{"title":"Zanzalintinib plus atezolizumab is first immunotherapy regimen to benefit patients with metastatic CRC.","authors":"Leah Lawrence","doi":"10.1002/cncr.70235","DOIUrl":"https://doi.org/10.1002/cncr.70235","url":null,"abstract":"","PeriodicalId":138,"journal":{"name":"Cancer","volume":"132 3","pages":"e70235"},"PeriodicalIF":5.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiefeng Luo, Zhengxiong Li, Jun Ge, Sizhen Cai, Xinyi Mo, Wensheng Liu, Chengxia Gui, Qiong Du, Jiyong Liu
Background: Nivolumab plus ipilimumab has shown survival benefits as first-line treatment for unresectable hepatocellular carcinoma (HCC) but their high cost raises concerns about value. This study assessed the cost-effectiveness of nivolumab plus ipilimumab compared with lenvatinib or sorafenib from a United States (US) health care payer perspective.
Methods: A partitioned survival model was developed using data from the CheckMate 9DW trial with a 10-year horizon. Costs and outcomes were discounted by 3% annually. Clinical inputs were derived from CheckMate 9DW trial, and cost inputs were obtained from public databases and published studies. Primary outcomes were quality-adjusted life years (QALYs), total costs, life years (LYs), and incremental cost-effectiveness ratios (ICERs). Sensitivity and scenario analyses were conducted to test uncertainties.
Results: Nivolumab plus ipilimumab produced an incremental gain of 0.66 QALYs at an additional cost of $132,652, yielding an ICER of $200,409/QALY, above US willingness-to-pay thresholds ($100,000/QALY and $150,000/QALY). Probabilistic sensitivity analysis indicated a low probability of cost-effectiveness at current prices (4.6%-20%). Scenario analyses showed that extending maintenance nivolumab dosing from every 4 weeks to every 8 weeks reduced the ICER to $82,202/QALY, making the regimen cost-effective. Moderate price reductions also substantially increased the likelihood of cost-effectiveness.
Conclusions: Nivolumab plus ipilimumab is unlikely to be cost-effective as first-line therapy for unresectable HCC from US health care payer perspective. However, extended dosing interval or price reductions may render the regimen economically viable, with important implications for clinical practice, payers, and policy.
{"title":"Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma: A cost-effectiveness analysis.","authors":"Jiefeng Luo, Zhengxiong Li, Jun Ge, Sizhen Cai, Xinyi Mo, Wensheng Liu, Chengxia Gui, Qiong Du, Jiyong Liu","doi":"10.1002/cncr.70259","DOIUrl":"10.1002/cncr.70259","url":null,"abstract":"<p><strong>Background: </strong>Nivolumab plus ipilimumab has shown survival benefits as first-line treatment for unresectable hepatocellular carcinoma (HCC) but their high cost raises concerns about value. This study assessed the cost-effectiveness of nivolumab plus ipilimumab compared with lenvatinib or sorafenib from a United States (US) health care payer perspective.</p><p><strong>Methods: </strong>A partitioned survival model was developed using data from the CheckMate 9DW trial with a 10-year horizon. Costs and outcomes were discounted by 3% annually. Clinical inputs were derived from CheckMate 9DW trial, and cost inputs were obtained from public databases and published studies. Primary outcomes were quality-adjusted life years (QALYs), total costs, life years (LYs), and incremental cost-effectiveness ratios (ICERs). Sensitivity and scenario analyses were conducted to test uncertainties.</p><p><strong>Results: </strong>Nivolumab plus ipilimumab produced an incremental gain of 0.66 QALYs at an additional cost of $132,652, yielding an ICER of $200,409/QALY, above US willingness-to-pay thresholds ($100,000/QALY and $150,000/QALY). Probabilistic sensitivity analysis indicated a low probability of cost-effectiveness at current prices (4.6%-20%). Scenario analyses showed that extending maintenance nivolumab dosing from every 4 weeks to every 8 weeks reduced the ICER to $82,202/QALY, making the regimen cost-effective. Moderate price reductions also substantially increased the likelihood of cost-effectiveness.</p><p><strong>Conclusions: </strong>Nivolumab plus ipilimumab is unlikely to be cost-effective as first-line therapy for unresectable HCC from US health care payer perspective. However, extended dosing interval or price reductions may render the regimen economically viable, with important implications for clinical practice, payers, and policy.</p>","PeriodicalId":138,"journal":{"name":"Cancer","volume":"132 3","pages":"e70259"},"PeriodicalIF":5.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12860969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146096698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Melanie Rodriguez, Qian Qin, Uttam K Tambar, James Brugarolas
Background: Clear cell renal cell carcinoma (ccRCC) is a common subtype of kidney cancer driven by the inactivation of the von Hippel-Lindau (VHL) gene, leading to the accumulation of hypoxia-inducible factor (HIF)-2α and tumorigenesis.
Methods: Targeting HIF-2α has emerged as a promising therapeutic strategy culminating in the development of a first-in-class inhibitor, belzutifan, invented by Peloton Therapeutics and marketed by Merck. This article presents the journey to belzutifan and subsequent developments.
Results: We discuss the structure-based design leading to the first-in-human drug, PT2385, as well as subsequent modifications to improve pharmacokinetic properties leading to PT2977/belzutifan. Detailed analyses are presented of key HIF-2α structural features, the mechanism of drug action, and how this family of drugs performed in preclinical models. Belzutifan's impact on patients with VHL syndrome, sporadic advanced ccRCC and pheochromocytoma/paraganglioma is discussed, three areas where belzutifan has obtained Food and Drug Administration approval. Drug combination strategies, mechanisms of resistance, and emerging strategies to overcome them, including siRNA-based therapeutics, are presented. Alternative HIF-2α inhibitors are examined, including NKT2152 and AB521.
Conclusions: By expanding upon the foundation established by belzutifan, the field is poised for further therapeutic advances.
{"title":"Targeting HIF-2α in renal cell carcinoma: Expanding upon belzutifan.","authors":"Melanie Rodriguez, Qian Qin, Uttam K Tambar, James Brugarolas","doi":"10.1002/cncr.70239","DOIUrl":"https://doi.org/10.1002/cncr.70239","url":null,"abstract":"<p><strong>Background: </strong>Clear cell renal cell carcinoma (ccRCC) is a common subtype of kidney cancer driven by the inactivation of the von Hippel-Lindau (VHL) gene, leading to the accumulation of hypoxia-inducible factor (HIF)-2α and tumorigenesis.</p><p><strong>Methods: </strong>Targeting HIF-2α has emerged as a promising therapeutic strategy culminating in the development of a first-in-class inhibitor, belzutifan, invented by Peloton Therapeutics and marketed by Merck. This article presents the journey to belzutifan and subsequent developments.</p><p><strong>Results: </strong>We discuss the structure-based design leading to the first-in-human drug, PT2385, as well as subsequent modifications to improve pharmacokinetic properties leading to PT2977/belzutifan. Detailed analyses are presented of key HIF-2α structural features, the mechanism of drug action, and how this family of drugs performed in preclinical models. Belzutifan's impact on patients with VHL syndrome, sporadic advanced ccRCC and pheochromocytoma/paraganglioma is discussed, three areas where belzutifan has obtained Food and Drug Administration approval. Drug combination strategies, mechanisms of resistance, and emerging strategies to overcome them, including siRNA-based therapeutics, are presented. Alternative HIF-2α inhibitors are examined, including NKT2152 and AB521.</p><p><strong>Conclusions: </strong>By expanding upon the foundation established by belzutifan, the field is poised for further therapeutic advances.</p>","PeriodicalId":138,"journal":{"name":"Cancer","volume":"132 3","pages":"e70239"},"PeriodicalIF":5.1,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146111812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Caitlin P. O’Connell MPH, Sonja I. Berndt PharmD, PhD, Kenechukwu Chudy-Onwugaje MBBS, MPH, MS, Andrew Kunzmann PhD, Wen-Yi Huang PhD, MSPH, Kathryn Hughes Barry PhD, MPH, Erikka Loftfield PhD, MPH
Background
Alcohol drinking is associated with higher colorectal cancer (CRC) risk, but research on lifetime alcohol drinking is limited. The objective of the current study was to estimate the association of lifetime alcohol drinking with incident colorectal adenoma and cancer.
Methods
US adults enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial reported alcohol intake during four age periods. Average lifetime alcohol intake was calculated as average drinks per week from age 18 years until study baseline. Alcohol intake patterns were defined by past and current drinking frequency. Among 12,327 participants with a negative baseline screen, 812 had an adenoma on the second screen. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for incident adenoma. During 20 years of follow-up, 1679 incident CRC cases occurred among 88,092 participants. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for CRC.
Results
Current drinkers with an average lifetime alcohol intake of 14 or more drinks per week, compared with one drink or less per week, had a higher risk of CRC (HR, 1.25; 95% CI, 1.01–1.53), especially rectal cancer (HR, 1.95; 95% CI, 1.17–3.28). Consistent heavy drinking versus light drinking was positively associated with CRC risk (HR, 1.91; 95% CI, 1.17–3.12). Compared with current drinkers averaging less than one drink per week, former drinkers had lower odds of nonadvanced adenoma (OR, 0.58; 95% CI, 0.39–0.84). Current drinkers averaging from seven to less than 14 drinks compared with less than one drink per week had a lower risk of CRC (HR, 0.79; 95% CI, 0.64–0.97), especially distal colon cancer (HR, 0.64; 95% CI, 0.42–1.00).
Conclusions
Consistent heavy alcohol intake and higher average lifetime alcohol drinking may increase CRC risk, whereas cessation may lower adenoma risk. Associations may differ by tumor site.
{"title":"Association of alcohol intake over the lifetime with colorectal adenoma and colorectal cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial","authors":"Caitlin P. O’Connell MPH, Sonja I. Berndt PharmD, PhD, Kenechukwu Chudy-Onwugaje MBBS, MPH, MS, Andrew Kunzmann PhD, Wen-Yi Huang PhD, MSPH, Kathryn Hughes Barry PhD, MPH, Erikka Loftfield PhD, MPH","doi":"10.1002/cncr.70201","DOIUrl":"10.1002/cncr.70201","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Alcohol drinking is associated with higher colorectal cancer (CRC) risk, but research on lifetime alcohol drinking is limited. The objective of the current study was to estimate the association of lifetime alcohol drinking with incident colorectal adenoma and cancer.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>US adults enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial reported alcohol intake during four age periods. Average lifetime alcohol intake was calculated as average drinks per week from age 18 years until study baseline. Alcohol intake patterns were defined by past and current drinking frequency. Among 12,327 participants with a negative baseline screen, 812 had an adenoma on the second screen. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for incident adenoma. During 20 years of follow-up, 1679 incident CRC cases occurred among 88,092 participants. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for CRC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Current drinkers with an average lifetime alcohol intake of 14 or more drinks per week, compared with one drink or less per week, had a higher risk of CRC (HR, 1.25; 95% CI, 1.01–1.53), especially rectal cancer (HR, 1.95; 95% CI, 1.17–3.28). Consistent heavy drinking versus light drinking was positively associated with CRC risk (HR, 1.91; 95% CI, 1.17–3.12). Compared with current drinkers averaging less than one drink per week, former drinkers had lower odds of nonadvanced adenoma (OR, 0.58; 95% CI, 0.39–0.84). Current drinkers averaging from seven to less than 14 drinks compared with less than one drink per week had a lower risk of CRC (HR, 0.79; 95% CI, 0.64–0.97), especially distal colon cancer (HR, 0.64; 95% CI, 0.42–1.00).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Consistent heavy alcohol intake and higher average lifetime alcohol drinking may increase CRC risk, whereas cessation may lower adenoma risk. Associations may differ by tumor site.</p>\u0000 </section>\u0000 </div>","PeriodicalId":138,"journal":{"name":"Cancer","volume":"132 3","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12833583/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146045745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rituparna Bhattacharya PhD, Kalé Kponee-Shovein ScD, MS, MPH, Yipeng Gao PhD, Yan Song PhD, Jingyi Liu MBI, Katherine Wei BA, Ekta Kapadia MD, Haojie Li PhD, Ashish M. Kamat MD, MBBS, FACS
Background
Event-free survival (EFS) and complete response rate (CRR) are recommended as primary endpoints in bladder cancer trials to enable timely assessment of therapeutic benefit. However, their surrogacy relationship with overall survival (OS) in high-risk non–muscle-invasive bladder cancer (HR NMIBC) remains unclear. This meta-analysis evaluated EFS and CRR as surrogate endpoints for OS in bacillus Calmette-Guérin (BCG)–naive or –remote HR NMIBC.
Methods
A systematic literature review identified trials enrolling BCG-naive or -remote HR NMIBC patients and reporting EFS, CRR, and OS. Weighted linear regression models estimated trial-level associations between the hazard ratio (HR) for EFS and HR for OS, odds ratio for CRR and HR for OS, and arm-level association between median EFS and median OS. Strength of association was quantified using the correlation coefficient (R) and coefficient of determination (R2). Sensitivity analyses evaluated consistency across EFS definitions, publication year, and BCG treatment history.
Results
Ten eligible trials were identified for surrogacy analyses of EFS and CRR. Strong correlations were observed between EFS and OS at the trial level (R = 0.85; R2 = 0.72) and arm level (R = 0.90; R2 = 0.82). Trial-level associations between CRR and OS were weaker (R2 = 0.36 for 3-month CRR; R2 = 0.30 for 6-month CRR). Sensitivity analyses confirmed robustness of the primary results.
Conclusion
In BCG-naive or -remote HR NMIBC, EFS shows strong correlation with OS at the trial and arm levels, supporting its potential as a surrogate endpoint. Further validation incorporating additional trials across varied therapeutic modalities is warranted.
{"title":"Event-free survival and complete response rate as surrogate endpoints for overall survival in high-risk non–muscle-invasive bladder cancer: A meta-analysis of bacillus Calmette-Guérin—naive or —remote cases","authors":"Rituparna Bhattacharya PhD, Kalé Kponee-Shovein ScD, MS, MPH, Yipeng Gao PhD, Yan Song PhD, Jingyi Liu MBI, Katherine Wei BA, Ekta Kapadia MD, Haojie Li PhD, Ashish M. Kamat MD, MBBS, FACS","doi":"10.1002/cncr.70220","DOIUrl":"10.1002/cncr.70220","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Event-free survival (EFS) and complete response rate (CRR) are recommended as primary endpoints in bladder cancer trials to enable timely assessment of therapeutic benefit. However, their surrogacy relationship with overall survival (OS) in high-risk non–muscle-invasive bladder cancer (HR NMIBC) remains unclear. This meta-analysis evaluated EFS and CRR as surrogate endpoints for OS in bacillus Calmette-Guérin (BCG)–naive or –remote HR NMIBC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A systematic literature review identified trials enrolling BCG-naive or -remote HR NMIBC patients and reporting EFS, CRR, and OS. Weighted linear regression models estimated trial-level associations between the hazard ratio (HR) for EFS and HR for OS, odds ratio for CRR and HR for OS, and arm-level association between median EFS and median OS. Strength of association was quantified using the correlation coefficient (<i>R</i>) and coefficient of determination (<i>R</i><sup><i>2</i></sup>). Sensitivity analyses evaluated consistency across EFS definitions, publication year, and BCG treatment history.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Ten eligible trials were identified for surrogacy analyses of EFS and CRR. Strong correlations were observed between EFS and OS at the trial level (<i>R</i> = 0.85; <i>R</i><sup><i>2</i></sup> = 0.72) and arm level (<i>R</i> = 0.90; <i>R</i><sup>2</sup> = 0.82). Trial-level associations between CRR and OS were weaker (<i>R</i><sup><i>2</i></sup> = 0.36 for 3-month CRR; <i>R</i><sup><i>2</i></sup> = 0.30 for 6-month CRR). Sensitivity analyses confirmed robustness of the primary results.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In BCG-naive or -remote HR NMIBC, EFS shows strong correlation with OS at the trial and arm levels, supporting its potential as a surrogate endpoint. Further validation incorporating additional trials across varied therapeutic modalities is warranted.</p>\u0000 </section>\u0000 </div>","PeriodicalId":138,"journal":{"name":"Cancer","volume":"132 3","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12831502/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yiyang Shan MD, Bo Ding MD, Feng Ji PhD, Hao Lin PhD, Weiwei Shi PhD, Enxiu Wang PhD, Chen Wang PhD, Yang Shen PhD
Background
Ovarian cancer remains a formidable therapeutic challenge due to late diagnosis, high recurrence rates, and limited treatment options. Mesothelin (MSLN) is highly expressed in ovarian cancer, making it a promising target for immunotherapy. Given this target profile, the authors developed a novel T-cell receptor (TCR)-like chimeric antigen receptor (CAR) T-cell therapy targeting MSLN, designated KT127.
Methods
A first-in-human, dose-escalation trial of KT127 was conducted following preclinical evaluation in vitro and in vivo. A combination of rapid titration and a standard “3 + 3” dose-escalation design was implemented. Eleven patients received KT127 at doses ranging from 1 × 106 to 2 × 107 cells/kg following lymphodepletion. The primary objectives were to assess the safety and tolerability of KT127. Secondary objectives included overall survival, disease control rate (DCR), and progression-free survival as efficacy measures. Quality of life (QOL) was assessed using the European Organisation for Research and Treatment of Cancer QLQ-OV28 questionnaire.
Results
No dose-limiting toxicities, cytokine release syndrome, or immune effector cell-associated neurotoxicity syndrome were observed. The DCR was 80% (95% confidence interval, 44.4%–97.5%). QOL assessments indicated improvement in abdominal/gastrointestinal symptoms post-treatment (p = .037), with no significant deterioration in other domains. Proteomic analysis identified differential expression of kallikrein-related peptidases (KLK13, KLK14) and chemokine CXCL17 at baseline, potentially linked to treatment outcomes.
Conclusions
This study highlights that KT127 has a manageable safety profile and shows preliminary biological activity in patients with advanced ovarian cancer, particularly those who have failed multiple lines of therapies.
{"title":"T-cell receptor–like chimeric antigen receptor T cells targeting mesothelin: A first-in-human dose-escalation trial for platinum-resistant advanced ovarian cancer","authors":"Yiyang Shan MD, Bo Ding MD, Feng Ji PhD, Hao Lin PhD, Weiwei Shi PhD, Enxiu Wang PhD, Chen Wang PhD, Yang Shen PhD","doi":"10.1002/cncr.70279","DOIUrl":"10.1002/cncr.70279","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Ovarian cancer remains a formidable therapeutic challenge due to late diagnosis, high recurrence rates, and limited treatment options. Mesothelin (MSLN) is highly expressed in ovarian cancer, making it a promising target for immunotherapy. Given this target profile, the authors developed a novel T-cell receptor (TCR)-like chimeric antigen receptor (CAR) T-cell therapy targeting MSLN, designated KT127.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A first-in-human, dose-escalation trial of KT127 was conducted following preclinical evaluation in vitro and in vivo. A combination of rapid titration and a standard “3 + 3” dose-escalation design was implemented. Eleven patients received KT127 at doses ranging from 1 × 10<sup>6</sup> to 2 × 10<sup>7</sup> cells/kg following lymphodepletion. The primary objectives were to assess the safety and tolerability of KT127. Secondary objectives included overall survival, disease control rate (DCR), and progression-free survival as efficacy measures. Quality of life (QOL) was assessed using the European Organisation for Research and Treatment of Cancer QLQ-OV28 questionnaire.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>No dose-limiting toxicities, cytokine release syndrome, or immune effector cell-associated neurotoxicity syndrome were observed. The DCR was 80% (95% confidence interval, 44.4%–97.5%). QOL assessments indicated improvement in abdominal/gastrointestinal symptoms post-treatment (<i>p</i> = .037), with no significant deterioration in other domains. Proteomic analysis identified differential expression of kallikrein-related peptidases (KLK13, KLK14) and chemokine CXCL17 at baseline, potentially linked to treatment outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study highlights that KT127 has a manageable safety profile and shows preliminary biological activity in patients with advanced ovarian cancer, particularly those who have failed multiple lines of therapies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":138,"journal":{"name":"Cancer","volume":"132 3","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12829732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Glucose-6-phosphate dehydrogenase (G6PD) deficiency impairs cellular redox balance through reduced NADPH production and is the most common enzymatic disorder-causing anemia. Venetoclax combined with azacitidine (Ven-Aza) targets leukemic stem cells by disrupting oxidative phosphorylation and inducing mitochondrial stress. This study hypothesized that G6PD deficiency may enhance the efficacy of Ven-Aza in acute myeloid leukemia (AML) by reducing leukemic cell metabolic resilience.
Methods
The authors studied 73 consecutive patients with newly diagnosed (ND) AML treated with Ven-Aza. G6PD activity was systematically assessed at diagnosis in all patients and categorized as normal (n = 47), borderline (n = 11), or deficient (n = 15).
Results
Composite complete remission rates were 93% in the G6PD deficient group versus 69% in the normal/borderline group (p = .03). Patients with G6PD deficiency had a significantly longer median overall survival (23.8 months; 95% confidence interval [CI], 8.9–38.7), as compared to 8.96 months (95% CI, 2.9–15.0) in the normal/borderline group (p = .034). In multivariate analysis, G6PD-deficiency was associated with improved survival as compared to patients with normal G6PD activity (hazard ratio, 0.417; 95% CI, 0.181–0.965, p = .043). No significant differences were observed across groups in rates of febrile neutropenia, pneumonia, sepsis, or grade 3–4 cytopenia.
Conclusion
G6PD deficiency is associated with higher response rates and improved survival in patients with ND-AML treated with Ven-Aza. These findings support G6PD deficiency as a potential biomarker of therapeutic sensitivity to Ven-AZA and may uncover metabolic vulnerabilities in AML with potential therapeutic implications.
{"title":"Glucose-6-phosphate dehydrogenase deficiency is associated with improved survival in patients with acute myeloid leukemia treated with venetoclax and azacitidine","authors":"Shira Buchrits MD, Alon Rozental MD, Noa Korngold BSc, Ofer Algor MD, Shirly Partouche PhD, Galit Granot PhD, Pia Raanani MD, Ofir Wolach MD","doi":"10.1002/cncr.70265","DOIUrl":"10.1002/cncr.70265","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Glucose-6-phosphate dehydrogenase (G6PD) deficiency impairs cellular redox balance through reduced NADPH production and is the most common enzymatic disorder-causing anemia. Venetoclax combined with azacitidine (Ven-Aza) targets leukemic stem cells by disrupting oxidative phosphorylation and inducing mitochondrial stress. This study hypothesized that G6PD deficiency may enhance the efficacy of Ven-Aza in acute myeloid leukemia (AML) by reducing leukemic cell metabolic resilience.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The authors studied 73 consecutive patients with newly diagnosed (ND) AML treated with Ven-Aza. G6PD activity was systematically assessed at diagnosis in all patients and categorized as normal (<i>n</i> = 47), borderline (<i>n</i> = 11), or deficient (<i>n</i> = 15).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Composite complete remission rates were 93% in the G6PD deficient group versus 69% in the normal/borderline group (<i>p</i> = .03). Patients with G6PD deficiency had a significantly longer median overall survival (23.8 months; 95% confidence interval [CI], 8.9–38.7), as compared to 8.96 months (95% CI, 2.9–15.0) in the normal/borderline group (<i>p</i> = .034). In multivariate analysis, G6PD-deficiency was associated with improved survival as compared to patients with normal G6PD activity (hazard ratio, 0.417; 95% CI, 0.181–0.965, <i>p</i> = .043). No significant differences were observed across groups in rates of febrile neutropenia, pneumonia, sepsis, or grade 3–4 cytopenia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>G6PD deficiency is associated with higher response rates and improved survival in patients with ND-AML treated with Ven-Aza. These findings support G6PD deficiency as a potential biomarker of therapeutic sensitivity to Ven-AZA and may uncover metabolic vulnerabilities in AML with potential therapeutic implications.</p>\u0000 </section>\u0000 </div>","PeriodicalId":138,"journal":{"name":"Cancer","volume":"132 3","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12824983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rachel E. Aubrey HBSc, BScN, RN, Pamela Psarianos PhD, MSc, HBSc, Anna T. Santiago MSc, MPH, BSc, Anthony M. Griffin MSc, Peter C. Ferguson MD, MSc, FRCSC, Abha A. Gupta MD, MSc, FRCPC, Hagit Peretz Soroka PhD, David B. Shultz MD, PhD, FRCPC
Background
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas with a 5-year survival rate of approximately 50%, secondary to their metastatic potential and resistance to therapy. MPNSTs can arise sporadically, as a late toxicity from therapeutic radiotherapy, or in patients with neurofibromatosis type 1 (NF1). Prior studies have demonstrated conflicting results regarding the prognosis of NF1 associated MPNST compared to non-NF1 associated MPNST (NF0). The authors hypothesized that NF1-associated MPNSTs metastasize at a higher rate and are therefore associated with worse clinical outcomes.
Methods
The authors collected data from 166 MPNST patients included in the Canadian Sarcoma Research and Clinical Collaboration (CanSaRCC) database. Of these, 54 had NF1. Patient demographics, overall survival (OS), cumulative incidence of progression or relapse (CIPR), and cumulative incidence of disease metastasis (CIDM) were assessed.
Results
Patients with NF1 were younger (p < .001) and had larger tumors at MPNST diagnosis (p < .001). Two-year OS was lower, and CIPR and CIDM were higher in NF1-associated compared to NF0 MPNST. NF1 status, stage at diagnosis, tumor size, and positive surgical margins were adversely correlated to OS. Tumor location was an adverse prognostic factor for CIPR, and tumor size was the only adverse predictor for the CIDM in patients who underwent surgery.
Conclusion
In summary, this study suggests that patients with NF1-associated MPNSTs experience worse outcomes. NF1 associated MPNSTs were larger and arose in locations less amenable to negative (R0) resections. Among resectable tumors, CIDM, the primary driver of survival in patients initially diagnosed with localized disease, was correlated to tumor size but not NF1 status.
{"title":"Outcomes following definitive treatment of malignant peripheral nerve sheath tumor are significantly worse for patients with neurofibromatosis type 1: A Canadian Sarcoma Research and Clinical Collaboration study","authors":"Rachel E. Aubrey HBSc, BScN, RN, Pamela Psarianos PhD, MSc, HBSc, Anna T. Santiago MSc, MPH, BSc, Anthony M. Griffin MSc, Peter C. Ferguson MD, MSc, FRCSC, Abha A. Gupta MD, MSc, FRCPC, Hagit Peretz Soroka PhD, David B. Shultz MD, PhD, FRCPC","doi":"10.1002/cncr.70263","DOIUrl":"10.1002/cncr.70263","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas with a 5-year survival rate of approximately 50%, secondary to their metastatic potential and resistance to therapy. MPNSTs can arise sporadically, as a late toxicity from therapeutic radiotherapy, or in patients with neurofibromatosis type 1 (NF1). Prior studies have demonstrated conflicting results regarding the prognosis of NF1 associated MPNST compared to non-NF1 associated MPNST (NF0). The authors hypothesized that NF1-associated MPNSTs metastasize at a higher rate and are therefore associated with worse clinical outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The authors collected data from 166 MPNST patients included in the Canadian Sarcoma Research and Clinical Collaboration (CanSaRCC) database. Of these, 54 had NF1. Patient demographics, overall survival (OS), cumulative incidence of progression or relapse (CIPR), and cumulative incidence of disease metastasis (CIDM) were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Patients with NF1 were younger (<i>p</i> < .001) and had larger tumors at MPNST diagnosis (<i>p</i> < .001). Two-year OS was lower, and CIPR and CIDM were higher in NF1-associated compared to NF0 MPNST. NF1 status, stage at diagnosis, tumor size, and positive surgical margins were adversely correlated to OS. Tumor location was an adverse prognostic factor for CIPR, and tumor size was the only adverse predictor for the CIDM in patients who underwent surgery.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In summary, this study suggests that patients with NF1-associated MPNSTs experience worse outcomes. NF1 associated MPNSTs were larger and arose in locations less amenable to negative (R0) resections. Among resectable tumors, CIDM, the primary driver of survival in patients initially diagnosed with localized disease, was correlated to tumor size but not NF1 status.</p>\u0000 </section>\u0000 </div>","PeriodicalId":138,"journal":{"name":"Cancer","volume":"132 3","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12824984/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Patients with metastatic breast cancer or metastatic non–small cell lung cancer (NSCLC) with leptomeningeal metastatic disease (LMD) who underwent proton craniospinal irradiation (pCSI) had improved central nervous system progression-free survival (CNS-PFS) in comparison with patients who underwent involved-field radiotherapy (IFRT) according to the results of a phase 2 study.<span><sup>1</sup></span></p><p>Receipt of pCSI resulted in a median 5.9-month improvement in CNS-PFS in comparison with the receipt of IFRT. This improvement, combined with an improvement in overall survival (OS) and a trend toward improved self-reported daily function, led study researcher Jonathan T. Yang, MD, PhD, a radiation oncology resident at Memorial Sloan Kettering Cancer Center in New York, New York (at the time of the study), and his colleagues to conclude “that patients should be considered for pCSI if available.”</p><p>The study included 98 patients with NSCLC or breast cancer with LMD. Patients with other solid tumors were enrolled as an exploratory pCSI cohort. Patients were randomly assigned 2:1 to pCSI or IFRT. The median follow-up was 26.8 months.</p><p>At 6 months, the patients assigned to IFRT had a cumulative incidence rate of CNS progression of 88% versus 22% for the patients who received pCSI (<i>p</i> < .001). The median CNS-PFS was 8.2 months with pCSI and 2.3 months with IFRT (<i>p</i> < .001). The median OS more than doubled in the pCSI arm in comparison with the IFRT arm (11 vs. 4.9 months; <i>p</i> = .04).</p><p>All patients in the exploratory arm of other solid tumor types received pCSI; the median CNS-PFS was 5.8 months, and the median OS was 7.0 months.</p><p>In discussing the results, Helen A. Shih, MD, MS, MPH, a radiation oncologist at Massachusetts General Hospital of Mass General Brigham in Boston, outlines the existing treatment options for patients with LMD.</p><p>“Once someone has LMD, disease can be anywhere in the cerebrospinal fluid, and if we want to treat it in entirety, we have to treat the entire spinal cord and brain and all the other tissue/fluid within the thecal sac. But doing so with a traditional photon technique is generally considered too toxic to be beneficial,” says Dr Shih. “Instead, we just treat the areas that are symptomatic. If a patient has bad headaches, for example, we may do whole brain irradiation.”</p><p>This approach of treating symptomatic areas is a palliative approach and was compared in this study with a more “curative” or comprehensive approach to managing the CNS disease with pCSI.</p><p>“It was predictable to have a positive study because we are treating the entire thecal sac, meaning all the CNS disease, versus a treatment that was never intended to result in a survival benefit,” says Dr Shih. “It is not apples to apples.”</p><p>Fortunately, these findings resulted in the initiation of the NRG-BN014 trial, which will compare pCSI and photon IFRT at a larger scale multi-institutionally to v
根据一项2期研究的结果，接受质子颅脊髓照射（pCSI）的转移性乳腺癌或转移性非小细胞肺癌（NSCLC）合并轻脑膜转移性疾病（LMD）的患者与接受受病灶放疗（IFRT）的患者相比，中枢神经系统无进展生存期（CNS-PFS）得到改善。与接受IFRT相比，接受pCSI导致CNS-PFS的中位改善5.9个月。这种改善，结合总生存期（OS）的改善和自我报告的日常功能改善的趋势，领导研究人员Jonathan T. Yang，医学博士，纽约纪念斯隆凯特琳癌症中心的放射肿瘤学住院医师（研究时），和他的同事得出结论：“如果有可能，患者应该考虑进行pCSI。”该研究纳入了98例伴有LMD的非小细胞肺癌或乳腺癌患者。其他实体肿瘤患者被纳入探索性pCSI队列。患者按2:1随机分配至pCSI或IFRT组。中位随访时间为26.8个月。在6个月时，分配给IFRT的患者的累积CNS进展发生率为88%，而接受pCSI的患者为22% （p < .001）。中位CNS-PFS为pCSI组8.2个月，IFRT组2.3个月（p < .001）。与IFRT组相比，pCSI组的中位生存期增加了一倍以上（11个月vs. 4.9个月；p = .04）。其他实体瘤类型探查组均行pCSI；中位CNS-PFS为5.8个月，中位OS为7.0个月。在讨论结果时，波士顿麻省总医院的放射肿瘤学家Helen a . Shih，医学博士，硕士，公共卫生硕士，概述了LMD患者现有的治疗方案。“一旦有人患有LMD，疾病可能出现在脑脊液的任何地方，如果我们想要全面治疗，我们必须治疗整个脊髓、大脑以及硬膜囊内的所有其他组织/液体。但是用传统的光子技术这样做通常被认为毒性太大而无益，”Shih博士说。“相反，我们只治疗有症状的部位。例如，如果患者头痛严重，我们可能会对其进行全脑照射。”这种治疗症状区域的方法是一种姑息性方法，在本研究中与pCSI治疗中枢神经系统疾病的更“治愈”或更全面的方法进行了比较。Shih博士说：“这是一个可以预测的阳性研究，因为我们治疗的是整个鞘囊，也就是所有的中枢神经系统疾病，而不是一种从未打算导致生存获益的治疗。”“这不是苹果对苹果。”幸运的是，这些发现导致了NRG-BN014试验的启动，该试验将在更大规模的多机构中比较pCSI和光子IFRT，以验证领先癌症中心的发现。“我们实际上已经有几十年没有做过光子治疗了，但随着质子治疗的进步，光子技术也在进步，”施博士说。“现在我们可以更准确地比较这些技术，也可以考虑使用更高度共形和现在广泛使用的强度调制放射治疗技术的光子CSI，更具体地说，是体积调制电弧治疗的亚型，与更有历史意义的光子CSI技术相比，它的副作用要小得多。”研究结果的另一个重要考虑因素是，大多数患者（88%）是新诊断的LMD。施博士说，在她的机构接受LMD放射治疗的患者通常经过大量的预处理，因为他们在CSI之前尝试了多种全身治疗。“[在这项研究中，]大多数患者在被诊断为LMD后立即接受放射治疗，我不确定所有患者都会这样做，”Shih博士说。鉴于越来越多的免疫治疗和靶向治疗方案，其中一些已显示出治疗中枢神经系统转移的有效性，患者可能会在决定尝试CSI之前选择全身治疗方案。这样做的好处是可以治疗中枢神经系统以外的潜在疾病，并避免辐射的其他风险，例如辐射整个大脑可能产生的神经认知影响。
{"title":"Proton craniospinal irradiation option for leptomeningeal metastatic disease","authors":"Leah Lawrence","doi":"10.1002/cncr.70209","DOIUrl":"10.1002/cncr.70209","url":null,"abstract":"<p>Patients with metastatic breast cancer or metastatic non–small cell lung cancer (NSCLC) with leptomeningeal metastatic disease (LMD) who underwent proton craniospinal irradiation (pCSI) had improved central nervous system progression-free survival (CNS-PFS) in comparison with patients who underwent involved-field radiotherapy (IFRT) according to the results of a phase 2 study.<span><sup>1</sup></span></p><p>Receipt of pCSI resulted in a median 5.9-month improvement in CNS-PFS in comparison with the receipt of IFRT. This improvement, combined with an improvement in overall survival (OS) and a trend toward improved self-reported daily function, led study researcher Jonathan T. Yang, MD, PhD, a radiation oncology resident at Memorial Sloan Kettering Cancer Center in New York, New York (at the time of the study), and his colleagues to conclude “that patients should be considered for pCSI if available.”</p><p>The study included 98 patients with NSCLC or breast cancer with LMD. Patients with other solid tumors were enrolled as an exploratory pCSI cohort. Patients were randomly assigned 2:1 to pCSI or IFRT. The median follow-up was 26.8 months.</p><p>At 6 months, the patients assigned to IFRT had a cumulative incidence rate of CNS progression of 88% versus 22% for the patients who received pCSI (<i>p</i> < .001). The median CNS-PFS was 8.2 months with pCSI and 2.3 months with IFRT (<i>p</i> < .001). The median OS more than doubled in the pCSI arm in comparison with the IFRT arm (11 vs. 4.9 months; <i>p</i> = .04).</p><p>All patients in the exploratory arm of other solid tumor types received pCSI; the median CNS-PFS was 5.8 months, and the median OS was 7.0 months.</p><p>In discussing the results, Helen A. Shih, MD, MS, MPH, a radiation oncologist at Massachusetts General Hospital of Mass General Brigham in Boston, outlines the existing treatment options for patients with LMD.</p><p>“Once someone has LMD, disease can be anywhere in the cerebrospinal fluid, and if we want to treat it in entirety, we have to treat the entire spinal cord and brain and all the other tissue/fluid within the thecal sac. But doing so with a traditional photon technique is generally considered too toxic to be beneficial,” says Dr Shih. “Instead, we just treat the areas that are symptomatic. If a patient has bad headaches, for example, we may do whole brain irradiation.”</p><p>This approach of treating symptomatic areas is a palliative approach and was compared in this study with a more “curative” or comprehensive approach to managing the CNS disease with pCSI.</p><p>“It was predictable to have a positive study because we are treating the entire thecal sac, meaning all the CNS disease, versus a treatment that was never intended to result in a survival benefit,” says Dr Shih. “It is not apples to apples.”</p><p>Fortunately, these findings resulted in the initiation of the NRG-BN014 trial, which will compare pCSI and photon IFRT at a larger scale multi-institutionally to v","PeriodicalId":138,"journal":{"name":"Cancer","volume":"132 2","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://acsjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/cncr.70209","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146008142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>Once daily low-dose aspirin significantly reduced the cumulative incidence of colorectal cancer recurrence at 3 years in comparison with a placebo in patients with <i>PIK3CA</i> hotspot mutations in Exon 9 or 20, with a similar benefit found for patients with other somatic alterations in the PI3K pathway, according to results of the ALASCCA trial.<span><sup>1</sup></span></p><p>Anna Martling, MD, PhD, a professor of surgery at the Karolinska Institutet in Stockholm, Sweden, and her colleagues identified 1103 patients with stage I–III colon and rectal cancer with somatic alterations in PI3K pathway genes and randomly assigned them to 160 mg of aspirin or a matched placebo once daily for 3 years.</p><p>For those patients with <i>PIK3CA</i> hotspot mutations in Exon 9 or 20 (Group A) assigned to an aspirin regimen, the estimated 3-year cumulative incidence of recurrence was almost half that of the patients assigned to a matched placebo (7.7% vs. 14.1%; hazard ratio [HR], 0.41; 95% CI, 0.24–0.98; <i>p</i> = .04).</p><p>The benefit was similar in patients with other moderate- or high-impact somatic variants in <i>PIK3CA</i>, <i>PIK3R1</i>, or <i>PTEN</i> (Group B); the estimated 3-year cumulative incidence of recurrence was 7.7% for those assigned to aspirin but 16.8% for those assigned to a placebo (HR, 0.42; 95% CI, 0.21–0.83).</p><p>Subgroup analyses showed an effect of aspirin in patients who had received neoadjuvant therapy, adjuvant therapy, both, or neither and revealed a larger effect of aspirin among female patients versus male patients.</p><p>The safety data reflected what is already known about low-dose aspirin according to the researchers. Severe adverse events occurred in 16.8% of the patients assigned to aspirin and in 11.6% of the patients assigned to a placebo. These severe adverse events commonly included postoperative complications, deep-vein thrombosis, embolism, and infection. Four deaths occurred, with one considered to be potentially related to aspirin use.</p><p>“It is not a standard of care to order next-generation sequencing for <i>PIK3CA</i> in early-stage disease,” says Cathy Eng, MD, FACP, the David H. Johnson Endowed Chair in Surgical and Medical Oncology at the Vanderbilt–Ingram Cancer Center in Nashville, Tennessee, “but more patients are asking for it, and I think it should be considered a standard if diagnosed with early-stage disease.”</p><p>In addition to results from ALASCCA, Dr Eng points out the SAKK 41/13 trial, which was underpowered because of early closure. It also supported the use of aspirin, as it demonstrated improved disease-free survival in favor of 100 mg of aspirin for 3 years in patients with stage II/III colon cancer (HR, 0.57).<span><sup>2</sup></span></p><p>Not all patients with <i>PIK3CA</i> mutations will qualify for use of low-dose aspirin, Dr Eng says. For example, low-dose aspirin should not be recommended for patients with a history of gastrointestinal bleeding, those with recent traumatic
根据ALASCCA试验的结果，与安慰剂相比，每日一次低剂量阿司匹林显著降低了PIK3CA外显子9或20热点突变患者3年结直肠癌复发的累积发生率，对于PI3K途径中其他体细胞改变的患者也有类似的益处。anna Martling，医学博士，瑞典斯德哥尔摩卡罗林斯卡学院的外科教授，和她的同事确定了1103例PI3K通路基因体细胞改变的I-III期结肠癌和直肠癌患者，并将他们随机分配到160毫克阿司匹林或匹配的安慰剂，每天一次，持续3年。对于那些具有PIK3CA外显子9或20热点突变的患者（A组），分配给阿司匹林方案，估计的3年累积复发率几乎是分配给匹配安慰剂的患者的一半（7.7% vs. 14.1%；风险比[HR]， 0.41; 95% CI, 0.24-0.98; p = 0.04）。在PIK3CA、PIK3R1或PTEN中其他中度或高影响体细胞变异的患者中，获益相似（B组）；阿司匹林组3年累积复发率为7.7%，安慰剂组为16.8% （HR, 0.42; 95% CI, 0.21-0.83）。亚组分析显示阿司匹林对接受新辅助治疗、辅助治疗、同时接受辅助治疗或不接受辅助治疗的患者的影响，并显示阿司匹林对女性患者的影响大于男性患者。研究人员表示，安全性数据反映了人们对低剂量阿司匹林的已知认识。严重不良事件发生在16.8%的阿司匹林组患者和11.6%的安慰剂组患者中。这些严重的不良事件通常包括术后并发症、深静脉血栓形成、栓塞和感染。发生了4例死亡，其中1例被认为可能与阿司匹林的使用有关。“在早期疾病中订购PIK3CA的下一代测序并不是标准的护理，”Cathy Eng，医学博士，FACP，田纳西州纳什维尔范德比尔特-英格拉姆癌症中心的大卫·h·约翰逊外科和内科肿瘤学教授说，“但越来越多的患者要求它，我认为如果诊断为早期疾病，它应该被视为标准。”除了ALASCCA的结果外，Eng博士还指出了SAKK 41/13试验，由于过早结束，该试验的动力不足。它也支持阿司匹林的使用，因为它表明，在II/III期结肠癌患者中，服用100 mg阿司匹林3年可提高无病生存期（HR, 0.57）。Eng博士说，并非所有PIK3CA突变患者都有资格使用低剂量阿司匹林。例如，低剂量阿司匹林不应推荐给有胃肠道出血史的患者、最近有创伤性头部创伤的患者或有出血性疾病的患者。“然而，我认为这些数据非常有趣，在遇到早期患者时应该考虑到这一点，”Eng博士说。“我已经开始与我所有的病人讨论这些结果，以及使用阿司匹林作为辅助治疗范例的一部分可能带来的好处。”
{"title":"Aspirin use reduced recurrence in a molecularly defined subgroup of patients with CRC","authors":"Leah Lawrence","doi":"10.1002/cncr.70208","DOIUrl":"10.1002/cncr.70208","url":null,"abstract":"<p>Once daily low-dose aspirin significantly reduced the cumulative incidence of colorectal cancer recurrence at 3 years in comparison with a placebo in patients with <i>PIK3CA</i> hotspot mutations in Exon 9 or 20, with a similar benefit found for patients with other somatic alterations in the PI3K pathway, according to results of the ALASCCA trial.<span><sup>1</sup></span></p><p>Anna Martling, MD, PhD, a professor of surgery at the Karolinska Institutet in Stockholm, Sweden, and her colleagues identified 1103 patients with stage I–III colon and rectal cancer with somatic alterations in PI3K pathway genes and randomly assigned them to 160 mg of aspirin or a matched placebo once daily for 3 years.</p><p>For those patients with <i>PIK3CA</i> hotspot mutations in Exon 9 or 20 (Group A) assigned to an aspirin regimen, the estimated 3-year cumulative incidence of recurrence was almost half that of the patients assigned to a matched placebo (7.7% vs. 14.1%; hazard ratio [HR], 0.41; 95% CI, 0.24–0.98; <i>p</i> = .04).</p><p>The benefit was similar in patients with other moderate- or high-impact somatic variants in <i>PIK3CA</i>, <i>PIK3R1</i>, or <i>PTEN</i> (Group B); the estimated 3-year cumulative incidence of recurrence was 7.7% for those assigned to aspirin but 16.8% for those assigned to a placebo (HR, 0.42; 95% CI, 0.21–0.83).</p><p>Subgroup analyses showed an effect of aspirin in patients who had received neoadjuvant therapy, adjuvant therapy, both, or neither and revealed a larger effect of aspirin among female patients versus male patients.</p><p>The safety data reflected what is already known about low-dose aspirin according to the researchers. Severe adverse events occurred in 16.8% of the patients assigned to aspirin and in 11.6% of the patients assigned to a placebo. These severe adverse events commonly included postoperative complications, deep-vein thrombosis, embolism, and infection. Four deaths occurred, with one considered to be potentially related to aspirin use.</p><p>“It is not a standard of care to order next-generation sequencing for <i>PIK3CA</i> in early-stage disease,” says Cathy Eng, MD, FACP, the David H. Johnson Endowed Chair in Surgical and Medical Oncology at the Vanderbilt–Ingram Cancer Center in Nashville, Tennessee, “but more patients are asking for it, and I think it should be considered a standard if diagnosed with early-stage disease.”</p><p>In addition to results from ALASCCA, Dr Eng points out the SAKK 41/13 trial, which was underpowered because of early closure. It also supported the use of aspirin, as it demonstrated improved disease-free survival in favor of 100 mg of aspirin for 3 years in patients with stage II/III colon cancer (HR, 0.57).<span><sup>2</sup></span></p><p>Not all patients with <i>PIK3CA</i> mutations will qualify for use of low-dose aspirin, Dr Eng says. For example, low-dose aspirin should not be recommended for patients with a history of gastrointestinal bleeding, those with recent traumatic","PeriodicalId":138,"journal":{"name":"Cancer","volume":"132 2","pages":""},"PeriodicalIF":5.1,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://acsjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/cncr.70208","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146008151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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