and patient-centred, thereby empowering future clinical and policy decisions.
BACKGROUND: Sarculator is a widely validated prognostic tool that estimates overall survival and crude cumulative incidence (CCI) of distant metastasis in patients with resected soft tissue sarcomas in the extremities. S...BACKGROUND: Sarculator is a widely validated prognostic tool that estimates overall survival and crude cumulative incidence (CCI) of distant metastasis in patients with resected soft tissue sarcomas in the extremities. Sarculator relied on external cohorts only for performance testing and could not incorporate new information or adapt to temporal changes. We aimed to develop BayeSarc, a prognostic model based on Bayesian sequential learning (BSL), which enables continuous updating by incorporating new clinical cohorts and provides more accurate estimates. METHODS: In this retrospective, multicentre cohort study, eligible patients were adults (aged ≥18 years) with primary, localised, surgically treated soft tissue sarcomas in the extremities (excluding desmoid tumours, undifferentiated small round cell sarcoma of soft tissue, alveolar or embryonal rhabdomyosarcoma, dermatofibrosarcoma protuberans, and well differentiated liposarcoma). Data were retrieved from institutional databases at each participating hospital. BayeSarc used the same clinicopathological variables as Sarculator (age, size, grade, and histology) and was developed with a historical cohort of consecutive patients treated surgically at the Istituto Nazionale dei Tumori (Milan, Italy) and sequentially updated with five independent cohorts from Canada, France, the UK, USA, and Italy. Bayesian Cox (overall survival) and Fine-Gray (CCI distant metastasis) models were reformulated within a BSL framework combining Bayesian updating with prior-information adaptive borrowing. The primary objective was to compare the discrimination and calibration of BayeSarc versus Sarculator for predicting overall survival and CCI-distant metastasis. We evaluated the performance of BayeSarc at each update using prequential estimates, reflecting model transport to a new cohort without local recalibration, and post-update estimates, reflecting performance after sequential updating. FINDINGS: We included a total of 4916 patients (2204 [44·8%] female, 2694 [54·8%] male, and 18 [0·4%] with sex not recorded) drawn from six cohorts: Istituto Nazionale dei Tumori, Milan, Italy (Jan 1, 1994-Dec 31, 2013; median follow-up 86 months [IQR 81-90]); Mount Sinai Hospital, Toronto, Canada (Jan 1, 1994-Dec 31, 2013; 85 months [81-90]); Institut Gustave Roussy, Villejuif, France (Jan 1, 1996-May 15, 2012; 75 months [68-82]); Royal Marsden Hospital, London, UK (Jan 1, 2006-Dec 31, 2013; 54 months [48-59]); Brigham and Women's Hospital, Boston, USA (Jan 1, 2014-Dec 31, 2021; 72 months [66-84]); and Istituto Nazionale dei Tumori, Milan, Italy (Jan 1, 2014-Dec 31, 2021; 61 months [57-64]). 12 patients from the UK were missing follow-up data and were excluded from survival analyses. At the final step of the BSL update, BayeSarc achieved higher discrimination than Sarculator for both overall survival (prequential mean C index: 0·784 [95% credible interval 0·759-0·794]; after update: 0·801 [0·790-0·809]; Sarculator: 0·773) and distant metastasis (prequential mean C index: 0·723 [0·704-0·738]; after update: 0·738 [0·730-0·743]; Sarculator: 0·718). Calibration improved consistently across updates, and uncertainty around estimates and predictions decreased. INTERPRETATION: BayeSarc is a continuously updatable, accurate, and precise prognostic tool for soft tissue sarcomas in the extremities. It reduces uncertainty, adapts to temporal changes, and refines variable weights. Its incorporation into the Sarculator app enables immediate clinical use, with potential to improve patient counselling, guide treatment decisions, and refine trial design. More broadly, the BSL framework provides an innovative and generalisable approach to prognostication in rare cancers, moving beyond the traditional two-step development-validation paradigm, enabling more efficient use of patient data. FUNDING: Associazione Italiana per la Ricerca sul Cancro, Cancer Research UK, Fundacion Científica, and Asociacion Espanola Contra el Cancer.
Kayani M, Murphy L, Dutey-Magni P
… +24 more, Howlett S, Sachdeva A, Padden-Modi M, Abdel-Aty H, Brown LC, Amos CL, Chan K, Gilbert DC, Langley RE, Brown M, Sydes MR, Parker CC, STAMPEDE Collaborators, Cross W, Malik Z, Varughese M, Turco F, Millman R, Matheson D, Gillessen S, Clarke NW, Parmar MKB, James ND, Attard G
BACKGROUND: Serum prostate-specific antigen (PSA) concentrations decrease after hormone therapy for prostate cancer, with the nadir serving as a potentially useful prognostic biomarker. To support clinical use, we evalua...BACKGROUND: Serum prostate-specific antigen (PSA) concentrations decrease after hormone therapy for prostate cancer, with the nadir serving as a potentially useful prognostic biomarker. To support clinical use, we evaluated the association between PSA nadir values and survival outcomes, stratified by pre-treatment metastatic volume or, in patients with non-metastatic cancer, stratified by lymph node status. METHODS: As part of the STAMPEDE platform trial, patients with metastatic or very high-risk non-metastatic prostate adenocarcinoma were recruited to five randomised, controlled, phase 3 trials conducted at 126 hospitals or oncology centres in Switzerland and the UK. Patients were randomly assigned to either standard of care (androgren deprivation therapy [ADT] alone or ADT plus docetaxel) or to one of five experimental treatment groups: ADT plus docetaxel with or without zoledronic acid, ADT plus abiraterone acetate with or without enzalutamide, or ADT plus prostate radiotherapy (only patients with metastatic disease). We used trial data from these participants to perform landmark analyses to test associations of PSA at 6, 12, and 24 weeks after randomisation with overall survival. Only patients with a PSA value were included in each landmark analysis. The Kaplan-Meier method was used to estimate 96-month overall survival rates and the corresponding 95% CIs for patients categorised by either metastatic volume or lymph node status. The STAMPEDE protocol platform is registered with ClinicalTrials.gov (NCT00268476), EUDRACT (2004-000193-31), and ISRCTN (ISRCTN78818544). FINDINGS: This study included 7129 patients from the STAMPEDE platform, who were recruited between Oct 5, 2005, and Sept 2, 2016; 4438 had metastases and 2691 had very high-risk non-metastatic disease. Among patients with metastasis and volumetric assessment, 2211 (55·9%) of 3956 had high-volume metastases, and among those with non-metastatic disease, 1033 (38·4%) were lymph node positive. A PSA concentration of 0·2 ng/mL or less was less frequent at 6 weeks or 12 weeks, but was associated with equivalent survival rates, compared with a PSA of 0·2 ng/mL or less at 24 weeks. Survival rates of PSA subcategories (≤0·2 ng/mL, >0·2 to 1·0 ng/mL, >1·0 to 3·0 ng/mL, and >3·0 ng/mL) differed by metastatic volume or, in patients with non-metastatic disease, by nodal status. Survival was longest for patients allocated to abiraterone with or without enzalutamide. Among patients with metastatic disease in the abiraterone with or without enzalutamide group who had a PSA of 0·2 ng/mL or less at 24 weeks, 96-month overall survival in patients with low-volume metastatic disease (64·1% [95% CI 57·8-69·8]) was higher than in patients with high-volume metastatic disease (44·6% [37·1-51·9]), but lower than in patients with non-metastatic, node-positive disease (79·4% [73·8-83·9]). 96-month overall survival was highest for patients with non-metastatic, node-negative disease (82·8% [95% CI 78·7-86·1]). INTERPRETATION: Metastatic volume or nodal status influence survival rates associated with on-treatment serum PSA categories, including for undetectable PSA. Radiological features and serum PSA could be combined to better predict survival. PSA at 24 weeks showed strongest associations with overall survival, although a PSA concentration of 0·2 ng/mL or less at any timepoint predicted favourable outcome. These findings could inform prognosis and warrant evaluation for treatment selection in clinical trials. FUNDING: Cancer Research UK, Prostate Cancer UK, UK Medical Research Council, and John Black Charitable Foundation.
BACKGROUND: Omitting sentinel lymph node biopsy (SLNB) and completion axillary lymph node dissection (cALND) in early-stage breast cancer reduces morbidity without compromising overall survival or recurrence rates. Howev...BACKGROUND: Omitting sentinel lymph node biopsy (SLNB) and completion axillary lymph node dissection (cALND) in early-stage breast cancer reduces morbidity without compromising overall survival or recurrence rates. However, reduced axillary surgery restricts staging information, impacting eligibility for CDK4/6 inhibitors. We evaluated the impact of omitting SLNB or cALND on CDK4/6 inhibitor eligibility and the associated benefits and harms. METHODS: We used data from the SOUND, INSEMA, SENOMAC, monarchE, and NATALEE randomised trials. These five trials evaluated the safety of de-escalated lymph node surgery and adjuvant CDK4/6 inhibitors in patients with early breast cancer. The primary outcome was the number needed to diagnose and treat with CDK4/6 inhibitor-ie, number of axillary surgeries leading to adjuvant CDK4/6 inhibitor use, preventing one invasive disease-free survival event, distant disease-free survival event, or overall survival event at 5 years. FINDINGS: Between Jan 31, 2015, and Dec 31, 2021, 19 541 patients were randomly assigned and analysed within five trials, of whom 19 475 (99·7%) were women and 66 (0·3%) were men; median follow-up was 57·2 months (IQR 44·1-81·6). For SLNB and ribociclib, the number needed to diagnose and treat for one prevented event was 123 for invasive disease-free survival, 129 for distant disease-free survival, and 345 for overall survival. For cALND and abemaciclib, the number needed to diagnose and treat for one prevented event was 106 invasive disease-free survival, 119 for distant disease-free survival, and 807 for overall survival. INTERPRETATION: Performing SLNB or cALND solely to determine eligibility for CDK4/6 inhibition requires very high number needed to diagnose and treat, adds substantial morbidity, and is costly, with only marginal overall survival benefit. FUNDING: None.
Beshr MS, Fahaid A, Shembesh RH
… +11 more, Valachis A, Lambertini M, Cortesi L, Alesawy AF, Abraheem A, Alsharedi M, Ali ME, Elkhanany A, Azim HA, Velikova G, Elhadi M
BACKGROUND: CDK4/6 inhibitors have shown clinical benefits in patients with hormone receptor-positive, HER2-negative advanced breast cancer. This meta-analysis aims to evaluate their effect on survival outcomes across cl...BACKGROUND: CDK4/6 inhibitors have shown clinical benefits in patients with hormone receptor-positive, HER2-negative advanced breast cancer. This meta-analysis aims to evaluate their effect on survival outcomes across clinically relevant subgroups. METHODS: For this reconstructed individual patient-level meta-analysis, we searched PubMed, Web of Science, the Cochrane Library, and Scopus on June 2, 2025, for phase 3 trials that compared CDK4/6 inhibitors plus endocrine therapy with endocrine monotherapy in patients with hormone receptor-positive, HER2-negative advanced breast cancer. Kaplan-Meier curves were reconstructed with the use of a time-to-event algorithm to retrieve survival data for individual patients. A series of pooled analyses for the reconstructed individual patient data were conducted with the use of a stratified Cox regression model. A pairwise random-effects meta-analysis was also conducted. Patients were stratified by endocrine sensitivity into endocrine-sensitive and endocrine-resistant, as well as by age, ethnicity, progesterone receptor status, menopausal status, Eastern Cooperative Oncology Group performance status, bone-only disease, and visceral metastasis. Primary outcomes analysed were progression-free survival and overall survival. The protocol is registered in PROSPERO (CRD420251073444). FINDINGS: 11 phase 3 trials, including 6035 patients and four agents-abemaciclib, ribociclib, palbociclib, and dalpiciclib-were included. CDK4/6 inhibitors plus endocrine therapy significantly improved progression-free survival in both endocrine-sensitive (HR 0·57, 95% CI 0·52-0·63; p<0·0001) and endocrine-resistant cancers (0·51, 0·45-0·57; p<0·0001). Overall survival was also improved with CDK4/6 inhibitors plus endocrine therapy in both subgroups: endocrine-sensitive (0·83; 0·74-0·92; p=0·0005) and endocrine-resistant (0·77; 0·67-0·89; p=0·0003). All individual agents, when combined with endocrine therapy showed progression-free survival benefits: abemaciclib (HR 0·53, 95% CI 0·46-0·61; p<0·0001), ribociclib (0·60, 0·52-0·68; p<0·0001), palbociclib (0·56, 0·49-0·65; p<0·0001), and dalpiciclib (0·49, 0·40-0·61; p<0·0001). However, only abemaciclib (0·79, 0·67-0·92; p=0·0031) and ribociclib (0·73, 0·64-0·84; p<0·0001) showed significant overall survival benefits; palbociclib did not reach statistical significance (0·89, 0·77-1·02; p=0·0920), and data for dalpiciclib remain immature. Other clinically relevant subgroups, stratified by age, ethnicity, progesterone receptor status, menopausal status, Eastern Cooperative Oncology Group performance status, bone-only disease, and visceral metastasis, showed progression-free survival and overall survival benefits in patients with endocrine-sensitive and endocrine-resistant tumours. INTERPRETATION: CDK4/6 inhibitors plus endocrine therapy significantly improved survival in hormone receptor-positive, HER2-negative advanced breast cancer. Benefits in progression-free survival and overall survival were consistent across major clinical subgroups. Although all agents improved progression-free survival, only ribociclib and abemaciclib showed statistically significant overall survival benefits, whereas palbociclib did not, and data for dalpiciclib remain immature. Further head-to-head comparisons and assessments of toxicity profiles, as well as patient-reported outcomes, are needed. FUNDING: None.
Wander SA, Lloyd MR, Keenan JC
… +27 more, Scott EC, Niemierko A, Spring LM, Fell GG, Shin J, Isakoff SJ, Moy B, Ryan L, Padden S, Fisher E, Newton A, Habin KR, Viscosi-Spieler ET, Scarpetti L, Varkaris A, Ellisen LW, Dubash T, Che D, Patel PS, de la Cruz FF, Sutaria DS, Sane RS, Micalizzi DS, Maheswaran S, Haber DA, Juric D, Bardia A
BACKGROUND: PI3K/AKT pathway activation is implicated in CDK4/6 inhibitor resistance. The use of AKT inhibition with continued CDK4/6 blockade after CDK4/6 inhibitor resistance remains unexplored. We evaluated the safety...BACKGROUND: PI3K/AKT pathway activation is implicated in CDK4/6 inhibitor resistance. The use of AKT inhibition with continued CDK4/6 blockade after CDK4/6 inhibitor resistance remains unexplored. We evaluated the safety of ipatasertib and an antioestrogen with or without palbociclib in patients with treatment refractory HR+/HER2- metastatic breast cancer. METHODS: This single-centre, open-label, phase 1b trial was conducted at the Massachusetts General Hospital (Boston, MA, USA). Eligible patients were women older than 18 years with biopsy proven HR+/HER2- locally advanced, unresectable, or metastatic breast cancer; an Eastern Cooperative Oncology Group performance status of 0-2; disease progression on at least one previous therapy for metastatic disease; and measurable disease or bone lesions. Patients received 400 mg oral ipatasertib with standard 500 mg intramuscular fulvestrant dosing (ipatasertib and fulvestrant group) or with an aromatase inhibitor (oral anastrozole 1 mg per day, exemestane 25 mg per day, or letrozole 2·5 mg per day; ipatasertib and aromatase inhibitor group) on days 1-28 of each cycle. The ipatasertib and fulvestrant plus palbociclib group included a dose-escalation phase with patients assigned sequentially to escalating doses of ipatasertib and palbociclib using a standard 3 + 3 design starting at the recommended dose of palbociclib (125 mg on days 1-21) and the lowest dose of ipatasertib (200 mg on days 1-21). The primary endpoint was safety and progression-free survival was a key secondary endpoint. Safety was analysed in all patients who received at least one dose of ipatasertib and progression-free survival was assessed in all enrolled participants. This study is registered with ClinicalTrials.gov, NCT03959891 (active, not recruiting). FINDINGS: Between June 5, 2019, and Feb 16, 2022, 77 patients were enrolled (19 assigned to ipatasertib and fulvestrant, 16 to ipatasertib and aromatase inhibitor, and 42 to ipatasertib and fulvestrant plus palbociclib). All patients were female (77 [100%]); 75 were White (97%) and two (3%) were Asian. The median age was 62 years (range 32-88) and 66 (86%) of 77 patients received previous CDK4/6 inhibitor (median number of previous lines was 3 [range 1-13]). The median follow-up was 12·5 months (IQR 7·6-19·7). The recommended phase 2 dose was established at 400 mg ipatasertib on days 1-21 with 100 mg palbociclib on days 8-28 and standard fulvestrant 500 mg. Median progression-free survival was 5·5 months (95% CI 3·8-7·4). Serious adverse events related to study treatment occurred in seven (17%) patients in the ipatasertib and fulvestrant plus palbociclib group and one (5%) in the ipatasertib and fulvestrant group, which were related to neutropenia, leukopenia, thrombocytopenia, and hyperglycaemia. Common grade 3-4 adverse events related to study treatment (occurring in >5% of patients) were neutropenia (30 [39%] of 77), leukopenia (15 [19%]), diarrhoea (14 [18%]), rash (seven [9%]), lymphopenia (three [4%]), and anaemia (four [5%]). Four deaths occurred during the study (one possibly treatment-related due to grade 5 hyperglycaemia in the ipatasertib and fulvestrant group and two due to infectious issues and one due to pulmonary complications in the ipatasertib and fulvestrant plus palbociclib group), deemed unrelated to study treatment. INTERPRETATION: The combination of fulvestrant, ipatasertib, and palbociclib showed preliminary signs of clinical activity and showed expected adverse events in heavily pretreated patients with HR+/HER2- metastatic breast cancer, warranting further evaluation in those with CDK4/6 inhibitor-refractory disease. FUNDING: Genentech, Howard Hughes Medical Institute, National Foundation for Cancer Research, and Breast Cancer Research Foundation.
BACKGROUND: The global burden of cancer continues to rise, disproportionately affecting low-income and middle-income countries, where cancer workforce shortages are especially acute and contribute to poor outcomes. In th...BACKGROUND: The global burden of cancer continues to rise, disproportionately affecting low-income and middle-income countries, where cancer workforce shortages are especially acute and contribute to poor outcomes. In this analysis, we estimate the effect on cancer mortality of scaling up specific workforce personnel types in order to provide global, regional, and country-specific guidance to inform cancer workforce policy. METHODS: Using the Global Cancer Workforce microsimulation model, which accounts for demographic, epidemiological, and health system factors related to cancer incidence and survival, we modelled the projected effect of scaling up 18 specific workforce personnel types on total cancer mortality (diagnosed and undiagnosed) from 17 cancers (oral, nasopharynx, oesophagus, stomach, colon, rectum, anus, liver, pancreas, lung, skin melanoma, breast, cervix uteri, ovary, prostate, bladder, and brain and CNS) in 200 countries and territories from 2030 to 2050. Workforce density (per 100 000 population) of each workforce personnel type was modelled based on estimates from various sources (including WHO Global Health Workforce Statistics, the IMAGINE database, and previous Lancet Commissions). Expert opinion surveys, with responses from 86 experts in 16 countries, informed the involvement of workforce personnel in specific model events. We also modelled scale-up of workforce by cadre (ie, teams of personnel that work together in a particular specialty) and level of training (ie, years of education). FINDINGS: Substantial disparities in cancer workforce were projected to persist in 2050, with especially large workforce shortages in Africa. Among single personnel types, scaling up surgeons was projected to yield the largest reduction in global cancer mortality (3·64% [95% uncertainty interval 2·68-4·66]), especially in Africa, Asia, and Oceania, but with considerable heterogeneity by country. Among workforce cadres, scaling up diagnostic and imaging personnel was projected to yield the greatest benefit (global cancer mortality reduction of 7·61% [5·23-9·88]), with some heterogeneity by country. Comprehensive scale-up of all workforce levels was projected to reduce cancer mortality by over 50% in 55 countries, most notably in Africa, central America, and southern Asia. INTERPRETATION: Investments to strengthen the cancer workforce will be essential to reduce global cancer mortality and improve timely diagnosis and survival. Strategic scale-up of personnel, particularly in diagnostics, alongside innovative strategies such as digital health solutions and role delegation, could result in substantial improvements in cancer outcomes. Policy makers should prioritise data-driven workforce planning as a crucial component of comprehensive cancer control strategies. FUNDING: American Cancer Society and Breast Cancer Research Foundation.
BACKGROUND: Cancer survival has improved in many countries in recent decades, but large disparities remain globally. Understanding the effects of workforce shortages, stage at diagnosis, and broader health system barrier...BACKGROUND: Cancer survival has improved in many countries in recent decades, but large disparities remain globally. Understanding the effects of workforce shortages, stage at diagnosis, and broader health system barriers on poor survival is important for the design and evaluation of policy interventions to improve cancer survival in diverse settings. We aimed to develop a model to estimate trends in cancer survival (overall and by stage), accounting for these factors. METHODS: We developed the Global Cancer Workforce microsimulation model to simulate 17 cancer types (oral, nasopharynx, oesophagus, stomach, colon, rectum, anus, liver, pancreas, lung, skin melanoma, breast, cervix uteri, ovary, prostate, bladder, and brain and CNS) in 200 countries and territories from 1990 to 2050, accounting for trends in stage-specific survival and health system factors, including 14 specific workforce personnel types relevant to cancer survival. We calibrated the survival module to empirical data on population-based 5-year net survival, and estimated survival in each country by cancer and overall (pooled and standardised for country-specific incidence of different cancer types). We also estimated stage-specific cancer survival, and cancer mortality rates based on both observed (diagnosed) and total (undiagnosed and diagnosed) cancer cases. FINDINGS: Between 2025 and 2050, global pooled 5-year net survival was projected to remain stable (47·6% [95% uncertainty interval (UI) 45·9-49·1] to 47·7% [46·0-49·4]), with persistent disparities by income group and geographical area. In 2050, pooled survival was projected to be lowest in Africa (34·4% [32·6-36·3]) and Asia (38·7% [36·0-40·6]), and highest in North America (63·9% [58·1-66·6]) and Oceania (70·4% [67·2-73·7]). Standardising survival for country-specific incidence of different cancer types resulted in decreased estimates for all world regions except eastern Asia, which has a higher proportion of cancer types with poor survival. Large disparities in survival by geographical region also existed within each cancer type. For example, in 2025, estimated 5-year net survival for melanoma ranged from 39·0% (22·2-57·2) in Africa to 91·7% (85·1-95·7) in North America. Global cancer mortality in 2025 was estimated to be 90·0 per 100 000 population (95% UI 79·6-97·2) based on diagnosed cases, which increased to 188·9 per 100 000 population (183·4-195·5) when total cancer cases were considered, with substantially higher estimates compared with those based on observed cases in settings such as Africa and south Asia. INTERPRETATION: Disparities in global cancer survival are large and are expected to persist on current trends without transformative policy action. Our modelling framework provides comprehensive, country-level projections of survival and mortality for multiple cancers, accounting for demographic and epidemiological trends, as well as health system barriers and workforce constraints. FUNDING: American Cancer Society and Breast Cancer Research Foundation.
BACKGROUND: Cancer incidence is increasing globally, with the largest burden in low-income and middle-income countries. Workforce shortages and health system barriers contribute to substantial diagnostic delays and under...BACKGROUND: Cancer incidence is increasing globally, with the largest burden in low-income and middle-income countries. Workforce shortages and health system barriers contribute to substantial diagnostic delays and underdiagnosis, but estimates of undiagnosed cancer burden are lacking. The aim of this study was to estimate incidence (total and diagnosed) and stage at diagnosis in each country for 17 cancers from 1990 to 2050. METHODS: We developed the Global Cancer Workforce microsimulation model to simulate 17 cancer types (oral, nasopharynx, oesophagus, stomach, colon, rectum, anus, liver, pancreas, lung, skin melanoma, breast, cervix uteri, ovary, prostate, bladder, and brain and CNS) in 200 countries and territories from 1990 to 2050, accounting for demographic trends and health system factors, including ten specific workforce personnel types relevant to cancer diagnosis. We calibrated the incidence module to empirical data on diagnosed cancer incidence and stage distribution at diagnosis. Using the calibrated model, we estimated both total (underlying) and diagnosed crude and age-standardised incidence rates (per 100 000 population) and numbers of cancer cases for each country and region from 1990 to 2050. We also estimated the proportion of cancers diagnosed at each stage (I-IV). FINDINGS: Globally, among the 17 cancers included in the model, diagnosed cancer incidence was projected to increase from 13·58 million (95% uncertainty interval [UI] 12·17-14·51) cases in 2025 to 19·32 million (17·65-21·33) in 2050. Lung, breast, and prostate cancers were projected to remain the most commonly diagnosed cancers globally. The proportions of incident cancers that die undiagnosed showed large disparities by region, ranging from 0·9% (95% UI 0·6-1·3) in western Europe to 67·4% (60·1-74·2) in western Africa, with a global average of 31·5% (28·1-36·7). Globally, the proportion of cancers diagnosed at advanced stages (III-IV) was projected to decline slightly, from 45·7% (44·7-46·7) in 2025 to 44·7% (43·7-45·7) in 2050, with worse stage distributions in Africa and Asia compared with other regions. INTERPRETATION: These findings highlight the substantial and growing burden of cancers, especially in low-income and middle-income countries, where many people who develop cancer die undiagnosed. Accounting for demographic and epidemiological trends as well as health system factors, our modelling framework enables evaluation of targeted interventions to strengthen the cancer workforce and improve diagnostic pathways across diverse geographical and socioeconomic settings. FUNDING: American Cancer Society and Breast Cancer Research Foundation.