Xinyuan Zhang, Longgang Zhao, Long H Ngo, Simon T Dillon, Xuesong Gu, Michelle Lai, Tracey G Simon, Andrew T Chan, Edward L Giovannucci, Towia A Libermann, Xuehong Zhang
Objective: Proteomics may discover pathophysiological changes related to hepatocellular carcinoma, an aggressive and lethal type of cancer with low sensitivity for early stage diagnosis.
Design: We measured 1305 prediagnostic (median = 12.7 years) SomaScan proteins from 54 pairs of healthy individuals who subsequently developed hepatocellular carcinoma and matched non-hepatocellular carcinoma control individuals from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Candidate proteins were validated in the independent, prospective UK Biobank Pharma Proteomics Project (UKB-PPP).
Results: In NHS and HPFS, we identified 56 elevated proteins in hepatocellular carcinoma with an absolute fold change of more than 1.2 and a Wald test P value less than .05 in conditional logistic regression analysis. Ingenuity pathway analysis identified enrichment of pathways associated with cell viability, adhesion, proteolysis, apoptosis, and inflammatory response. Four proteins-chitinase-3-like protein 1, growth differentiation factor 15, interleukin-1 receptor antagonist protein, and E-selectin-showed strong positive associations with hepatocellular carcinoma and were thus validated by enzyme-linked immunosorbent assay (odds ratio = 2.48-14.7, all P < .05) in the NHS and HPFS and by Olink platform (hazard ratio = 1.90-3.93, all P < .05) in the UKB-PPP. Adding these 4 proteins to a logistic regression model of traditional hepatocellular carcinoma risk factors increased the area under the curve from 0.67 to 0.87 in the NHS and HPFS. Consistently, model area under the curve was 0.88 for hepatocellular carcinoma risk prediction in the UKB-PPP.
Conclusion: However, the limited number of hepatocellular carcinoma patients in the cohorts necessitates caution in interpreting our findings, emphasizing the need for further validation in high-risk populations.
{"title":"Prediagnostic plasma proteomics profile for hepatocellular carcinoma.","authors":"Xinyuan Zhang, Longgang Zhao, Long H Ngo, Simon T Dillon, Xuesong Gu, Michelle Lai, Tracey G Simon, Andrew T Chan, Edward L Giovannucci, Towia A Libermann, Xuehong Zhang","doi":"10.1093/jnci/djae079","DOIUrl":"10.1093/jnci/djae079","url":null,"abstract":"<p><strong>Objective: </strong>Proteomics may discover pathophysiological changes related to hepatocellular carcinoma, an aggressive and lethal type of cancer with low sensitivity for early stage diagnosis.</p><p><strong>Design: </strong>We measured 1305 prediagnostic (median = 12.7 years) SomaScan proteins from 54 pairs of healthy individuals who subsequently developed hepatocellular carcinoma and matched non-hepatocellular carcinoma control individuals from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Candidate proteins were validated in the independent, prospective UK Biobank Pharma Proteomics Project (UKB-PPP).</p><p><strong>Results: </strong>In NHS and HPFS, we identified 56 elevated proteins in hepatocellular carcinoma with an absolute fold change of more than 1.2 and a Wald test P value less than .05 in conditional logistic regression analysis. Ingenuity pathway analysis identified enrichment of pathways associated with cell viability, adhesion, proteolysis, apoptosis, and inflammatory response. Four proteins-chitinase-3-like protein 1, growth differentiation factor 15, interleukin-1 receptor antagonist protein, and E-selectin-showed strong positive associations with hepatocellular carcinoma and were thus validated by enzyme-linked immunosorbent assay (odds ratio = 2.48-14.7, all P < .05) in the NHS and HPFS and by Olink platform (hazard ratio = 1.90-3.93, all P < .05) in the UKB-PPP. Adding these 4 proteins to a logistic regression model of traditional hepatocellular carcinoma risk factors increased the area under the curve from 0.67 to 0.87 in the NHS and HPFS. Consistently, model area under the curve was 0.88 for hepatocellular carcinoma risk prediction in the UKB-PPP.</p><p><strong>Conclusion: </strong>However, the limited number of hepatocellular carcinoma patients in the cohorts necessitates caution in interpreting our findings, emphasizing the need for further validation in high-risk populations.</p>","PeriodicalId":14809,"journal":{"name":"JNCI Journal of the National Cancer Institute","volume":null,"pages":null},"PeriodicalIF":9.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11308170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140854864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alexandra Gilbert, Robert Samuel, Daniel Cagney, David Sebag-Montefiore, Julia Brown, Sarah R Brown
The aim of this review was to highlight why the use of master protocols trial design is particularly useful for radiotherapy intervention trials where complex setup pathways (including quality assurance, user training, and integrating multiple modalities of treatment) may hinder clinical advances. We carried out a systematic review according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, reviewing the findings using a landscape analysis. Results were summarized descriptively, reporting on trial characteristics highlighting the benefits, limitations, and challenges of developing and implementing radiotherapy master protocols, with three case studies selected to explore these issues in more detail. Twelve studies were suitable for inclusion (4 platform trials, 3 umbrella trials, and 5 basket trials), evaluating a mix of solid tumor sites in both curative and palliative settings. The interventions were categorized into 1) novel agent and radiotherapy combinations; 2) radiotherapy dose personalization; and 3) device evaluation, with a case study provided for each intervention. Benefits of master protocol trials for radiotherapy intervention include protocol efficiency for implementation of novel radiotherapy techniques; accelerating the evaluation of novel agent drug and radiotherapy combinations; and more efficient translational research opportunities, leading to cost savings and research efficiency to improve patient outcomes. Master protocols offer an innovative platform under which multiple clinical questions can be addressed within a single trial. Due to the complexity of radiotherapy trial setup, cost and research efficiency savings may be more apparent than in systemic treatment trials. Use of this research approach may be the change needed to push forward oncological innovation within radiation oncology.
{"title":"The use of master protocols for efficient trial design to evaluate radiotherapy interventions: a systematic review.","authors":"Alexandra Gilbert, Robert Samuel, Daniel Cagney, David Sebag-Montefiore, Julia Brown, Sarah R Brown","doi":"10.1093/jnci/djae084","DOIUrl":"10.1093/jnci/djae084","url":null,"abstract":"<p><p>The aim of this review was to highlight why the use of master protocols trial design is particularly useful for radiotherapy intervention trials where complex setup pathways (including quality assurance, user training, and integrating multiple modalities of treatment) may hinder clinical advances. We carried out a systematic review according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, reviewing the findings using a landscape analysis. Results were summarized descriptively, reporting on trial characteristics highlighting the benefits, limitations, and challenges of developing and implementing radiotherapy master protocols, with three case studies selected to explore these issues in more detail. Twelve studies were suitable for inclusion (4 platform trials, 3 umbrella trials, and 5 basket trials), evaluating a mix of solid tumor sites in both curative and palliative settings. The interventions were categorized into 1) novel agent and radiotherapy combinations; 2) radiotherapy dose personalization; and 3) device evaluation, with a case study provided for each intervention. Benefits of master protocol trials for radiotherapy intervention include protocol efficiency for implementation of novel radiotherapy techniques; accelerating the evaluation of novel agent drug and radiotherapy combinations; and more efficient translational research opportunities, leading to cost savings and research efficiency to improve patient outcomes. Master protocols offer an innovative platform under which multiple clinical questions can be addressed within a single trial. Due to the complexity of radiotherapy trial setup, cost and research efficiency savings may be more apparent than in systemic treatment trials. Use of this research approach may be the change needed to push forward oncological innovation within radiation oncology.</p>","PeriodicalId":14809,"journal":{"name":"JNCI Journal of the National Cancer Institute","volume":null,"pages":null},"PeriodicalIF":9.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11308198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140891191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Colton Duncan, Suraj Sarvode Mothi, Teresa C Santiago, Jordan A Coggins, Dylan E Graetz, Michael W Bishop, Elizabeth A Mullen, Andrew J Murphy, Daniel M Green, Matthew J Krasin, Andrew M Davidoff
Background: Patients with bilateral Wilms tumor initially receive neoadjuvant chemotherapy to shrink the tumors and increase the likelihood of successful nephron-sparing surgery. Biopsy of poorly responding tumors is often done to better understand therapy resistance. The purpose of this retrospective, single-institution study was to determine whether initial chemotherapy response is associated with tumor histology, potentially obviating the need for biopsy or change in chemotherapy.
Methods: Patients with synchronous bilateral Wilms tumors who underwent surgery at St Jude Children's Research Hospital from January 2000 to March 2022 were considered for this study. A mixed-effects logistic regression model was used to evaluate the likelihood of the tumor being stromal predominant, as predicted by tumor response to neoadjuvant chemotherapy.
Results: A total of 68 patients were eligible for this study. Tumors that increased in size had an odds ratio of 19.5 (95% confidence interval [CI] = 2.46 to 155.03) for being stromal predominant vs any other histologic subtype. Age at diagnosis was youngest in patients with stromal-predominant tumors, with a mean age of 18.8 (14.1) months compared with all other histologic subtypes (χ2 = 7.05, P = .07). The predictive value of a tumor growing combined with patient aged younger than 18 months for confirming stromal-predominant histology was 85.7% (95% CI = 57.18% to 93.5%).
Conclusions: Tumors that increased in size during neoadjuvant chemotherapy were most frequently stromal-predominant bilateral Wilms tumor, especially in younger patients. Therefore, nephron-sparing surgery, rather than biopsy, or extension or intensification of neoadjuvant chemotherapy, should be considered for bilateral Wilms tumors that increase in volume during neoadjuvant chemotherapy, particularly in patients aged younger than 18 months.
{"title":"Response of bilateral Wilms tumor to chemotherapy suggests histologic subtype and guides treatment.","authors":"Colton Duncan, Suraj Sarvode Mothi, Teresa C Santiago, Jordan A Coggins, Dylan E Graetz, Michael W Bishop, Elizabeth A Mullen, Andrew J Murphy, Daniel M Green, Matthew J Krasin, Andrew M Davidoff","doi":"10.1093/jnci/djae072","DOIUrl":"10.1093/jnci/djae072","url":null,"abstract":"<p><strong>Background: </strong>Patients with bilateral Wilms tumor initially receive neoadjuvant chemotherapy to shrink the tumors and increase the likelihood of successful nephron-sparing surgery. Biopsy of poorly responding tumors is often done to better understand therapy resistance. The purpose of this retrospective, single-institution study was to determine whether initial chemotherapy response is associated with tumor histology, potentially obviating the need for biopsy or change in chemotherapy.</p><p><strong>Methods: </strong>Patients with synchronous bilateral Wilms tumors who underwent surgery at St Jude Children's Research Hospital from January 2000 to March 2022 were considered for this study. A mixed-effects logistic regression model was used to evaluate the likelihood of the tumor being stromal predominant, as predicted by tumor response to neoadjuvant chemotherapy.</p><p><strong>Results: </strong>A total of 68 patients were eligible for this study. Tumors that increased in size had an odds ratio of 19.5 (95% confidence interval [CI] = 2.46 to 155.03) for being stromal predominant vs any other histologic subtype. Age at diagnosis was youngest in patients with stromal-predominant tumors, with a mean age of 18.8 (14.1) months compared with all other histologic subtypes (χ2 = 7.05, P = .07). The predictive value of a tumor growing combined with patient aged younger than 18 months for confirming stromal-predominant histology was 85.7% (95% CI = 57.18% to 93.5%).</p><p><strong>Conclusions: </strong>Tumors that increased in size during neoadjuvant chemotherapy were most frequently stromal-predominant bilateral Wilms tumor, especially in younger patients. Therefore, nephron-sparing surgery, rather than biopsy, or extension or intensification of neoadjuvant chemotherapy, should be considered for bilateral Wilms tumors that increase in volume during neoadjuvant chemotherapy, particularly in patients aged younger than 18 months.</p>","PeriodicalId":14809,"journal":{"name":"JNCI Journal of the National Cancer Institute","volume":null,"pages":null},"PeriodicalIF":9.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11308166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140305665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jacqueline B Vo, Cody Ramin, Lene H S Veiga, Carolyn Brandt, Rochelle E Curtis, Clara Bodelon, Ana Barac, Véronique L Roger, Heather Spencer Feigelson, Diana S M Buist, Erin J Aiello Bowles, Gretchen L Gierach, Amy Berrington de González
Background: Although breast cancer survivors are at risk for cardiovascular disease (CVD) from treatment late effects, evidence to inform long-term and age-specific cardiovascular surveillance recommendations is lacking.
Methods: We conducted a retrospective cohort study of 10 211 women diagnosed with first primary unilateral breast cancer in Kaiser Permanente Washington or Colorado (aged 20 years and older, survived ≥1 year). We estimated multivariable adjusted hazard ratios (HRs) for associations between initial chemotherapy regimen type (anthracycline and/or trastuzumab, other chemotherapies, no chemotherapy [referent]) and CVD risk, adjusted for patient characteristics, other treatments, and CVD risk factors. Cumulative incidence was calculated considering competing events.
Results: After 5.79 median years, 14.67% of women developed CVD (cardiomyopathy and/or heart failure [HF], ischemic heart disease, stroke). Women treated with anthracyclines and/or trastuzumab had a higher risk of CVD compared with no chemotherapy (adjusted HR = 1.53, 95% confidence interval [CI] = 1.31 to 1.79), persisting at least 5 years postdiagnosis (adjusted HR5-<10 years = 1.85, 95% CI = 1.44 to 2.39; adjusted HR≥10 years = 1.83, 95% CI = 1.34 to 2.49). Cardiomyopathy and/or HF risks were elevated among women treated with anthracyclines and/or trastuzumab compared with no chemotherapy, especially for those aged younger than 65 years (adjusted HR20-54years = 2.97, 95% CI = 1.72 to 5.12; adjusted HR55-64years = 2.21, 95% CI = 1.52 to 3.21), differing for older women (adjusted HR≥65 years = 1.32, 95% CI = 0.97 to 1.78), and at least 5 years postdiagnosis (adjusted HR5-<10years = 1.89, 95% CI = 1.35 to 2.64; adjusted HR≥10 years = 2.21, 95% CI = 1.52 to 3.20). Anthracyclines and/or trastuzumab receipt was associated with increased ischemic heart disease risks after 5 or more years (adjusted HR5-<10years = 1.51, 95% CI = 1.06 to 2.14; adjusted HR≥10 years = 1.86, 95% CI = 1.18 to 2.93) with no clear age effects, and stroke risk (adjusted HR = 1.33, 95% CI = 1.05 to 1.69), which did not vary by time or age. There was some evidence of long-term cardiomyopathy and/or HF and ischemic heart disease risks with other chemotherapies. Among women aged younger than 65 treated with anthracyclines and/or trastuzumab, up to 16% developed CVD by 10 years (20-54 years = 6.91%; 55-64 years = 16.00%), driven by cardiomyopathy and/or HF (20-54 years = 3.90%; 55-64 years = 9.78%).
Conclusions: We found increased long-term risks of cardiomyopathy and/or HF and ischemic heart disease among breast cancer survivors treated with anthracyclines and/or trastuzumab and increased cardiomyopathy and/or HF risk among women aged younger than 65 years.
{"title":"Long-term cardiovascular disease risk after anthracycline and trastuzumab treatments in US breast cancer survivors.","authors":"Jacqueline B Vo, Cody Ramin, Lene H S Veiga, Carolyn Brandt, Rochelle E Curtis, Clara Bodelon, Ana Barac, Véronique L Roger, Heather Spencer Feigelson, Diana S M Buist, Erin J Aiello Bowles, Gretchen L Gierach, Amy Berrington de González","doi":"10.1093/jnci/djae107","DOIUrl":"10.1093/jnci/djae107","url":null,"abstract":"<p><strong>Background: </strong>Although breast cancer survivors are at risk for cardiovascular disease (CVD) from treatment late effects, evidence to inform long-term and age-specific cardiovascular surveillance recommendations is lacking.</p><p><strong>Methods: </strong>We conducted a retrospective cohort study of 10 211 women diagnosed with first primary unilateral breast cancer in Kaiser Permanente Washington or Colorado (aged 20 years and older, survived ≥1 year). We estimated multivariable adjusted hazard ratios (HRs) for associations between initial chemotherapy regimen type (anthracycline and/or trastuzumab, other chemotherapies, no chemotherapy [referent]) and CVD risk, adjusted for patient characteristics, other treatments, and CVD risk factors. Cumulative incidence was calculated considering competing events.</p><p><strong>Results: </strong>After 5.79 median years, 14.67% of women developed CVD (cardiomyopathy and/or heart failure [HF], ischemic heart disease, stroke). Women treated with anthracyclines and/or trastuzumab had a higher risk of CVD compared with no chemotherapy (adjusted HR = 1.53, 95% confidence interval [CI] = 1.31 to 1.79), persisting at least 5 years postdiagnosis (adjusted HR5-<10 years = 1.85, 95% CI = 1.44 to 2.39; adjusted HR≥10 years = 1.83, 95% CI = 1.34 to 2.49). Cardiomyopathy and/or HF risks were elevated among women treated with anthracyclines and/or trastuzumab compared with no chemotherapy, especially for those aged younger than 65 years (adjusted HR20-54years = 2.97, 95% CI = 1.72 to 5.12; adjusted HR55-64years = 2.21, 95% CI = 1.52 to 3.21), differing for older women (adjusted HR≥65 years = 1.32, 95% CI = 0.97 to 1.78), and at least 5 years postdiagnosis (adjusted HR5-<10years = 1.89, 95% CI = 1.35 to 2.64; adjusted HR≥10 years = 2.21, 95% CI = 1.52 to 3.20). Anthracyclines and/or trastuzumab receipt was associated with increased ischemic heart disease risks after 5 or more years (adjusted HR5-<10years = 1.51, 95% CI = 1.06 to 2.14; adjusted HR≥10 years = 1.86, 95% CI = 1.18 to 2.93) with no clear age effects, and stroke risk (adjusted HR = 1.33, 95% CI = 1.05 to 1.69), which did not vary by time or age. There was some evidence of long-term cardiomyopathy and/or HF and ischemic heart disease risks with other chemotherapies. Among women aged younger than 65 treated with anthracyclines and/or trastuzumab, up to 16% developed CVD by 10 years (20-54 years = 6.91%; 55-64 years = 16.00%), driven by cardiomyopathy and/or HF (20-54 years = 3.90%; 55-64 years = 9.78%).</p><p><strong>Conclusions: </strong>We found increased long-term risks of cardiomyopathy and/or HF and ischemic heart disease among breast cancer survivors treated with anthracyclines and/or trastuzumab and increased cardiomyopathy and/or HF risk among women aged younger than 65 years.</p>","PeriodicalId":14809,"journal":{"name":"JNCI Journal of the National Cancer Institute","volume":null,"pages":null},"PeriodicalIF":9.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11308182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140891186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Casper W F van Eijck, Disha Vadgama, Casper H J van Eijck, Johanna W Wilmink
Background: Beyond demographic and immune factors, metabolic considerations, particularly metformin's recognized impact in oncology, warrant exploration in treating pancreatic cancer. This study aimed to investigate the influence of metformin on patient survival and its potential correlation with distinct immune profiles in pancreatic ductal adenocarcinoma (PDAC) tumors.
Methods: We included 82 upfront resected and 66 gemcitabine-based neoadjuvant chemoradiotherapy (nCRT)-treated patients from the PREOPANC randomized controlled trial (RCT). Transcriptomic NanoString immunoprofiling was performed for a subset of 96 available resected specimens.
Results: Disparities in survival outcomes and immune profiles were apparent between metformin and non-metformin users in upfront resected patients but lacking in nCRT-treated patients. Compared to non-metformin users, upfront resected metformin users showed a higher median overall survival (OS) of 29 vs 14 months and a better 5-year OS rate of 19% vs 5%. Furthermore, metformin use was a favorable prognostic factor for OS in the upfront surgery group (HR = 0.56; 95% CI = 0.32 to 0.99). Transcriptomic data revealed that metformin users significantly underexpressed genes related to pro-tumoral immunity, including monocyte to M2 macrophage polarization and activation. Furthermore, the relative abundance of anti-inflammatory CD163+ MRC1+ M2 macrophages in non-metformin users and immune-activating CD1A+ CD1C+ dendritic cells in metformin users was heightened (P < .001).
Conclusion: This study unveils immune profile changes resulting from metformin use in upfront resected pancreatic cancer patients, possibly contributing to prolonged survival outcomes. Specifically, metformin use may decrease the abundance and activity of pro-tumoral M2 macrophages and increase the recruitment and function of tumor-resolving DCs, favoring antitumor immunity.[PREOPANC trial EudraCT: 2012-003181-40].
{"title":"Metformin boosts antitumor immunity and improves prognosis in upfront resected pancreatic cancer: an observational study.","authors":"Casper W F van Eijck, Disha Vadgama, Casper H J van Eijck, Johanna W Wilmink","doi":"10.1093/jnci/djae070","DOIUrl":"10.1093/jnci/djae070","url":null,"abstract":"<p><strong>Background: </strong>Beyond demographic and immune factors, metabolic considerations, particularly metformin's recognized impact in oncology, warrant exploration in treating pancreatic cancer. This study aimed to investigate the influence of metformin on patient survival and its potential correlation with distinct immune profiles in pancreatic ductal adenocarcinoma (PDAC) tumors.</p><p><strong>Methods: </strong>We included 82 upfront resected and 66 gemcitabine-based neoadjuvant chemoradiotherapy (nCRT)-treated patients from the PREOPANC randomized controlled trial (RCT). Transcriptomic NanoString immunoprofiling was performed for a subset of 96 available resected specimens.</p><p><strong>Results: </strong>Disparities in survival outcomes and immune profiles were apparent between metformin and non-metformin users in upfront resected patients but lacking in nCRT-treated patients. Compared to non-metformin users, upfront resected metformin users showed a higher median overall survival (OS) of 29 vs 14 months and a better 5-year OS rate of 19% vs 5%. Furthermore, metformin use was a favorable prognostic factor for OS in the upfront surgery group (HR = 0.56; 95% CI = 0.32 to 0.99). Transcriptomic data revealed that metformin users significantly underexpressed genes related to pro-tumoral immunity, including monocyte to M2 macrophage polarization and activation. Furthermore, the relative abundance of anti-inflammatory CD163+ MRC1+ M2 macrophages in non-metformin users and immune-activating CD1A+ CD1C+ dendritic cells in metformin users was heightened (P < .001).</p><p><strong>Conclusion: </strong>This study unveils immune profile changes resulting from metformin use in upfront resected pancreatic cancer patients, possibly contributing to prolonged survival outcomes. Specifically, metformin use may decrease the abundance and activity of pro-tumoral M2 macrophages and increase the recruitment and function of tumor-resolving DCs, favoring antitumor immunity.[PREOPANC trial EudraCT: 2012-003181-40].</p>","PeriodicalId":14809,"journal":{"name":"JNCI Journal of the National Cancer Institute","volume":null,"pages":null},"PeriodicalIF":9.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11308183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140293561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Davide Massa, Claudio Vernieri, Lorenzo Nicolè, Carmen Criscitiello, Florence Boissière-Michot, Séverine Guiu, Angélique Bobrie, Gaia Griguolo, Federica Miglietta, Andrea Vingiani, Riccardo Lobefaro, Beatrice Taurelli Salimbeni, Claudia Pinato, Francesca Schiavi, Silvia Brich, Carlo Pescia, Nicola Fusco, Giancarlo Pruneri, Matteo Fassan, Giuseppe Curigliano, Valentina Guarneri, William Jacot, Maria Vittoria Dieci
Background: The cut-off of < 1% positive cells to define estrogen receptor (ER) negativity by immunohistochemistry (IHC) in breast cancer (BC) is debated. We explored the tumor immune microenvironment and gene-expression profile of patients with early-stage HER2-negative ER-low (ER 1-9%) BC, comparing them to ER-negative (ER < 1%) and ER-intermediate (ER 10-50%) tumors.
Patients and methods: Among 921 patients with early-stage I-III, ER ≤ 50%, HER2-negative BCs, tumors were classified as ER-negative (n = 712), ER-low (n = 128), or ER-intermediate (n = 81). Tumor-infiltrating lymphocytes (TILs) were evaluated. CD8+, FOXP3+ cells, and PD-L1 status were assessed by IHC and quantified by digital pathology. We analyzed 776 BC-related genes in 116 samples. All tests were 2-sided at < 0.05 significance level.
Results: ER-low and ER-negative tumors exhibited similar median TILs, significantly higher than ER-intermediate tumors. CD8/FOXP3 ratio and PD-L1 positivity rates were comparable between ER-low and ER-negative groups. These groups showed similar enrichment in Basal-like intrinsic subtypes and comparable expression of immune-related genes. ER-low and ER-intermediate tumors showed significant transcriptomic differences. High TILs (≥30%) were associated with improved relapse-free survival (RFS) in ER-low (5-year RFS 78.6% vs 66.2%, log-rank p = .033, hazard ratio (HR) 0.37 [95% CI 0.15-0.96]) and ER-negative patients (5-year RFS 85.2% vs 69.8%, log-rank p < .001, HR 0.41 [95% CI 0.27-0.60]).
Conclusions: ER-low and ER-negative tumors are similar biological and molecular entities, supporting their comparable clinical outcomes and treatment responses, including to immunotherapy. Our findings contribute to the growing evidence calling for a reevaluation of ER-positive BC classification and management, aligning ER-low and ER-negative tumors more closely.
背景:患者和方法:在921例早期I-III期、ER≤50%、HER2阴性的BC患者中,肿瘤被分为ER阴性(n = 712)、ER低(n = 128)或ER中期(n = 81)。对肿瘤浸润淋巴细胞(TILs)进行了评估。通过 IHC 评估 CD8+、FOXP3+ 细胞和 PD-L1 状态,并通过数字病理学进行量化。我们分析了 116 份样本中的 776 个 BC 相关基因。所有测试结果均为双侧结果:ER低和ER阴性肿瘤的TILs中位数相似,但明显高于ER中间型肿瘤。ER低度组和ER阴性组的CD8/FOXP3比率和PD-L1阳性率相当。这些组别显示出相似的基底样内在亚型富集,免疫相关基因的表达也相当。ER-低和ER-中间型肿瘤的转录组差异显著。高TILs(≥30%)与ER低患者(5年RFS为78.6% vs 66.2%,log-rank p = .033,危险比(HR)为0.37 [95% CI 0.15-0.96])和ER阴性患者(5年RFS为85.2% vs 69.8%,log-rank p = .033,危险比(HR)为0.37 [95% CI 0.15-0.96])的无复发生存期(RFS)改善有关:ER低和ER阴性肿瘤是相似的生物学和分子实体,支持其可比的临床结果和治疗反应,包括对免疫疗法的反应。我们的研究结果为越来越多的证据提供了依据,这些证据呼吁重新评估ER阳性BC的分类和管理,使ER低和ER阴性肿瘤更加接近。
{"title":"Immune and Gene-expression Profiling in Estrogen Receptor Low and Negative Early Breast Cancer.","authors":"Davide Massa, Claudio Vernieri, Lorenzo Nicolè, Carmen Criscitiello, Florence Boissière-Michot, Séverine Guiu, Angélique Bobrie, Gaia Griguolo, Federica Miglietta, Andrea Vingiani, Riccardo Lobefaro, Beatrice Taurelli Salimbeni, Claudia Pinato, Francesca Schiavi, Silvia Brich, Carlo Pescia, Nicola Fusco, Giancarlo Pruneri, Matteo Fassan, Giuseppe Curigliano, Valentina Guarneri, William Jacot, Maria Vittoria Dieci","doi":"10.1093/jnci/djae178","DOIUrl":"https://doi.org/10.1093/jnci/djae178","url":null,"abstract":"<p><strong>Background: </strong>The cut-off of < 1% positive cells to define estrogen receptor (ER) negativity by immunohistochemistry (IHC) in breast cancer (BC) is debated. We explored the tumor immune microenvironment and gene-expression profile of patients with early-stage HER2-negative ER-low (ER 1-9%) BC, comparing them to ER-negative (ER < 1%) and ER-intermediate (ER 10-50%) tumors.</p><p><strong>Patients and methods: </strong>Among 921 patients with early-stage I-III, ER ≤ 50%, HER2-negative BCs, tumors were classified as ER-negative (n = 712), ER-low (n = 128), or ER-intermediate (n = 81). Tumor-infiltrating lymphocytes (TILs) were evaluated. CD8+, FOXP3+ cells, and PD-L1 status were assessed by IHC and quantified by digital pathology. We analyzed 776 BC-related genes in 116 samples. All tests were 2-sided at < 0.05 significance level.</p><p><strong>Results: </strong>ER-low and ER-negative tumors exhibited similar median TILs, significantly higher than ER-intermediate tumors. CD8/FOXP3 ratio and PD-L1 positivity rates were comparable between ER-low and ER-negative groups. These groups showed similar enrichment in Basal-like intrinsic subtypes and comparable expression of immune-related genes. ER-low and ER-intermediate tumors showed significant transcriptomic differences. High TILs (≥30%) were associated with improved relapse-free survival (RFS) in ER-low (5-year RFS 78.6% vs 66.2%, log-rank p = .033, hazard ratio (HR) 0.37 [95% CI 0.15-0.96]) and ER-negative patients (5-year RFS 85.2% vs 69.8%, log-rank p < .001, HR 0.41 [95% CI 0.27-0.60]).</p><p><strong>Conclusions: </strong>ER-low and ER-negative tumors are similar biological and molecular entities, supporting their comparable clinical outcomes and treatment responses, including to immunotherapy. Our findings contribute to the growing evidence calling for a reevaluation of ER-positive BC classification and management, aligning ER-low and ER-negative tumors more closely.</p>","PeriodicalId":14809,"journal":{"name":"JNCI Journal of the National Cancer Institute","volume":null,"pages":null},"PeriodicalIF":9.9,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The \"PRO\"mise and \"PRO\"gress of PROs in cancer clinical trials.","authors":"Amrita Basu, Dawn L Hershman","doi":"10.1093/jnci/djae157","DOIUrl":"https://doi.org/10.1093/jnci/djae157","url":null,"abstract":"","PeriodicalId":14809,"journal":{"name":"JNCI Journal of the National Cancer Institute","volume":null,"pages":null},"PeriodicalIF":9.9,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stefanie Nelson, Danielle Carrick, Danielle Daee, Ian Fingerman, Elizabeth Gillanders
Research conducted over the past 15+ years has identified hundreds of common germline genetic variants associated with cancer risk but understanding the biological impact of these primarily non-protein coding variants has been challenging [1]. The National Cancer Institute sought to better understand and address those challenges by requesting input from the scientific community via a survey and a 2-day virtual meeting, which focused on discussions among participants. Here, we discuss challenges identified through the survey as important to advancing functional analysis of common cancer risk variants: 1) When is a variant truly characterized; 2) Developing and standardizing databases and computational tools; 3) Optimization and implementation of high throughput assays; 4) Use of model organisms for understanding variant function; 5) Diversity in data and assays; and 6) Creating and improving large multidisciplinary collaborations. We define these six challenges, describe how success in addressing them may look, propose potential solutions, and note issues that span all the challenges. Implementation of these ideas could help develop a framework for methodically analyzing common cancer risk variants to understand their function and make effective and efficient use of the wealth of existing genomic association data.
{"title":"Variation to Biology: Optimizing Functional Analysis of Cancer Risk Variants.","authors":"Stefanie Nelson, Danielle Carrick, Danielle Daee, Ian Fingerman, Elizabeth Gillanders","doi":"10.1093/jnci/djae173","DOIUrl":"https://doi.org/10.1093/jnci/djae173","url":null,"abstract":"<p><p>Research conducted over the past 15+ years has identified hundreds of common germline genetic variants associated with cancer risk but understanding the biological impact of these primarily non-protein coding variants has been challenging [1]. The National Cancer Institute sought to better understand and address those challenges by requesting input from the scientific community via a survey and a 2-day virtual meeting, which focused on discussions among participants. Here, we discuss challenges identified through the survey as important to advancing functional analysis of common cancer risk variants: 1) When is a variant truly characterized; 2) Developing and standardizing databases and computational tools; 3) Optimization and implementation of high throughput assays; 4) Use of model organisms for understanding variant function; 5) Diversity in data and assays; and 6) Creating and improving large multidisciplinary collaborations. We define these six challenges, describe how success in addressing them may look, propose potential solutions, and note issues that span all the challenges. Implementation of these ideas could help develop a framework for methodically analyzing common cancer risk variants to understand their function and make effective and efficient use of the wealth of existing genomic association data.</p>","PeriodicalId":14809,"journal":{"name":"JNCI Journal of the National Cancer Institute","volume":null,"pages":null},"PeriodicalIF":9.9,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141758796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kassem S Faraj, Mary Oerline, Samuel R Kaufman, Christopher Dall, Arnav Srivastava, Megan E V Caram, Vahakn B Shahinian, Brent K Hollenbeck
Background: The use of androgen biosynthesis and second-generation androgen receptor inhibitors for advanced prostate cancer is increasing. Because these therapies alter the androgen pathway, they have been associated with cardiometabolic and neurocognitive toxicities. Although their safety profiles have been assessed in clinical trials, real-world data are limited.
Methods: A 20% sample of national Medicare claims was used to perform a retrospective cohort study of Medicare beneficiaries with advanced prostate cancer treated with androgen biosynthesis (ie, abiraterone) and second-generation androgen receptor inhibitors between 2012 and 2019. Outcomes were assessed after the first fill of either class of drug for the 12-month period after starting therapy. The primary outcome was a hospital admission or emergency department visit for a cardiometabolic event. Secondary outcomes included neurocognitive events and fractures. Multivariable regression was used to assess the association between the class of drug and occurrence of an adverse event.
Results: There were 3488 (60%) men started on an androgen biosynthesis inhibitor and 2361 (40%) started on an androgen receptor inhibitor for the first time. Cardiometabolic adverse events were more common in men managed with androgen biosynthesis inhibitor (9.2% vs 7.5%, P = .027). No difference between androgen biosynthesis and androgen receptor inhibitors was observed for neurocognitive events (3.3% vs 3.4%, respectively; P = .71) or fractures (4.2% vs 3.6%, respectively; P = .26).
Conclusions: Men with advanced prostate cancer initiating an androgen biosynthesis inhibitor for the first time more commonly had cardiometabolic events than those started on androgen receptor inhibitors. Neurocognitive events and fractures did not differ by drug class.
背景:使用雄激素生物合成抑制剂和第二代雄激素受体抑制剂治疗晚期前列腺癌的患者越来越多。由于这些疗法改变了雄激素通路,因此与心脏代谢和神经认知毒性有关。虽然这些疗法的安全性已在临床试验中进行了评估,但真实世界的数据却很有限:采用全国医疗保险报销单的 20% 样本,对 2012 年至 2019 年期间接受雄激素生物合成(即阿比特龙)和第二代雄激素受体抑制剂治疗的晚期前列腺癌医疗保险受益人进行回顾性队列研究。在开始治疗后的 12 个月内,对首次服用任一类药物后的结果进行了评估。主要结果是因心脏代谢事件入院或急诊就诊。次要结果包括神经认知事件和骨折。多变量回归用于评估药物类别与不良事件发生之间的关联:3488名男性(60%)开始使用雄激素生物合成抑制剂,2361名男性(40%)首次使用雄激素受体抑制剂。在使用雄激素生物合成抑制剂的男性中,心脏代谢不良事件更为常见(9.2% vs 7.5%,P = .027)。在神经认知事件(分别为3.3% vs 3.4%;P = .71)或骨折(分别为4.2% vs 3.6%;P = .26)方面,雄激素生物合成抑制剂和雄激素受体抑制剂之间没有差异:结论:首次使用雄激素生物合成抑制剂的晚期前列腺癌患者比开始使用雄激素受体抑制剂的患者更容易发生心脏代谢事件。神经认知事件和骨折并不因药物类别而异。
{"title":"Adverse events in men with advanced prostate cancer treated with androgen biosynthesis inhibitors and androgen receptor inhibitors.","authors":"Kassem S Faraj, Mary Oerline, Samuel R Kaufman, Christopher Dall, Arnav Srivastava, Megan E V Caram, Vahakn B Shahinian, Brent K Hollenbeck","doi":"10.1093/jnci/djae155","DOIUrl":"https://doi.org/10.1093/jnci/djae155","url":null,"abstract":"<p><strong>Background: </strong>The use of androgen biosynthesis and second-generation androgen receptor inhibitors for advanced prostate cancer is increasing. Because these therapies alter the androgen pathway, they have been associated with cardiometabolic and neurocognitive toxicities. Although their safety profiles have been assessed in clinical trials, real-world data are limited.</p><p><strong>Methods: </strong>A 20% sample of national Medicare claims was used to perform a retrospective cohort study of Medicare beneficiaries with advanced prostate cancer treated with androgen biosynthesis (ie, abiraterone) and second-generation androgen receptor inhibitors between 2012 and 2019. Outcomes were assessed after the first fill of either class of drug for the 12-month period after starting therapy. The primary outcome was a hospital admission or emergency department visit for a cardiometabolic event. Secondary outcomes included neurocognitive events and fractures. Multivariable regression was used to assess the association between the class of drug and occurrence of an adverse event.</p><p><strong>Results: </strong>There were 3488 (60%) men started on an androgen biosynthesis inhibitor and 2361 (40%) started on an androgen receptor inhibitor for the first time. Cardiometabolic adverse events were more common in men managed with androgen biosynthesis inhibitor (9.2% vs 7.5%, P = .027). No difference between androgen biosynthesis and androgen receptor inhibitors was observed for neurocognitive events (3.3% vs 3.4%, respectively; P = .71) or fractures (4.2% vs 3.6%, respectively; P = .26).</p><p><strong>Conclusions: </strong>Men with advanced prostate cancer initiating an androgen biosynthesis inhibitor for the first time more commonly had cardiometabolic events than those started on androgen receptor inhibitors. Neurocognitive events and fractures did not differ by drug class.</p>","PeriodicalId":14809,"journal":{"name":"JNCI Journal of the National Cancer Institute","volume":null,"pages":null},"PeriodicalIF":9.9,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141758739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Oguzhan Alagoz, Folasade P May, Chyke A Doubeni, A Mark Fendrick, Vahab Vahdat, Chris Estes, Travelle Ellis, Paul J Limburg, Durado Brooks
Background: The benefits of colorectal cancer (CRC) screening programs rely on completing follow-up colonoscopy when a noncolonoscopy test is abnormal and on quality of colonoscopy screening as measured by the endoscopists' adenoma detection rate. Existing data demonstrate substantially lower follow-up colonoscopy rates and adenoma detection rate for Black Americans than White Americans. However, the contributions of racial differences in follow-up colonoscopy and adenoma detection rate on CRC outcomes have not been rigorously evaluated.
Methods: We used established and validated CRC-Adenoma Incidence and Mortality (CRC-AIM) model as our analysis platform, with inputs from published literature that report lower follow-up colonoscopy rates and adenoma detection rate in Black adults compared with White adults (15% and 10% lower, respectively). We simulated screening with annual fecal immunochemical test, triennial multitarget stool DNA, and colonoscopy every 10 years between ages 45 and 75 years using real-world utilization of the screening modalities vs no screening. We reported lifetime outcomes per 1000 Black adults.
Results: Elimination of Black-White disparities in follow-up colonoscopy rates would reduce CRC incidence and mortality by 5.2% and 9.3%, respectively, and improve life-years gained with screening by 3.4%. Elimination of Black-White disparities in endoscopists' adenoma detection rate would reduce CRC incidence and mortality by 9.4% and improve life-years gained by 3.7%. Elimination of both disparities would reduce CRC incidence and mortality by 14.6% and 18.7%, respectively, and improve life-years gained by 7.1%.
Conclusions: This modeling study predicts eliminating racial differences in follow-up colonoscopy rates, and quality of screening colonoscopy would substantially reduce Black-White disparities in CRC incidence and mortality.
{"title":"Impact of racial disparities in follow-up and quality of colonoscopy on colorectal cancer outcomes.","authors":"Oguzhan Alagoz, Folasade P May, Chyke A Doubeni, A Mark Fendrick, Vahab Vahdat, Chris Estes, Travelle Ellis, Paul J Limburg, Durado Brooks","doi":"10.1093/jnci/djae140","DOIUrl":"10.1093/jnci/djae140","url":null,"abstract":"<p><strong>Background: </strong>The benefits of colorectal cancer (CRC) screening programs rely on completing follow-up colonoscopy when a noncolonoscopy test is abnormal and on quality of colonoscopy screening as measured by the endoscopists' adenoma detection rate. Existing data demonstrate substantially lower follow-up colonoscopy rates and adenoma detection rate for Black Americans than White Americans. However, the contributions of racial differences in follow-up colonoscopy and adenoma detection rate on CRC outcomes have not been rigorously evaluated.</p><p><strong>Methods: </strong>We used established and validated CRC-Adenoma Incidence and Mortality (CRC-AIM) model as our analysis platform, with inputs from published literature that report lower follow-up colonoscopy rates and adenoma detection rate in Black adults compared with White adults (15% and 10% lower, respectively). We simulated screening with annual fecal immunochemical test, triennial multitarget stool DNA, and colonoscopy every 10 years between ages 45 and 75 years using real-world utilization of the screening modalities vs no screening. We reported lifetime outcomes per 1000 Black adults.</p><p><strong>Results: </strong>Elimination of Black-White disparities in follow-up colonoscopy rates would reduce CRC incidence and mortality by 5.2% and 9.3%, respectively, and improve life-years gained with screening by 3.4%. Elimination of Black-White disparities in endoscopists' adenoma detection rate would reduce CRC incidence and mortality by 9.4% and improve life-years gained by 3.7%. Elimination of both disparities would reduce CRC incidence and mortality by 14.6% and 18.7%, respectively, and improve life-years gained by 7.1%.</p><p><strong>Conclusions: </strong>This modeling study predicts eliminating racial differences in follow-up colonoscopy rates, and quality of screening colonoscopy would substantially reduce Black-White disparities in CRC incidence and mortality.</p>","PeriodicalId":14809,"journal":{"name":"JNCI Journal of the National Cancer Institute","volume":null,"pages":null},"PeriodicalIF":9.9,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141751778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}