Arasu VA, Gadgil T, Rothstein JH
… +31 more, Alexeeff SE, Achacoso NS, Bhattacharya A, Cord JB, Esserman LJ, Galbraith W, Gerstley LD, Head ST, Hylton NM, Kushi LH, Lee C, Leimpeter AD, Lewis DA, Liu V, Marafino BJ, Margolies LR, Navarro DA, Pu A, Sakoda LC, Shan J, Shieh Y, Sistig A, Smith Gueye CL, Veer LV, Villaseñor M, Westley M, Wisner DJ, Tice JA, Shen L, Habel LA, Sieh W
J Natl Cancer Inst
· 2026 Jun · PMID 42331353
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BACKGROUND: We compared performance across 3 breast cancer risk domains-clinical, polygenic, and mammography artificial intelligence-alone and in combination over a 10-year time horizon among women with a negative screen...BACKGROUND: We compared performance across 3 breast cancer risk domains-clinical, polygenic, and mammography artificial intelligence-alone and in combination over a 10-year time horizon among women with a negative screening mammogram within a Kaiser Permanente Research Bank (KPRB) prospective cohort. METHODS: The study included 82 957 women (61 962 non-Hispanic White, 7256 Asian, 3414 Black, and 5466 Latina) who enrolled in KPRB between 2003 to 2020. Women with a prior history of breast cancer or high/moderate-penetrant gene mutation were excluded. The negative screening mammogram (no clinically visible cancer) closest to enrollment was used to generate the Mirai mammography AI risk score. KPRB survey and electronic health record data were used to generate the Breast Cancer Surveillance Consortium version 3 (BCSCv3) clinical risk score. Genome-wide genotypes were used to compute the 313-SNP polygenic risk score, adjusted for genetic ancestry (PRS313adj). Risks of breast cancer (invasive or ductal carcinoma in situ) at 0 to 10 years after the mammogram were estimated using Cox models, with 5-fold cross-validation used to estimate the C-index. RESULTS: During 10 years of follow-up, 2471 women developed breast cancer. The C-index (95% CI) for the combined model with all 3 risk scores (0.70; 95% CI = 0.69 to 0.71) was significantly higher than for univariate models with only the BCSCv3 (0.62; 95% CI = 0.61 to 0.63), PRS313adj (0.61; 95% CI = 0.60 to 0.62), or Mirai (0.66; 95% CI = 0.65 to 0.67) risk score. CONCLUSIONS: Integrating mammographic AI and polygenic risk scores with clinical risk models significantly improved breast cancer risk discrimination, supporting use of combined models for personalized screening and prevention.
Garitaonaindia Y, Witteveen S, Dionisio E
… +6 more, Weiss A, Ellebaek E, Rolfo C, Provencio M, Blank C, Donia M
J Natl Cancer Inst
· 2026 Jun · PMID 42317065
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BACKGROUND: Pathological complete response (pCR) and circulating tumor DNA (ctDNA) clearance are increasingly used as intermediate endpoints in neoadjuvant and perioperative immunotherapy (IO) trials. However, whether co...BACKGROUND: Pathological complete response (pCR) and circulating tumor DNA (ctDNA) clearance are increasingly used as intermediate endpoints in neoadjuvant and perioperative immunotherapy (IO) trials. However, whether complete pathological and molecular responders share comparable residual risk across tumor types remains uncertain. METHODS: We performed a post-hoc pan-tumor analysis using reconstructed individual patient data from published Kaplan-Meier curves of phase II/III trials. All included trials contained a neoadjuvant immunotherapy component; trials that additionally incorporated postoperative adjuvant immunotherapy were classified as perioperative. We evaluated associations of pCR and ctDNA clearance, defined as conversion from baseline ctDNA positivity to undetectable ctDNA after neoadjuvant therapy, with event-free survival (EFS) and tested whether these biomarkers modified the association between treatment timing (neoadjuvant-only versus perioperative) and EFS. FINDINGS: We reconstructed survival data for 1,867 patients achieving pCR and 352 patients achieving ctDNA clearance across 8 tumor types. Among patients with pCR, 3-year EFS varied substantially by tumor type (from 78.6% to 100%). In tumor types where such a comparison was possible, postoperative adjuvant IO did not improve EFS among patients achieving pCR. In contrast, ctDNA clearance showed heterogeneous prognostic dynamics. In within-tumor analyses restricted to trials reporting both endpoints, pCR was associated with superior EFS. CONCLUSION: pCR remains the most reproducible prognostic indicator across tumor types following neoadjuvant or perioperative IO. In cross-trial comparisons, no EFS benefit from postoperative adjuvant IO was observed among patients with pCR. ctDNA clearance showed substantial variability across tumors, likely reflecting both biological heterogeneity in tumor shedding and inter-trial assay differences.
Garitaonaindia Y, Luczak AA, Ruhlmann CH
… +9 more, Petersen SK, Friis RB, Borch TH, Guldbrandt LM, Svane IM, Schmidt H, Bastholt L, Ellebaek E, Donia M
J Natl Cancer Inst
· 2026 Jun · PMID 42308548
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PURPOSE: Pivotal phase III trials underpin regulatory approval of immunotherapy (IO) and BRAF/MEK inhibitors (BRAF/MEKi) in metastatic melanoma (MM). However, how trial-derived efficacy benchmarks translate into real-wor...PURPOSE: Pivotal phase III trials underpin regulatory approval of immunotherapy (IO) and BRAF/MEK inhibitors (BRAF/MEKi) in metastatic melanoma (MM). However, how trial-derived efficacy benchmarks translate into real-world effectiveness across eligibility strata remains insufficiently quantified. METHODS: We conducted a nationwide registry-based cohort study using the Danish Metastatic Melanoma Database, including patients with stage IV MM treated in first line with anti-PD-1 monotherapy, anti-PD-1/anti-CTLA-4, or BRAF/MEKi between 2014 and 2023. Real-world outcomes were compared with reconstructed pseudo-individual patient data from pivotal trials as regulatory efficacy benchmarks. Trial eligibility was defined using key exclusion criteria from pivotal studies. Overall survival (OS), progression-free survival (PFS), and melanoma-specific survival (MSS) were analyzed using Kaplan-Meier and Cox regression methods. RESULTS: Among 1909 patients, 41.7-44.9% of IO-treated and 74.3% of BRAF/MEKi-treated patients were trial-ineligible. In eligible populations, IO outcomes mirrored regulatory benchmarks. In contrast, trial-ineligible patients experienced substantial effectiveness deviations, with significantly higher mortality hazards for anti-PD-1 monotherapy (OS HR 1.61, 95% CI 1.39-1.86; p < 0.001) and nivolumab/ipilimumab (OS HR 1.30, 95% CI 1.02-1.66; p = 0.035) compared to their reference trials. For BRAF/MEKi, real-world outcomes were inferior to regulatory benchmarks even among trial-eligible patients and were markedly worse in trial-ineligible populations, with hazard ratios >2.5 across OS, MSS, and PFS (all p < 0.001). CONCLUSION: Real-world effectiveness of first-line therapies in MM deviates from regulatory trial benchmarks in trial-ineligible populations, with larger discrepancies for BRAF/MEKi than IO. These findings support population-specific effectiveness evaluation to complement trial-based efficacy estimates and inform health-technology assessment and clinical decision-making.
Miyakawa T, Lie JJ, Hu CY
… +7 more, Ochiai K, Behman RS, Keeling S, Shi Q, Nagtegaal ID, Goldberg R, Chang GJ
J Natl Cancer Inst
· 2026 Jun · PMID 42308525
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PURPOSE: The TNM classification at pathological evaluation determines prognosis following cancer treatment. For rectal cancer patients undergoing neoadjuvant therapy, whether ypTNM likely confers different prognosis than...PURPOSE: The TNM classification at pathological evaluation determines prognosis following cancer treatment. For rectal cancer patients undergoing neoadjuvant therapy, whether ypTNM likely confers different prognosis than pTNM. We compared survival outcomes of patients classified by ypTNM vs pTNM staging. PATIENTS AND METHODS: Patients with resected locoregional rectal cancer from the National Cancer Database who underwent upfront surgery (pTNM) and had ≥5 years follow-up (2010 to 2017) were compared with those receiving neoadjuvant therapy followed by surgery (ypTNM). To address treatment selection bias, analyses were stratified by receipt of guideline-concordant care. Overall survival was compared using Kaplan-Meier and multivariable Cox regression analyses. RESULTS: Of 50,436 patients (median age 60; 61.4% male), 11,732 (23.3%) underwent upfront surgery and 38,704 (76.7%) received neoadjuvant therapy; 78.8% of the upfront surgery group received guideline-concordant care. In analyses stratified by guideline-concordant care, overall survival was similar for stage 0-I (hazard ratio [HR] 1.05; 95% CI 0.96-1.15) but significantly worse for ypTNM vs pTNM in stage II (HR 1.50; 95% CI 1.27-1.77; 5-year OS 75.6% vs 83.2%) and stage III (HR 1.60; 95% CI 1.46-1.75; 5-year OS 67.0% vs 78.2%). Multivariable analysis confirmed ypTNM was associated with worse survival at each stage (stage 0-HR 1.14, P=.004; stage II: HR 1.49, P<.001; stage III: HR 1.60, P<.001). CONCLUSION: Stage for stage, ypTNM classification is associated with worse survival than pTNM classification, with increasing difference at higher stages. Future staging systems and management guidelines should account for these differences to optimize prognostication and stratification for clinical trials and surveillance strategies.
Orme SE, Lo SN, Saw RP
… +16 more, Shannon KF, Spillane A, Stretch JR, Ch'ng S, Nieweg OE, Thompson JF, Dugan MM, DePalo DK, Ghali H, Zager JS, Heaton MJ, Snelling AP, Johansson I, Olofsson Bagge R, Nessim C, Moncrieff MD
J Natl Cancer Inst
· 2026 Jun · PMID 42295855
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PURPOSE: Surrogate endpoints are widely used to support interim analyses and regulatory approval of adjuvant therapies in resected solid tumours, yet many lack formal trial-level validation. We evaluated disease-free sur...PURPOSE: Surrogate endpoints are widely used to support interim analyses and regulatory approval of adjuvant therapies in resected solid tumours, yet many lack formal trial-level validation. We evaluated disease-free survival (DFS) and distant metastasis-free survival (DMFS) as surrogate endpoints for disease-specific survival (DSS) and overall survival (OS) in resected melanoma and assessed the suitability of OS as primary endpoint. PATIENTS AND METHODS: A total of 10,379 patients with AJCC stage I-III melanoma treated between 2000 and 2023 at five international centres were analysed; all underwent sentinel node biopsy. Trial-level surrogacy was assessed using centre-specific log hazard ratios and restricted mean survival time at prespecified surrogate horizons (12 to 48 months), with primary endpoints truncated at 60 months. Individual-level surrogacy was evaluated using Kendall's τ. Prespecified subgroup analyses compared pT-defined IB-IIA and IIB-IIC disease. RESULTS: There were 2,418 DFS events, 1,833 DMFS events, and 1,235 melanoma-specific deaths. Trial-level surrogacy for DFS with DSS was strongest at 24 to 36 months (R2 up to 0.95). DMFS showed consistently high surrogacy for DSS from 24 to 48 months (R2 0.87 to 0.91). Correlations with OS were weak at all horizons (R2 < 0.40). Surrogacy was stage-dependent, with robust performance in pT-defined IIB-IIC disease and limited surrogacy in IB-IIA disease. CONCLUSION: DFS and DMFS are valid surrogate endpoints for DSS in resected melanoma at later time horizons, particularly in higher-risk disease. OS shows attenuated correlation with recurrence-based endpoints, limiting its utility for early endpoint evaluation in adjuvant trials.
Harrison NJ, Rankin NM, Paul CL
… +8 more, Bowden JA, Bendotti H, Roseleur J, Bartlett GE, Marshall HM, Stone E, Allerton S, Bonevski B
J Natl Cancer Inst
· 2026 Jun · PMID 42287080
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BACKGROUND: Although evidence-based smoking cessation interventions are widely recommended in lung cancer screening programs, real-world implementation remains poorly understood. METHODS: This scoping review aimed to ide...BACKGROUND: Although evidence-based smoking cessation interventions are widely recommended in lung cancer screening programs, real-world implementation remains poorly understood. METHODS: This scoping review aimed to identify and characterize smoking cessation interventions implemented in lung cancer screening programs, guided by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework. Eligible sources described real-world (nontrial) lung cancer screening programs from 2013 onward. We searched 6 databases in February 2025 and multiple grey literature sources and categorized implementation data by RE-AIM domains in narrative form. RESULTS: Of 55 unique studies, most were from the United States (84%), described a wide range of behavioral support (96%) and/or pharmacological (58%) interventions, and focused primarily on individual-level outcomes across RE-AIM domains. Reflecting strong Reach, most cessation interventions offered were generally acceptable to lung cancer screening participants and providers. Opt-out referral to embedded programs showed consistently high uptake. More intensive (eg, group/multicomponent) interventions had evidence of relatively high cessation (ie, Effectiveness) outcomes. Implementation most often involved delivery of low-intensity behavioral interventions. Program-level implementation factors under the Adoption (eg, provider readiness to adopt: 7%), Implementation (time and cost: 5%), and Maintenance (sustained intervention delivery: 4%) domains were rarely reported. CONCLUSIONS: Future real-world studies should generate and comprehensively report implementation data across key domains, particularly program-level conditions that support sustainable, long-term integration of cessation into lung cancer screening. This is critical given that many lung cancer screening programs globally still have not implemented formal cessation supports. Strengthening the evidence base will inform scalable, context-specific approaches and maximize reach across the diverse populations and settings of jurisdictions implementing lung cancer screening.
Yu ST, Huang L, Tang H
… +7 more, Ouyang R, Miao G, Zhou N, Mao S, Yu J, Liu R, Lei S
J Natl Cancer Inst
· 2026 Jun · PMID 42286408
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BACKGROUND: To comprehensively investigate the relationship between common genetic alterations and tumor recurrence in patients with papillary thyroid cancer (PTC) and evaluate whether integrating genetic status could im...BACKGROUND: To comprehensively investigate the relationship between common genetic alterations and tumor recurrence in patients with papillary thyroid cancer (PTC) and evaluate whether integrating genetic status could improve the performance of the 2025 American Thyroid Association (ATA) tumor recurrence risk stratification system (RSS). METHODS: This retrospective study included 2,056 patients (1,414 females and 642 males) with a median age of 39 years [interquartile range (IQR), 31-50 years] and a median follow-up time of 25 months (IQR, 13-35 months) who were treated for PTC at three medical centers in China between 2020 and 2024. RESULTS: Tumor recurrence rates were significantly higher in patients carrying RET fusions alone or genetic alteration combination, but not in patients carrying BRAF V600E alone, RAS mutations alone, or NTRK fusions alone, than that in patients without any genetic alteration, with an HR of 2.64 (95% CI, 1.31-5.32) and 3.37 (95% CI, 1.21-9.35) after adjusted for clinicopathological factors, respectively. RET fusions or genetic alteration combination were significantly associated with increased risk of tumor recurrence in all the ATA RSS categories, with an adjusted HR of 14.02 (95% CI, 3.75-52.48) in patients with ATA RSS low or low-intermediate categories, an HR of 3.01 (95% CI, 1.51-5.99) in the intermediate-high category, and an HR of 3.75 (95% CI, 2.17-6.48) in the high category, respectively. CONCLUSION: RET fusions and genetic alteration combination are independent prognostic markers for tumor recurrence of PTC, integrating tumors' genetic status into the 2025 ATA RSS system improves the accuracy of risk stratification for PTC.
Maclin BJ, Pfeiffer RM, Luo Q
… +8 more, Archer N, Hayes J, Monterosso A, Pawlish K, Ortiz AP, Shiels MS, Engels EA, Jackson SS
J Natl Cancer Inst
· 2026 Jun · PMID 42286371
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OBJECTIVE: Males have a higher incidence of most non-reproductive cancers than females, which has often been attributed to differences in lifestyle or behaviors. We examined whether sex differences in cancer incidence ar...OBJECTIVE: Males have a higher incidence of most non-reproductive cancers than females, which has often been attributed to differences in lifestyle or behaviors. We examined whether sex differences in cancer incidence are attenuated among immunocompromised adults. METHODS: Using data from population-based linkage study of HIV and cancer registries (2001-2019), we estimated male-to-female incidence rate ratios (M:F IRRs) among people with HIV (PWH) for 20 cancer sites. We used Poisson regression to adjust for age, race/ethnicity, calendar year, HIV transmission category, and HIV diagnosis year. We compared the M:F IRRs among PWH (M:F IRRPWH) to M:F IRRs in the general population (M:F IRRGP) with a chi-square test. RESULTS: PWH contributed 3,956,838 person-years of follow-up (53.6% among males, 46.4% among females). The M:F IRRPWH was significantly attenuated compared to the M:F IRRGP for 9 cancer sites: tongue (M:F IRRPWH 1.39 vs. M:F IRRGP 2.94; P<0.0001), oropharynx (1.80 vs 4.74; P<0.0001), esophagus (1.36 vs 3.43; P<0.0001), colon (0.90 vs 1.19; P=0.0002), liver (2.20 vs 4.22; P < 0.0001), larynx (1.50 vs 4.32; P<0.0001), lung (0.92 vs 1.39; P < 0.0001), bladder (1.21 vs 3.02; P<0.0001), and diffuse large B-cell lymphoma (1.35 vs 1.65; P<0.0001). Hodgkin lymphoma was the only site where the M:F IRRPWH was significantly larger than the M:F IRRGP (1.96 vs 1.45; P=0.0001). CONCLUSIONS: Although the incidence of most cancers remained higher among male than female PWH, the sex difference was attenuated among PWH for 9 cancers, suggesting that important immune differences between males and females in the general population contribute to differences in cancer incidence.
Rogers JR, Ward ZJ, Stratton KL
… +13 more, Leisenring WM, Taylor CS, Armstrong GT, Chow EJ, Feraco AM, Howell RM, Hudson MM, McMahon M, Morton LM, Oeffinger KC, Smith SA, Diller L, Yeh JM
J Natl Cancer Inst
· 2026 Jun · PMID 42286308
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BACKGROUND: Long-term survivors of pediatric Hodgkin lymphoma are at risk of late treatment-related mortality, cancer, and heart disease. While modified treatments have reduced radiation exposure, long-term risks in late...BACKGROUND: Long-term survivors of pediatric Hodgkin lymphoma are at risk of late treatment-related mortality, cancer, and heart disease. While modified treatments have reduced radiation exposure, long-term risks in late adulthood are unknown. METHODS: Using a simulation model based on data from the Childhood Cancer Survivor Study and national databases, we projected overall survival and cumulative incidence of breast cancer and heart failure for 5-year survivors treated with extended-field RT, chest RT ≥ 35 Gy, chest RT < 35 Gy, or chemotherapy only. Estimates were compared with general population individuals who faced only age-related risks. We report the mean and 95% uncertainty intervals (UIs) among 1000 iterations. RESULTS: At age 65, projected overall survival ranged from 24.7% (95% UI, 17.7 to 32.5) after extended-field RT to 71.8% (44.9 to 81.8) after chemotherapy only, compared with 86.4% (83.8 to 88.8) in the general population. Cumulative breast cancer incidence among female survivors was 61.1% for extended-field RT, 59.7% for chest RT ≥ 35 Gy, 49.8% for chest RT < 35 Gy, and 17.9% for chemotherapy only, respectively, versus 6.1% in the general population. Heart failure risks among all survivors were 34.8%, 33.4%, 28.4%, and 16.0, respectively, versus 4.3%. Across all subgroups, breast cancer and heart failure were projected to occur 16.1-31.7 and 21.0-25.9 years earlier, respectively, relative to general population risks at age 65. CONCLUSIONS: Although historical reductions in RT dose and field have substantially improved long-term survival, survivors treated with lower-dose or chemotherapy alone remain at markedly elevated risk for early-onset breast cancer and heart failure.
Westerveld ASR, van der Pal HJH, Wilbers J
… +17 more, de Vries ACH, Louwerens M, Koopman MMW, Kok JL, Van den Heuvel-Eibrink MM, van der Heiden-van der Loo M, Bresters D, van Noesel MM, Hoving EW, Loeffen JLC, van Santen HM, van Leeuwen FE, Visser O, Janssens GO, Ronckers CM, Kremer LCM, Teepen JC
J Natl Cancer Inst
· 2026 Jun · PMID 42286208
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BACKGROUND: The growing population of childhood cancer survivors faces an elevated risk of developing subsequent malignant neoplasms (SMNs). Over the past decades, childhood cancer treatments have evolved. Although reduc...BACKGROUND: The growing population of childhood cancer survivors faces an elevated risk of developing subsequent malignant neoplasms (SMNs). Over the past decades, childhood cancer treatments have evolved. Although reductions in radiation dose have been shown to lower SMN risk, the impact of changes in chemotherapy remains unclear. We evaluated whether treatment changes have affected SMN risk over time and examined treatment-related risk factors. METHODS: We included 10,612 five-year survivors from the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER cohort (1963 to 2014). Multivariable Cox proportional hazard regression was used to estimate SMN risks, and to evaluate effects of treatment changes over time. RESULTS: After a median follow-up of 20.4 years, 493 survivors developed an SMN. Overall, the risk for SMN declined over period of diagnosis (p-trend 0.04). The decline in SMN risk was primarily associated with a decreased use of radiotherapy (p-trend after radiotherapy adjustment : 0.51). Chemotherapy seemed to have the opposite effect, mainly due to the use of anthracyclines and/or epipodophyllotoxins (p-trend after chemotherapy adjustment:<0.001). Survivors treated with anthracyclines (HR : 1.3, 95%CI : 1.0 to 1.6), epipodophyllotoxins (HR : 1.3,95%CI : 1.0 to 1.7) or radiotherapy (HR : 2.3, 95%CI : 1.9-2.8) had significantly increased risks of SMN. CONCLUSIONS: While reductions in radiotherapy have lowered SMN risk throughout periods of diagnosis, the increased use of chemotherapy, especially anthracyclines and epipodophyllotoxins, increased SMN risk. Furthermore, survivors treated with radiotherapy, anthracyclines, or epipodophyllotoxins have an elevated risk of any SMN. This highlights the importance of continued optimization of treatment protocols, eg through chemotherapy dose reduction, to balance treatment efficacy with long-term health risks and to better identify survivors at risk.
Xiao Q, Xiang H, Liu Y
… +6 more, Tong J, Tang Q, Li K, Li Y, Zhu R, Xu Y
J Natl Cancer Inst
· 2026 Jun · PMID 42262912
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BACKGROUND: The global burden of cutaneous melanoma (CM) remains substantial, yet its temporal trends and relationships with ultraviolet radiation (UVR) and socioeconomic context remain incompletely understood. METHODS:...BACKGROUND: The global burden of cutaneous melanoma (CM) remains substantial, yet its temporal trends and relationships with ultraviolet radiation (UVR) and socioeconomic context remain incompletely understood. METHODS: Global Burden of Disease Study data from 1990 to 2021 were analyzed using Joinpoint regression, mixed-effects models, and time-lagged random forest models to assess CM burden and its associations with MODIS-derived UVR and gross domestic product (GDP). A UVR-enhanced ARIMA-X model projected burden to 2032. RESULTS: CM burden showed marked spatiotemporal heterogeneity. Age-standardized incidence was highest in Australasia (47.71 per 100,000) and lowest in Sub-Saharan Africa. Male mortality exceeded female mortality by 26%, with the largest increases among adults aged ≥70 years. UVR was positively associated with CM incidence (β = 0.001, P = 0.038). Time-lagged analysis showed a biphasic UVR pattern, with predictive contribution peaking at 18.2% at an 11-year lag. GDP per capita showed an inverse association with CM incidence (β = -0.200, P = 0.040), but this finding should be interpreted as a contextual population-level association. By 2032, mortality and incidence are projected to decline by 1.2% and 1.6%, respectively, whereas prevalence and DALYs are projected to rise. CONCLUSIONS: Global CM burden remains heterogeneous and is positively associated with ambient UVR, with the strongest predictive contribution at an 11-year lag. Socioeconomic associations should be interpreted cautiously. UVR-oriented prevention, early detection, and context-specific strategies remain essential.