{"title":"Lung cancer screening: are race- and risk-aware criteria needed?","authors":"Jonathan M Samet,Jamie L Studts","doi":"10.1093/jnci/djaf328","DOIUrl":"https://doi.org/10.1093/jnci/djaf328","url":null,"abstract":"","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Barbara Melosky,Rosalyn A Juergens,Quincy S C Chu,Parneet Cheema,Stephanie Snow,Natasha B Leighl,Normand Blais,Diana N Ionescu,Deanna McLeod,Ming-Sound Tsao,Adrian Sacher,Paul Wheatley-Price,Geoffrey Liu
Mutations of the epidermal growth factor receptor (EGFR) are frequent oncogenic drivers in non-small cell lung cancer (NSCLC). Third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs), which target common EGFR mutations and the acquired T790M resistance mutation, offer improved inhibitory potency and selectivity. Our review critically assesses the evolving role of these agents for management of NSCLC harboring common EGFR mutations. Multiple global phase III trials have recently evaluated third-generation EGFR-TKIs in NSCLC patients with common EGFR mutations. The addition of osimertinib to curative-intent strategies have demonstrated improvements in disease-free survival and overall survival (OS) as adjuvant therapy in resected stage IB-IIIa patients, major pathological responses compared to chemotherapy when used as neoadjuvant therapy, and progression-free survival (PFS) compared to placebo when used as consolidation therapy in unresectable stage III patients. Furthermore, third-generation EGFR-TKI monotherapy improved PFS compared to first-generation EGFR-TKIs in the first-line treatment of advanced disease. Intensification strategies, such as the addition of chemotherapy or a bi-specific antibody have further enhanced both PFS and OS outcomes. Several new therapeutic options are emerging for patients previously treated with third-generation EGFR-TKIs. Currently, subsequent treatment recommendations include chemotherapy or datopotamab deruxtecan following progression on a third-generation EGFR-TKI combination and amivantamab plus platinum-based chemotherapy following progression on monotherapy. The treatment landscape for NSCLC with common EGFR mutations is rapidly evolving and third-generation EGFR-TKIs play an integral role in both the curative-intent and palliative settings.
{"title":"Targeting common EGFR mutations in NSCLC-review of global phase III trials of third-generation inhibitors.","authors":"Barbara Melosky,Rosalyn A Juergens,Quincy S C Chu,Parneet Cheema,Stephanie Snow,Natasha B Leighl,Normand Blais,Diana N Ionescu,Deanna McLeod,Ming-Sound Tsao,Adrian Sacher,Paul Wheatley-Price,Geoffrey Liu","doi":"10.1093/jnci/djag008","DOIUrl":"https://doi.org/10.1093/jnci/djag008","url":null,"abstract":"Mutations of the epidermal growth factor receptor (EGFR) are frequent oncogenic drivers in non-small cell lung cancer (NSCLC). Third-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs), which target common EGFR mutations and the acquired T790M resistance mutation, offer improved inhibitory potency and selectivity. Our review critically assesses the evolving role of these agents for management of NSCLC harboring common EGFR mutations. Multiple global phase III trials have recently evaluated third-generation EGFR-TKIs in NSCLC patients with common EGFR mutations. The addition of osimertinib to curative-intent strategies have demonstrated improvements in disease-free survival and overall survival (OS) as adjuvant therapy in resected stage IB-IIIa patients, major pathological responses compared to chemotherapy when used as neoadjuvant therapy, and progression-free survival (PFS) compared to placebo when used as consolidation therapy in unresectable stage III patients. Furthermore, third-generation EGFR-TKI monotherapy improved PFS compared to first-generation EGFR-TKIs in the first-line treatment of advanced disease. Intensification strategies, such as the addition of chemotherapy or a bi-specific antibody have further enhanced both PFS and OS outcomes. Several new therapeutic options are emerging for patients previously treated with third-generation EGFR-TKIs. Currently, subsequent treatment recommendations include chemotherapy or datopotamab deruxtecan following progression on a third-generation EGFR-TKI combination and amivantamab plus platinum-based chemotherapy following progression on monotherapy. The treatment landscape for NSCLC with common EGFR mutations is rapidly evolving and third-generation EGFR-TKIs play an integral role in both the curative-intent and palliative settings.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Changchuan Jiang,Lesi He,Chuan Angel Lu,Ryan D Nipp,K Robin Yabroff,Xuesong Han,Xin Hu,Joshua M Liao
BACKGROUNDZero-premium Medicare Advantage (MA) plans have rapidly become the most popular MA plan type in the US, despite potentially restrictive benefit design. It remains unclear whether the growth of these plans aligns with the county-level cancer mortality.METHODSWe conducted a two-part, county-level ecological study. First, using CMS enrollment data (2019-2024) and NCHS mortality data (2018-2022), we examined longitudinal trends in the market share of zero-premium MA plans overall and across counties by their cancer-mortality rate quartiles. Second, we performed a cross-sectional, mixed-effects logistic regression analysis of 2019-2024 plan-level data to evaluate the association between zero-premium MA and low plan quality (<4 stars) and whether this relationship varied by county cancer-mortality rate quartile.RESULTSThe market share of zero-premium MA plans increased from 60.2% to 75.9% of the MA market between 2019 and 2024, with disproportionately greater growth in counties with higher cancer mortality rates (Q4: +28.7 percentage points[pp] vs Q1: +23.8pp; p-interaction < 0.001). In adjusted analyses, zero-premium plans also had significantly higher odds of having <4 star ratings compared with premium-charging plans (aOR 1.68; 95% CI, 1.64-1.72), particularly in counties with highest cancer mortality rates (aOR 1.83; 95% CI, 1.69-1.98, p-interaction < 0.01).CONCLUSIONSThe rapid expansion of zero-premium MA plans has been disproportionately concentrated in communities with highest cancer mortality rates. These plans are more likely to have lower CMS star ratings than premium-charging MA plans. Rapid zero-premium MA plan adoption raises concerns about equitable access to high-quality care for patients with cancer.
{"title":"Growth of zero-premium Medicare Advantage plans in counties with high cancer mortality.","authors":"Changchuan Jiang,Lesi He,Chuan Angel Lu,Ryan D Nipp,K Robin Yabroff,Xuesong Han,Xin Hu,Joshua M Liao","doi":"10.1093/jnci/djag006","DOIUrl":"https://doi.org/10.1093/jnci/djag006","url":null,"abstract":"BACKGROUNDZero-premium Medicare Advantage (MA) plans have rapidly become the most popular MA plan type in the US, despite potentially restrictive benefit design. It remains unclear whether the growth of these plans aligns with the county-level cancer mortality.METHODSWe conducted a two-part, county-level ecological study. First, using CMS enrollment data (2019-2024) and NCHS mortality data (2018-2022), we examined longitudinal trends in the market share of zero-premium MA plans overall and across counties by their cancer-mortality rate quartiles. Second, we performed a cross-sectional, mixed-effects logistic regression analysis of 2019-2024 plan-level data to evaluate the association between zero-premium MA and low plan quality (<4 stars) and whether this relationship varied by county cancer-mortality rate quartile.RESULTSThe market share of zero-premium MA plans increased from 60.2% to 75.9% of the MA market between 2019 and 2024, with disproportionately greater growth in counties with higher cancer mortality rates (Q4: +28.7 percentage points[pp] vs Q1: +23.8pp; p-interaction < 0.001). In adjusted analyses, zero-premium plans also had significantly higher odds of having <4 star ratings compared with premium-charging plans (aOR 1.68; 95% CI, 1.64-1.72), particularly in counties with highest cancer mortality rates (aOR 1.83; 95% CI, 1.69-1.98, p-interaction < 0.01).CONCLUSIONSThe rapid expansion of zero-premium MA plans has been disproportionately concentrated in communities with highest cancer mortality rates. These plans are more likely to have lower CMS star ratings than premium-charging MA plans. Rapid zero-premium MA plan adoption raises concerns about equitable access to high-quality care for patients with cancer.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"84 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aasma Shaukat,Zhen Meng,Karolina Kutnik,Chung-Kai Sun,David K Edwards V,Andy Piscitello,Cosmin Deciu,Lilian C Lee,Theodore R Levin
The performance of a CRC screening blood test was validated in a prospective, multicenter, observational study (PREEMPT CRC). The composition of the clinical study population can impact performance measures, potentially affecting the generalizability of the observed outcomes. We conducted a prespecified post-stratification adjustment analysis in which PREEMPT CRC performance values were adjusted to US Census age and sex distribution. The PREEMPT CRC evaluable cohort had a higher proportion of younger individuals and females than the census population. Compared to observed values, census adjustment demonstrated nominally higher CRC sensitivity (81.1% [95% confidence interval or CI, 71.3-88.1%] vs 79.2% [95% CI, 68.4-86.9%]) and advanced precancerous lesion sensitivity (13.7% [95% CI, 12.4-15.0%] vs 12.5% [95% CI, 11.3-13.8%]), with lower advanced colorectal neoplasia specificity (90.4% [95% CI, 90.0-90.7%) vs 91.5% [95% CI, 91.2-91.9%]). Negative and positive predictive values were consistent across age groups, highlighting consistent clinical interpretability of test results regardless of patient age.
一项前瞻性、多中心、观察性研究（PREEMPT CRC）证实了CRC筛查血液检查的效果。临床研究人群的组成可能会影响绩效指标，潜在地影响观察结果的普遍性。我们进行了预先指定的分层后调整分析，其中PREEMPT CRC表现值调整为美国人口普查年龄和性别分布。PREEMPT CRC可评估队列中年轻个体和女性的比例高于普查人口。与观察值相比，普查调整显示名义上更高的结直肠癌敏感性（81.1%[95%置信区间或CI， 71.3-88.1%] vs 79.2% [95% CI, 68.4-86.9%]）和晚期癌前病变敏感性（13.7% [95% CI, 12.4-15.0%] vs 12.5% [95% CI, 11.3-13.8%]），晚期结直肠癌特异性较低（90.4% [95% CI, 90.0-90.7%） vs 91.5% [95% CI, 91.2-91.9%])。阴性和阳性预测值在各个年龄组中是一致的，强调了无论患者年龄如何，检测结果的临床可解释性是一致的。
{"title":"Age- and sex-adjusted performance of a colorectal cancer screening test using US census distribution.","authors":"Aasma Shaukat,Zhen Meng,Karolina Kutnik,Chung-Kai Sun,David K Edwards V,Andy Piscitello,Cosmin Deciu,Lilian C Lee,Theodore R Levin","doi":"10.1093/jnci/djag007","DOIUrl":"https://doi.org/10.1093/jnci/djag007","url":null,"abstract":"The performance of a CRC screening blood test was validated in a prospective, multicenter, observational study (PREEMPT CRC). The composition of the clinical study population can impact performance measures, potentially affecting the generalizability of the observed outcomes. We conducted a prespecified post-stratification adjustment analysis in which PREEMPT CRC performance values were adjusted to US Census age and sex distribution. The PREEMPT CRC evaluable cohort had a higher proportion of younger individuals and females than the census population. Compared to observed values, census adjustment demonstrated nominally higher CRC sensitivity (81.1% [95% confidence interval or CI, 71.3-88.1%] vs 79.2% [95% CI, 68.4-86.9%]) and advanced precancerous lesion sensitivity (13.7% [95% CI, 12.4-15.0%] vs 12.5% [95% CI, 11.3-13.8%]), with lower advanced colorectal neoplasia specificity (90.4% [95% CI, 90.0-90.7%) vs 91.5% [95% CI, 91.2-91.9%]). Negative and positive predictive values were consistent across age groups, highlighting consistent clinical interpretability of test results regardless of patient age.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"244 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mark E Sherman,Lola Etievant,Robert A Vierkant,Stacey J Winham,Kathryn J Ruddy,Laura Pacheco-Spann,Daniel P Wickland,Nicole Cruz-Reyes,Melody Stallings-Mann,Derek Radisky,E Aubrey Thompson,Jennifer M Kachergus,Ji Shi,Shoshana M Rosenberg,Craig Snow,Gregory J Kirkner,Lidia Schapira,Jeffrey M Peppercorn,Steven Come,Virginia F Borges,Ellen Warner,Laura C Collins,Ann H Partridge,Ruth M Pfeiffer
The incidence of early onset breast cancers (BCs) has increased, paralleling rising trends in delayed childbearing. We hypothesize that a distinct postpartum BC subtype (PPBC), identifiable by time since last birth (TSLB) and biomarker expression, contributes to this trend. We applied GeoMx Digital Spatial Profiling (DSP) to measure associations between TSLB and 71 proteins in 640 BCs from women ages ≤40 years included in the Young Women's BC Study. We analyzed data using univariable linear regression and multivariable Sliced Inverse Regression to account for higher order interactions among biomarkers. In keratin-rich segments, PR (p = 1.00x10-4) and PTEN (p = 1.00x10-3) were associated with longer TSLB; multivariable analyses revealed positive associations for GZMB (p = 4.00X10-4), SMA (1.00X10-4) and NF-1 (p = 1.00X10-3). In keratin-poor segments, univariable significant positive associations were found for PR (p = 2.00x10-4) and PTEN (p = 1.00x10-3), whereas CD20 (p = 3.00x10-4) and CTLA4 (p = 4.00x10-5) were negatively associated; multivariable significant associations were found for fibronectin (p = 3.00x10-5) and pan-Akt (p = 1.00x10-3). Associations persisted after adjustment for multiple comparisons and BC molecular subtypes. Associations including for PR, PTEN and CD20 were strongest among women with shortest TSLB. OPAL multiplex immunofluorescence assays for PR, PTEN, CD20, SMA and CTLA4, replicated several DSP findings, particularly when stratified by subtype and with compartment matching. In TCGA, RNA species linked to proteins associated with TSLB correlated strongly with a T cell exhaustion signature previously linked to poor prognosis among premenopausal women. These data support PPBC as a biologically coherent phenotype defined by TSLB and biomarker profile, with potential implications for prevention and therapy.
{"title":"Postpartum breast cancer: evidence for a distinct phenotype.","authors":"Mark E Sherman,Lola Etievant,Robert A Vierkant,Stacey J Winham,Kathryn J Ruddy,Laura Pacheco-Spann,Daniel P Wickland,Nicole Cruz-Reyes,Melody Stallings-Mann,Derek Radisky,E Aubrey Thompson,Jennifer M Kachergus,Ji Shi,Shoshana M Rosenberg,Craig Snow,Gregory J Kirkner,Lidia Schapira,Jeffrey M Peppercorn,Steven Come,Virginia F Borges,Ellen Warner,Laura C Collins,Ann H Partridge,Ruth M Pfeiffer","doi":"10.1093/jnci/djag003","DOIUrl":"https://doi.org/10.1093/jnci/djag003","url":null,"abstract":"The incidence of early onset breast cancers (BCs) has increased, paralleling rising trends in delayed childbearing. We hypothesize that a distinct postpartum BC subtype (PPBC), identifiable by time since last birth (TSLB) and biomarker expression, contributes to this trend. We applied GeoMx Digital Spatial Profiling (DSP) to measure associations between TSLB and 71 proteins in 640 BCs from women ages ≤40 years included in the Young Women's BC Study. We analyzed data using univariable linear regression and multivariable Sliced Inverse Regression to account for higher order interactions among biomarkers. In keratin-rich segments, PR (p = 1.00x10-4) and PTEN (p = 1.00x10-3) were associated with longer TSLB; multivariable analyses revealed positive associations for GZMB (p = 4.00X10-4), SMA (1.00X10-4) and NF-1 (p = 1.00X10-3). In keratin-poor segments, univariable significant positive associations were found for PR (p = 2.00x10-4) and PTEN (p = 1.00x10-3), whereas CD20 (p = 3.00x10-4) and CTLA4 (p = 4.00x10-5) were negatively associated; multivariable significant associations were found for fibronectin (p = 3.00x10-5) and pan-Akt (p = 1.00x10-3). Associations persisted after adjustment for multiple comparisons and BC molecular subtypes. Associations including for PR, PTEN and CD20 were strongest among women with shortest TSLB. OPAL multiplex immunofluorescence assays for PR, PTEN, CD20, SMA and CTLA4, replicated several DSP findings, particularly when stratified by subtype and with compartment matching. In TCGA, RNA species linked to proteins associated with TSLB correlated strongly with a T cell exhaustion signature previously linked to poor prognosis among premenopausal women. These data support PPBC as a biologically coherent phenotype defined by TSLB and biomarker profile, with potential implications for prevention and therapy.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"49 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zeni Wu, Aika Wojt, Britton Trabert, Andrea A Almeida, Nader Rifai, Frank Z Stanczyk, Barry I Graubard, Katherine A Mcglynn
Background Testicular germ cell tumors (TGCT) are thought to be endocrine-related. The hypothesis, however, has not been thoroughly investigated. As a result, pre-diagnostic serum samples from the U.S. Servicemen’s Testicular Tumor Environmental and Endocrine Determinants (STEED) were analyzed to assess the relationship of hormones and gonadotropins to TGCT risk. Methods The study included 517 men who subsequently developed TGCT and 790 comparison men. The hormones/gonadotropins examined included testosterone, estradiol, sex-hormone binding globulin (SHBG), 5α-androstane-3α,17β-diol glucuronide (3α-diol G), follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression. Analyses stratified by histology (seminoma, nonseminoma) were also conducted. Results Compared to men in the middle quintile of LH concentrations, men with the lowest concentrations had an increased risk of TGCT (OR 1.88, 95% CI 1.31-2.70), as did men with FSH concentrations in the lowest (OR 1.77, 95% CI 1.21-2.60) and highest quintiles (OR 2.20, 95% CI 1.53-3.17). An increased risk of seminoma was found with both low and high LH, and high FSH, while an increased risk of nonseminoma was found with low LH, and both low and high FSH. Decreased levels of 3α-diol G were associated with increased risk of seminoma (OR 1.65, 95%CI 1.02-2.67). Conclusion These results suggest that gonadotropin disruption may be a critical event in the development of TGCT. Further examination of upstream and downstream metabolites in the hormone pathways may help elucidate the underlying mechanism that distinguishes men who develop TGCT from men who do not.
背景睾丸生殖细胞肿瘤（TGCT）被认为与内分泌有关。然而，这一假设尚未得到彻底的调查。因此，分析了美国军人睾丸肿瘤环境和内分泌决定因素（STEED）的诊断前血清样本，以评估激素和促性腺激素与TGCT风险的关系。方法纳入517例TGCT患者和790例对照患者。检测的激素/促性腺激素包括睾酮、雌二醇、性激素结合球蛋白（SHBG）、5α-雄烷-3α、17β-二醇葡萄糖醛酸（3α-二醇G）、促卵泡激素（FSH）和黄体生成素（LH）。校正优势比（OR）和95%置信区间（CI）使用逻辑回归估计。按组织学（精原细胞瘤和非精原细胞瘤）分层进行分析。结果：与处于LH浓度中间五分位数的男性相比，最低浓度的男性TGCT风险增加（OR 1.88, 95% CI 1.31-2.70）， FSH浓度最低（OR 1.77, 95% CI 1.21-2.60）和最高五分位数（OR 2.20, 95% CI 1.53-3.17）的男性TGCT风险增加。低LH和高LH以及高FSH的患者发生精原细胞瘤的风险增加，而低LH和低FSH和高FSH的患者发生非精原细胞瘤的风险增加。3α-二醇G水平降低与精原细胞瘤风险增加相关（OR 1.65, 95%CI 1.02-2.67）。结论促性腺激素紊乱可能是TGCT发生的关键因素。进一步检查激素通路中的上游和下游代谢物可能有助于阐明区分TGCT男性与非TGCT男性的潜在机制。
{"title":"Sex steroid hormones, gonadotropins and risk of testicular germ cell tumors: results from the STEED study","authors":"Zeni Wu, Aika Wojt, Britton Trabert, Andrea A Almeida, Nader Rifai, Frank Z Stanczyk, Barry I Graubard, Katherine A Mcglynn","doi":"10.1093/jnci/djaf376","DOIUrl":"https://doi.org/10.1093/jnci/djaf376","url":null,"abstract":"Background Testicular germ cell tumors (TGCT) are thought to be endocrine-related. The hypothesis, however, has not been thoroughly investigated. As a result, pre-diagnostic serum samples from the U.S. Servicemen’s Testicular Tumor Environmental and Endocrine Determinants (STEED) were analyzed to assess the relationship of hormones and gonadotropins to TGCT risk. Methods The study included 517 men who subsequently developed TGCT and 790 comparison men. The hormones/gonadotropins examined included testosterone, estradiol, sex-hormone binding globulin (SHBG), 5α-androstane-3α,17β-diol glucuronide (3α-diol G), follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression. Analyses stratified by histology (seminoma, nonseminoma) were also conducted. Results Compared to men in the middle quintile of LH concentrations, men with the lowest concentrations had an increased risk of TGCT (OR 1.88, 95% CI 1.31-2.70), as did men with FSH concentrations in the lowest (OR 1.77, 95% CI 1.21-2.60) and highest quintiles (OR 2.20, 95% CI 1.53-3.17). An increased risk of seminoma was found with both low and high LH, and high FSH, while an increased risk of nonseminoma was found with low LH, and both low and high FSH. Decreased levels of 3α-diol G were associated with increased risk of seminoma (OR 1.65, 95%CI 1.02-2.67). Conclusion These results suggest that gonadotropin disruption may be a critical event in the development of TGCT. Further examination of upstream and downstream metabolites in the hormone pathways may help elucidate the underlying mechanism that distinguishes men who develop TGCT from men who do not.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eric J Hsu,Alexander D Sherry,Timothy A Lin,Joseph Abi Jaoude,Ramez Kouzy,Zachary Mccaw,Tomer Meirson,Pavlos Msaouel,Ethan B Ludmir
In phase 3 oncology clinical trials, identifying and understanding potential sources of differential censoring (DC), which describes censoring imbalance between treatment arms, in overall survival (OS) endpoints is vital to reduce bias and misinterpretation of OS benefit. Among 322 trials, 34 (11%) trials exhibited DC overrepresented in the control arm (DCC). Compared to trials without DC or those with DC overrepresented in the experimental arm (DCE), trials with DCC showed higher rates of OS benefit (56% vs 32%; odds ratio [OR] 2.26, 95% CI 1.04-4.90; P=.04) and were associated with patient withdrawal (median 8.0% vs 3.8%; P=.0002), lack of double blinding (15% vs 48%, OR 0.19, 95% CI 0.06-0.56; P=.003), and better global quality of life in the experimental arm (32% vs 13%, OR 3.01, 95% CI 1.26-7.19; P=.01). OS DCC is a prominent challenge that requires rigorous trial design and comprehensive patient and mortality follow-up to reduce bias in interpreting OS benefit.
在3期肿瘤学临床试验中，识别和理解总生存期（OS）终点差异审查（DC）的潜在来源（DC描述了治疗组之间的审查不平衡）对于减少对OS益处的偏见和误解至关重要。在322项试验中，34项（11%）试验显示DC在对照组（DCC）中过度代表。与没有DC的试验或实验组中DC过度代表的试验（DCE）相比，DCC的试验显示出更高的OS获益率（56% vs 32%；比值比[or] 2.26, 95% CI 1.04-4.90； P= 0.04），并且与患者戒断（中位数8.0% vs 3.8%； P= 0.0002）、缺乏双盲（15% vs 48%, or 0.19, 95% CI 0.06-0.56； P= 0.003）以及实验组中更好的总体生活质量（32% vs 13%, or 3.01, 95% CI 1.26-7.19； P= 0.01）相关。OS DCC是一个突出的挑战，需要严格的试验设计和全面的患者和死亡率随访，以减少解释OS获益的偏倚。
{"title":"Differential censoring in overall survival in phase 3 oncology clinical trials.","authors":"Eric J Hsu,Alexander D Sherry,Timothy A Lin,Joseph Abi Jaoude,Ramez Kouzy,Zachary Mccaw,Tomer Meirson,Pavlos Msaouel,Ethan B Ludmir","doi":"10.1093/jnci/djaf378","DOIUrl":"https://doi.org/10.1093/jnci/djaf378","url":null,"abstract":"In phase 3 oncology clinical trials, identifying and understanding potential sources of differential censoring (DC), which describes censoring imbalance between treatment arms, in overall survival (OS) endpoints is vital to reduce bias and misinterpretation of OS benefit. Among 322 trials, 34 (11%) trials exhibited DC overrepresented in the control arm (DCC). Compared to trials without DC or those with DC overrepresented in the experimental arm (DCE), trials with DCC showed higher rates of OS benefit (56% vs 32%; odds ratio [OR] 2.26, 95% CI 1.04-4.90; P=.04) and were associated with patient withdrawal (median 8.0% vs 3.8%; P=.0002), lack of double blinding (15% vs 48%, OR 0.19, 95% CI 0.06-0.56; P=.003), and better global quality of life in the experimental arm (32% vs 13%, OR 3.01, 95% CI 1.26-7.19; P=.01). OS DCC is a prominent challenge that requires rigorous trial design and comprehensive patient and mortality follow-up to reduce bias in interpreting OS benefit.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145845030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Adoma Manful, Sarah Mercaldo, Jeffrey D Blume, Melinda C Aldrich
Background The United States Preventive Services Task Force (USPSTF) lung cancer screening eligibility guidelines and proposed risk models have been developed using data predominantly from White populations. Studies show that these eligibility strategies perform inconsistently across racially diverse populations, suggesting evidence of algorithmic bias. We assessed several lung cancer screening eligibility strategies and explored how algorithmic bias can be resolved to improve equity in eligibility. Methods Using the Southern Community Cohort Study, a large US study of predominantly Black/African American (AA) individuals, we evaluated the performance of eight existing lung cancer screening eligibility strategies (USPSTF 2021, American Cancer Society 2023 recommendations, USPSTFSmokeDuration, PLCOm2012, PLCOm2012NoRace, PLCOm2012Update, LCRAT, and LCDRAT) and two new race-aware strategies proposed by our team (USPSTFRaceSpecific and PLCOm2012RaceSpecific). Results Among 52,667 adults (65% Black/AA, 31% White, 4% Multiracial/Other) with a smoking history, 1,689 developed lung cancer over 15 years. Almost all screening strategies identified fewer Black/AA participants who developed lung cancer as eligible for screening versus their White counterparts (SensitivityBlack/AA 0.46-0.73 vs SensitivityWhite: 0.72-0.80). Racial eligibility disparities were not resolved by removing race, removing the ‘years since quit’ criterion, or using uniform risk-thresholds. Replacing pack-years with smoke duration improved equity but overinflated the false positive rate (FPRBlack/AA: 0.71; FPRWhite: 0.61). Instead, race-aware approaches that tailored eligibility thresholds by race yielded the best sensitivity-specificity trade-off and minimized inequities (SensitivityBlack/AA: 0.71-0.73 vs SensitivityWhite: 0.72-0.74; FPRBlack/AA: 0.49-0.50; FPRWhite: 0.50-0.53). Conclusion Our findings suggest that race-aware approaches are necessary to address algorithmic bias and ensure equitable opportunities for lung cancer screening.
{"title":"Addressing algorithmic bias in lung cancer screening eligibility","authors":"Adoma Manful, Sarah Mercaldo, Jeffrey D Blume, Melinda C Aldrich","doi":"10.1093/jnci/djaf298","DOIUrl":"https://doi.org/10.1093/jnci/djaf298","url":null,"abstract":"Background The United States Preventive Services Task Force (USPSTF) lung cancer screening eligibility guidelines and proposed risk models have been developed using data predominantly from White populations. Studies show that these eligibility strategies perform inconsistently across racially diverse populations, suggesting evidence of algorithmic bias. We assessed several lung cancer screening eligibility strategies and explored how algorithmic bias can be resolved to improve equity in eligibility. Methods Using the Southern Community Cohort Study, a large US study of predominantly Black/African American (AA) individuals, we evaluated the performance of eight existing lung cancer screening eligibility strategies (USPSTF 2021, American Cancer Society 2023 recommendations, USPSTFSmokeDuration, PLCOm2012, PLCOm2012NoRace, PLCOm2012Update, LCRAT, and LCDRAT) and two new race-aware strategies proposed by our team (USPSTFRaceSpecific and PLCOm2012RaceSpecific). Results Among 52,667 adults (65% Black/AA, 31% White, 4% Multiracial/Other) with a smoking history, 1,689 developed lung cancer over 15 years. Almost all screening strategies identified fewer Black/AA participants who developed lung cancer as eligible for screening versus their White counterparts (SensitivityBlack/AA 0.46-0.73 vs SensitivityWhite: 0.72-0.80). Racial eligibility disparities were not resolved by removing race, removing the ‘years since quit’ criterion, or using uniform risk-thresholds. Replacing pack-years with smoke duration improved equity but overinflated the false positive rate (FPRBlack/AA: 0.71; FPRWhite: 0.61). Instead, race-aware approaches that tailored eligibility thresholds by race yielded the best sensitivity-specificity trade-off and minimized inequities (SensitivityBlack/AA: 0.71-0.73 vs SensitivityWhite: 0.72-0.74; FPRBlack/AA: 0.49-0.50; FPRWhite: 0.50-0.53). Conclusion Our findings suggest that race-aware approaches are necessary to address algorithmic bias and ensure equitable opportunities for lung cancer screening.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145847230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Giulia Maddalena, Ymke van der Pol, Oscar E Villarreal, Oluwadara Coker, Hey Min Lee, Zach Rivers, Wendy Covert, Stacy Diao, Sara Lonardi, Jane E Rogers, Arvind Dasari, Justin Guinney, Scott Kopetz, Kanwal Raghav
Background Clinical benefit from later lines of therapy in metastatic colorectal cancer (mCRC) is limited. Patient selection for treatment is crucial for optimal risk-benefit evaluation. Codon-specific KRAS mutations have been implicated as predictive biomarkers for efficacy of trifluridine/tipiracil (TAS-102). However, their predictive impact for TAS-102 plus Bevacizumab (TAS-Bev), the new standard of care in mCRC, is unknown. Methods This large patient-based, real-world, retrospective cohort study of mCRC patients who received TAS-102 alone or in combination with bevacizumab between January 1, 2020 and March 1, 2023. A sensitivity analysis was performed in two independent cohorts from MD Anderson Cancer Center, Houston, TX and Tempus, AI, Inc., Chicago, IL, prior to polling the data together. Results A total of 946 mCRC patients were evaluated; KRAS was mutated in 57.8% cases, 39.4% involving G12 codon and 9.8% G13. We found no association of KRAS-G12 mutations with overall survival (HR = 1.1; 95%CI : 0.90–1.25; p = .441) on TAS-102 contradicting the reported predictive impact of these biomarkers. Moreover, we reported inferior OS for KRAS-G13 mutant patients (HR = 1.3; 95%CI : 1.02–1.69; p = .045). On TAS-Bev, no association was found between KRAS-G12 (HR = 0.8; 95%CI : 0.59-1.11; p = .188) or KRAS-G13 (HR = 1.66; 95%CI : 0.99–2.79, p = .072) mutations and overall survival. Conclusions In conclusion, no significant associations between KRAS-G12 and overall survival were found for TAS-102 or TAS-Bev. Further research is needed to assess the impact of these mutations on combined TAS-Bev therapy prior to any clinical application.
背景：转移性结直肠癌（mCRC）后期治疗的临床获益有限。患者选择治疗方案对于最佳风险-收益评估至关重要。密码子特异性KRAS突变已被认为是trifluridine/tipiracil疗效的预测性生物标志物（TAS-102）。然而，它们对TAS-102联合贝伐单抗（TAS-Bev） （mCRC的新护理标准）的预测影响尚不清楚。该研究是一项大型的、真实的、基于患者的回顾性队列研究，研究对象是在2020年1月1日至2023年3月1日期间接受TAS-102单独或联合贝伐单抗治疗的mCRC患者。在对数据进行民意调查之前，对来自德克萨斯州休斯顿的MD安德森癌症中心和伊利诺伊州芝加哥的Tempus， AI, Inc.的两个独立队列进行敏感性分析。结果共评估946例mCRC患者；KRAS突变占57.8%，其中G12密码子占39.4%，G13密码子占9.8%。我们发现KRAS-G12突变与TAS-102的总生存率（HR = 1.1; 95%CI: 0.90-1.25; p = .441）没有关联，这与报道的这些生物标志物的预测作用相矛盾。此外，我们报道KRAS-G13突变患者的OS较差（HR = 1.3; 95%CI: 1.02-1.69; p = 0.045）。在TAS-Bev上，没有发现KRAS-G12 （HR = 0.8; 95%CI: 0.59-1.11; p = 0.188）或KRAS-G13 （HR = 1.66; 95%CI: 0.99-2.79, p = 0.072）突变与总生存率之间的关联。综上所述，TAS-102或TAS-Bev的KRAS-G12与总生存期无显著相关性。在任何临床应用之前，需要进一步的研究来评估这些突变对TAS-Bev联合治疗的影响。
{"title":"Impact of KRAS codon-specific mutations on survival in metastatic CRC on trifluridine-tipiracil with/without bevacizumab","authors":"Giulia Maddalena, Ymke van der Pol, Oscar E Villarreal, Oluwadara Coker, Hey Min Lee, Zach Rivers, Wendy Covert, Stacy Diao, Sara Lonardi, Jane E Rogers, Arvind Dasari, Justin Guinney, Scott Kopetz, Kanwal Raghav","doi":"10.1093/jnci/djaf385","DOIUrl":"https://doi.org/10.1093/jnci/djaf385","url":null,"abstract":"Background Clinical benefit from later lines of therapy in metastatic colorectal cancer (mCRC) is limited. Patient selection for treatment is crucial for optimal risk-benefit evaluation. Codon-specific KRAS mutations have been implicated as predictive biomarkers for efficacy of trifluridine/tipiracil (TAS-102). However, their predictive impact for TAS-102 plus Bevacizumab (TAS-Bev), the new standard of care in mCRC, is unknown. Methods This large patient-based, real-world, retrospective cohort study of mCRC patients who received TAS-102 alone or in combination with bevacizumab between January 1, 2020 and March 1, 2023. A sensitivity analysis was performed in two independent cohorts from MD Anderson Cancer Center, Houston, TX and Tempus, AI, Inc., Chicago, IL, prior to polling the data together. Results A total of 946 mCRC patients were evaluated; KRAS was mutated in 57.8% cases, 39.4% involving G12 codon and 9.8% G13. We found no association of KRAS-G12 mutations with overall survival (HR = 1.1; 95%CI : 0.90–1.25; p = .441) on TAS-102 contradicting the reported predictive impact of these biomarkers. Moreover, we reported inferior OS for KRAS-G13 mutant patients (HR = 1.3; 95%CI : 1.02–1.69; p = .045). On TAS-Bev, no association was found between KRAS-G12 (HR = 0.8; 95%CI : 0.59-1.11; p = .188) or KRAS-G13 (HR = 1.66; 95%CI : 0.99–2.79, p = .072) mutations and overall survival. Conclusions In conclusion, no significant associations between KRAS-G12 and overall survival were found for TAS-102 or TAS-Bev. Further research is needed to assess the impact of these mutations on combined TAS-Bev therapy prior to any clinical application.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mousumi Ghosh, Ying Huang, Heather K Basehore, Nathaniel H Boyd, Joseph A Flores-Toro, Subhashini Jagu, Freddie Pruitt, Brandon J Wright, Jaime M Guidry Auvil, Emily S Boja
The US federal government is committed to maximizing its return on biomedical research investment. This tenet is exemplified by policies that promote broad, responsible sharing of research products generated with public funds, including the recent National Institutes of Health (NIH) Final Data Management and Sharing (DMS) Policy and the NIH Updated Public Access Policy. Scientific data management and sharing must occur in a FAIR (findable, accessible, interoperable and reusable) manner for it to be broadly usable and thereby most impactful [1,2]. The NCI Office of Data Sharing (ODS) conducted a series of workshops to identify clinical features and profiles derived from patients and study participants that inform these respective basic, translational, clinical, and populational science research analyses. The workshop outputs lay the groundwork for developing best practice recommendations on high-value, impactful clinical data features to collect and share with the wider research community. The workshop also highlighted additional data types and methodologies represented across the NCI-funded research portfolio that need structured outputs to be better defined to similarly allow broad sharing in a FAIR manner. In this article we summarize the workshop discussions on data use challenges, present potential solutions, and outline attendee consensus on the minimum patient-derived clinical information needed to complete a wide spectrum of cancer research. We further propose preliminary guidance for policymakers and researchers to implement regarding collection and management of human derived clinical data in consistent and impactful ways that can improve the sharing process and outcomes for data end users.
{"title":"Making human derived data FAIR: feedback from NCI office of data sharing workshop","authors":"Mousumi Ghosh, Ying Huang, Heather K Basehore, Nathaniel H Boyd, Joseph A Flores-Toro, Subhashini Jagu, Freddie Pruitt, Brandon J Wright, Jaime M Guidry Auvil, Emily S Boja","doi":"10.1093/jnci/djaf379","DOIUrl":"https://doi.org/10.1093/jnci/djaf379","url":null,"abstract":"The US federal government is committed to maximizing its return on biomedical research investment. This tenet is exemplified by policies that promote broad, responsible sharing of research products generated with public funds, including the recent National Institutes of Health (NIH) Final Data Management and Sharing (DMS) Policy and the NIH Updated Public Access Policy. Scientific data management and sharing must occur in a FAIR (findable, accessible, interoperable and reusable) manner for it to be broadly usable and thereby most impactful [1,2]. The NCI Office of Data Sharing (ODS) conducted a series of workshops to identify clinical features and profiles derived from patients and study participants that inform these respective basic, translational, clinical, and populational science research analyses. The workshop outputs lay the groundwork for developing best practice recommendations on high-value, impactful clinical data features to collect and share with the wider research community. The workshop also highlighted additional data types and methodologies represented across the NCI-funded research portfolio that need structured outputs to be better defined to similarly allow broad sharing in a FAIR manner. In this article we summarize the workshop discussions on data use challenges, present potential solutions, and outline attendee consensus on the minimum patient-derived clinical information needed to complete a wide spectrum of cancer research. We further propose preliminary guidance for policymakers and researchers to implement regarding collection and management of human derived clinical data in consistent and impactful ways that can improve the sharing process and outcomes for data end users.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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