Andrea Y. Gu, Tet Woo Lee, Aziza Khan, Xuenan Zhang, Francis W. Hunter, Dean C. Singleton, Stephen M. F. Jamieson
Mutations in the oncogene NRAS that induce constitutive RAS-GTPase activity lead to unchecked cell proliferation and migration through downstream activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signalling pathways [1]. These mutations occur in approximately 20% of melanomas and very rarely coexist with BRAF V600 mutations. NRAS-mutant melanoma is associated with poor survival [2] and represents an unmet clinical need, with no effective therapies available following immunotherapy failure.
Identification of contextual essential genes that exert stronger fitness effects on NRAS-mutant melanoma cells presents an opportunity for the discovery of targeted therapies. In this study, we employed CRISPR-Cas9-mediated whole-genome dropout screens to identify genetic dependencies in NRAS-mutant melanoma. Typically, melanoma cell lines are cultured under ambient (∼20%) O2 conditions, despite O2 concentrations of < 8% at the epidermal-dermal junction where melanocytes reside, resulting in adaptations in gene and protein expression [3]. Therefore, for our screens, we used a panel of early-passage New Zealand Melanoma (NZM) cell lines that were established and cultured under physiological (5%) O2 conditions [4].
Six NRAS-mutant and seven NRAS-wildtype (five BRAF-mutant, two BRAF/NRAS/NF1-wildtype) NZM cell lines (Supplementary Table S1) were transduced in multiple replicates with the Brunello single guide RNA (sgRNA) library at a multiplicity of infection of approximately 0.3 and screened at 5% O2 for up to 35 days (Supplementary Methods and Materials). All NZM lines were cultured for transduction at fewer than 10 passages from derivation. The representation of the sgRNA libraries was assessed to evaluate transducibility, with any cell lines exhibiting poor sgRNA representation (< 80% of sgRNAs detected with ≥1 count) excluded from further analyses (Supplementary Table S2). Moderate to high representation was observed in nine of the 13 NZM cell lines, whereas four cell lines were excluded due to < 80% of sgRNAs being detected (Figure 1A). Reduced sgRNA representation was accompanied by dropout of non-targeting control (NTC) sgRNAs (Figure 1A), greater read count inequality (Supplementary Figure S1, Supplementary Table S2) and reduced correlation with the Brunello library plasmids and between individual cell line replicates (Supplementary Figure S2), suggesting stochastic evolution rather than knockout-induced fitness effects.
We used BAGEL2 to estimate gene essentiality relative to reference sets of common essential and nonessential genes. Typically, tissue-agnostic gene sets are used for this purpose [5], but we established a combined essential gene set incorporating both tissue-agnostic and melanoma-sp
{"title":"Whole-genome CRISPR-Cas9 knockout screens identify SHOC2 as a genetic dependency in NRAS-mutant melanoma","authors":"Andrea Y. Gu, Tet Woo Lee, Aziza Khan, Xuenan Zhang, Francis W. Hunter, Dean C. Singleton, Stephen M. F. Jamieson","doi":"10.1002/cac2.70013","DOIUrl":"10.1002/cac2.70013","url":null,"abstract":"<p>Mutations in the oncogene <i>NRAS</i> that induce constitutive RAS-GTPase activity lead to unchecked cell proliferation and migration through downstream activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signalling pathways [<span>1</span>]. These mutations occur in approximately 20% of melanomas and very rarely coexist with <i>BRAF</i> V600 mutations. <i>NRAS</i>-mutant melanoma is associated with poor survival [<span>2</span>] and represents an unmet clinical need, with no effective therapies available following immunotherapy failure.</p><p>Identification of contextual essential genes that exert stronger fitness effects on <i>NRAS</i>-mutant melanoma cells presents an opportunity for the discovery of targeted therapies. In this study, we employed CRISPR-Cas9-mediated whole-genome dropout screens to identify genetic dependencies in <i>NRAS</i>-mutant melanoma. Typically, melanoma cell lines are cultured under ambient (∼20%) O<sub>2</sub> conditions, despite O<sub>2</sub> concentrations of < 8% at the epidermal-dermal junction where melanocytes reside, resulting in adaptations in gene and protein expression [<span>3</span>]. Therefore, for our screens, we used a panel of early-passage New Zealand Melanoma (NZM) cell lines that were established and cultured under physiological (5%) O<sub>2</sub> conditions [<span>4</span>].</p><p>Six <i>NRAS</i>-mutant and seven <i>NRAS</i>-wildtype (five <i>BRAF</i>-mutant, two <i>BRAF</i>/<i>NRAS</i>/<i>NF1</i>-wildtype) NZM cell lines (Supplementary Table S1) were transduced in multiple replicates with the Brunello single guide RNA (sgRNA) library at a multiplicity of infection of approximately 0.3 and screened at 5% O<sub>2</sub> for up to 35 days (Supplementary Methods and Materials). All NZM lines were cultured for transduction at fewer than 10 passages from derivation. The representation of the sgRNA libraries was assessed to evaluate transducibility, with any cell lines exhibiting poor sgRNA representation (< 80% of sgRNAs detected with ≥1 count) excluded from further analyses (Supplementary Table S2). Moderate to high representation was observed in nine of the 13 NZM cell lines, whereas four cell lines were excluded due to < 80% of sgRNAs being detected (Figure 1A). Reduced sgRNA representation was accompanied by dropout of non-targeting control (NTC) sgRNAs (Figure 1A), greater read count inequality (Supplementary Figure S1, Supplementary Table S2) and reduced correlation with the Brunello library plasmids and between individual cell line replicates (Supplementary Figure S2), suggesting stochastic evolution rather than knockout-induced fitness effects.</p><p>We used BAGEL2 to estimate gene essentiality relative to reference sets of common essential and nonessential genes. Typically, tissue-agnostic gene sets are used for this purpose [<span>5</span>], but we established a combined essential gene set incorporating both tissue-agnostic and melanoma-sp","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 6","pages":"709-713"},"PeriodicalIF":20.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646894","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}
Florian Henning Geyer, Alina Ritter, Seneca Kinn-Gurzo, Tobias Faehling, Jing Li, Armin Jarosch, Carine Ngo, Endrit Vinca, Karim Aljakouch, Azhar Orynbek, Shunya Ohmura, Thomas Kirchner, Roland Imle, Laura Romero-Pérez, Juan Díaz-Martín, Stefanie Bertram, Enrique de Álava, Clémence Henon, Sophie Postel-Vilnay, Ana Banito, Martin Sill, Yvonne Versleijen-Jonkers, Benjamin Friedrich Berthold Mayer, Martin Ebinger, Monika Sparber-Sauer, Sabine Stegmaier, Daniel Baumhoer, Wolfgang Hartmann, Jeroen Krijgsveld, David Horst, Olivier Delattre, Patrick Joseph Grohar, Thomas Georg Phillip Grünewald, Florencia Cidre-Aranaz
<p>Desmoplastic small round cell tumor (DSRCT) is an aggressive cancer that predominantly affects adolescents and young adults, typically developing at sites lined by mesothelium [<span>1, 2</span>]. DSRCT is genetically defined by a chromosomal translocation that fuses the N-terminus of EWS RNA binding protein 1 (<i>EWSR1</i>) to the C-terminus of Wilms tumor protein (<i>WT1)</i>, forming EWSR1::WT1 [<span>3</span>]. This fusion encodes a potent transcription factor and is the only known driver of oncogenic transformation in DSRCT [<span>4</span>]. The lack of a comprehensive understanding of DSRCT biology parallels its dismal survival rate (5%-20%) [<span>1</span>]. These challenges are exacerbated by the absence of clinical trials, the limited systematic collection and analysis of DSRCT biomaterial [<span>1</span>], and the notable lack of specific diagnostic markers, necessitating resource-intensive molecular testing for an accurate diagnosis.</p><p>Here we first focused on identifying promising candidates for validation as single, fast, and reliable diagnostic DSRCT markers. For this, we performed differential gene expression (DEG) analysis on datasets comprising patient samples from 32 DSRCT and 20 morphological mimics, identifying 23 genes overexpressed in DSRCT (log<sub>2</sub> fold change (log<sub>2</sub>FC) > 2.5; adjusted <i>P</i>-value (<i>Padj)</i> < 0.01; Figure 1A, Supplementary Figure S1A). Secondly, we analyzed EWSR1::WT1 binding sites derived from chromatin immunoprecipitation followed by sequencing (ChIP-seq) data [<span>5</span>] obtained from the JN-DSRCT-1 cell line, identifying 2,065 genomic loci likely regulated by EWSR1::WT1 (Figure 1A). Third, we established JN-DSRCT-1 and SK-DSRCT2 cell lines expressing doxycycline (DOX)-inducible short hairpin RNA (shRNA)-mediated EWSR1::WT1 knockdown (KD) (Supplementary Figure S1B). Differential protein expression (DEP) analysis of these cells identified 104 proteins consistently regulated across both cell lines (log<sub>2</sub>FC > 1.0 and <i>Padj</i> < 0.01; Figure 1A, Supplementary Table S1). The intersection of these analyses revealed calcium voltage-gated channel auxiliary subunit alpha2delta 2 (CACNA2D2) and IQ motif containing G (IQCG) as potential DSRCT biomarkers (Figure 1A). <i>CACNA2D2</i> was selected for validation due to its significantly higher expression in DSRCTs compared to <i>IQCG</i> (<i>P</i> < 0.001; Figure 1A). Indeed, DSRCT exhibited the highest expression of <i>CACNA2D2</i> among all studied morphological mimics and normal tissues (<i>P <</i> 0.001; Supplementary Figures S1C-D). Further ChIP-seq data and motif analyses of EWSR1::WT1 binding coordinates and histone marks in JN-DSRCT-1 and four DSRCT patient samples [<span>5, 6</span>] suggested a direct regulatory role of EWSR1::WT1 through an enhancer interaction at the <i>CACNA2D2</i> locus (Figure 1B). Notably, KD of EWSR1::WT1 in JN-DSRCT-1 resulted in a loss of the EWSR1::WT1 signal and H
{"title":"Comprehensive DSRCT multi-omics analyses unveil CACNA2D2 as a diagnostic hallmark and super-enhancer-driven EWSR1::WT1 signature gene","authors":"Florian Henning Geyer, Alina Ritter, Seneca Kinn-Gurzo, Tobias Faehling, Jing Li, Armin Jarosch, Carine Ngo, Endrit Vinca, Karim Aljakouch, Azhar Orynbek, Shunya Ohmura, Thomas Kirchner, Roland Imle, Laura Romero-Pérez, Juan Díaz-Martín, Stefanie Bertram, Enrique de Álava, Clémence Henon, Sophie Postel-Vilnay, Ana Banito, Martin Sill, Yvonne Versleijen-Jonkers, Benjamin Friedrich Berthold Mayer, Martin Ebinger, Monika Sparber-Sauer, Sabine Stegmaier, Daniel Baumhoer, Wolfgang Hartmann, Jeroen Krijgsveld, David Horst, Olivier Delattre, Patrick Joseph Grohar, Thomas Georg Phillip Grünewald, Florencia Cidre-Aranaz","doi":"10.1002/cac2.70015","DOIUrl":"10.1002/cac2.70015","url":null,"abstract":"<p>Desmoplastic small round cell tumor (DSRCT) is an aggressive cancer that predominantly affects adolescents and young adults, typically developing at sites lined by mesothelium [<span>1, 2</span>]. DSRCT is genetically defined by a chromosomal translocation that fuses the N-terminus of EWS RNA binding protein 1 (<i>EWSR1</i>) to the C-terminus of Wilms tumor protein (<i>WT1)</i>, forming EWSR1::WT1 [<span>3</span>]. This fusion encodes a potent transcription factor and is the only known driver of oncogenic transformation in DSRCT [<span>4</span>]. The lack of a comprehensive understanding of DSRCT biology parallels its dismal survival rate (5%-20%) [<span>1</span>]. These challenges are exacerbated by the absence of clinical trials, the limited systematic collection and analysis of DSRCT biomaterial [<span>1</span>], and the notable lack of specific diagnostic markers, necessitating resource-intensive molecular testing for an accurate diagnosis.</p><p>Here we first focused on identifying promising candidates for validation as single, fast, and reliable diagnostic DSRCT markers. For this, we performed differential gene expression (DEG) analysis on datasets comprising patient samples from 32 DSRCT and 20 morphological mimics, identifying 23 genes overexpressed in DSRCT (log<sub>2</sub> fold change (log<sub>2</sub>FC) > 2.5; adjusted <i>P</i>-value (<i>Padj)</i> < 0.01; Figure 1A, Supplementary Figure S1A). Secondly, we analyzed EWSR1::WT1 binding sites derived from chromatin immunoprecipitation followed by sequencing (ChIP-seq) data [<span>5</span>] obtained from the JN-DSRCT-1 cell line, identifying 2,065 genomic loci likely regulated by EWSR1::WT1 (Figure 1A). Third, we established JN-DSRCT-1 and SK-DSRCT2 cell lines expressing doxycycline (DOX)-inducible short hairpin RNA (shRNA)-mediated EWSR1::WT1 knockdown (KD) (Supplementary Figure S1B). Differential protein expression (DEP) analysis of these cells identified 104 proteins consistently regulated across both cell lines (log<sub>2</sub>FC > 1.0 and <i>Padj</i> < 0.01; Figure 1A, Supplementary Table S1). The intersection of these analyses revealed calcium voltage-gated channel auxiliary subunit alpha2delta 2 (CACNA2D2) and IQ motif containing G (IQCG) as potential DSRCT biomarkers (Figure 1A). <i>CACNA2D2</i> was selected for validation due to its significantly higher expression in DSRCTs compared to <i>IQCG</i> (<i>P</i> < 0.001; Figure 1A). Indeed, DSRCT exhibited the highest expression of <i>CACNA2D2</i> among all studied morphological mimics and normal tissues (<i>P <</i> 0.001; Supplementary Figures S1C-D). Further ChIP-seq data and motif analyses of EWSR1::WT1 binding coordinates and histone marks in JN-DSRCT-1 and four DSRCT patient samples [<span>5, 6</span>] suggested a direct regulatory role of EWSR1::WT1 through an enhancer interaction at the <i>CACNA2D2</i> locus (Figure 1B). Notably, KD of EWSR1::WT1 in JN-DSRCT-1 resulted in a loss of the EWSR1::WT1 signal and H","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 6","pages":"702-708"},"PeriodicalIF":20.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633515","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}
Glioblastoma (GBM) is largely refractory to antibodies against programmed cell death 1 (anti-PD-1) therapy. Fully understanding the cellular heterogeneity and immune adaptations in response to anti-PD-1 therapy is necessary to design more effective immunotherapies for GBM. This study aimed to dissect the molecular mechanisms of specific immunosuppressive subpopulations to drive anti-PD-1 resistance in GBM.
Methods
We systematically analysed single-cell RNA sequencing and spatial transcriptomics data from GBM tissues receiving anti-PD-1 therapy to characterize the microenvironment alterations. The biological functions of a novel circular RNA (circRNA) were validated both in vitro and in vivo. Mechanically, co-immunoprecipitation, RNA immunoprecipitation and pull-down assays were conducted.
Results
Mesenchymal GBM (MES-GBM) cells, which were associated with a poor prognosis, and secreted phosphoprotein 1 (SPP1)+ myeloid-derived macrophages (SPP1+ MDMs), a unique subpopulation of MDMs with complex functions, preferentially accumulated in non-responders to anti-PD-1 therapy, indicating that MES-GBM cells and SPP1+ MDMs were the main anti-PD-1-resistant cell subpopulations. Functionally, we determined that circular RNA succinate dehydrogenase complex assembly factor 2 (circSDHAF2), which was positively associated with the abundance of these two anti-PD-1-resistant cell subpopulations, facilitated the formation of a regional MES-GBM and SPP1+ MDM cell interaction loop, resulting in a spatially specific adaptive immunosuppressive microenvironment. Mechanically, we found that circSDHAF2 promoted MES-GBM cell formation by stabilizing the integrin alpha 5 (ITGA5) protein through N-glycosylation. Meanwhile, the N-glycosylation of the ITGA5 protein facilitated its translocation into exosomes and subsequent delivery to MDMs to induce the formation of SPP1+ MDMs, which in turn maintained the MES-GBM cell status and induced T-cell dysfunction via the SPP1-ITGA5 pathway, ultimately promoting GBM immune escape. Importantly, our findings demonstrated that antibody-mediated ITGA5 blockade enhanced anti-PD-1-mediated antitumor immunity.
Conclusions
This work elucidated the potential tissue adaptation mechanism of intratumoral dynamic interactions between MES-GBM cells, MDMs and T cells in anti-PD-1 non-responders and identified the therapeutic potential of target
{"title":"Blocking ITGA5 potentiates the efficacy of anti-PD-1 therapy on glioblastoma by remodeling tumor-associated macrophages","authors":"Rongrong Zhao, Ziwen Pan, Jiawei Qiu, Boyan Li, Yanhua Qi, Zijie Gao, Wei Qiu, Weijie Tang, Xiaofan Guo, Lin Deng, Gang Li, Hao Xue","doi":"10.1002/cac2.70016","DOIUrl":"10.1002/cac2.70016","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Glioblastoma (GBM) is largely refractory to antibodies against programmed cell death 1 (anti-PD-1) therapy. Fully understanding the cellular heterogeneity and immune adaptations in response to anti-PD-1 therapy is necessary to design more effective immunotherapies for GBM. This study aimed to dissect the molecular mechanisms of specific immunosuppressive subpopulations to drive anti-PD-1 resistance in GBM.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We systematically analysed single-cell RNA sequencing and spatial transcriptomics data from GBM tissues receiving anti-PD-1 therapy to characterize the microenvironment alterations. The biological functions of a novel circular RNA (circRNA) were validated both in vitro and in vivo. Mechanically, co-immunoprecipitation, RNA immunoprecipitation and pull-down assays were conducted.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Mesenchymal GBM (MES-GBM) cells, which were associated with a poor prognosis, and secreted phosphoprotein 1 (SPP1)<sup>+</sup> myeloid-derived macrophages (SPP1<sup>+</sup> MDMs), a unique subpopulation of MDMs with complex functions, preferentially accumulated in non-responders to anti-PD-1 therapy, indicating that MES-GBM cells and SPP1<sup>+</sup> MDMs were the main anti-PD-1-resistant cell subpopulations. Functionally, we determined that circular RNA succinate dehydrogenase complex assembly factor 2 (circSDHAF2), which was positively associated with the abundance of these two anti-PD-1-resistant cell subpopulations, facilitated the formation of a regional MES-GBM and SPP1<sup>+</sup> MDM cell interaction loop, resulting in a spatially specific adaptive immunosuppressive microenvironment. Mechanically, we found that circSDHAF2 promoted MES-GBM cell formation by stabilizing the integrin alpha 5 (ITGA5) protein through N-glycosylation. Meanwhile, the N-glycosylation of the ITGA5 protein facilitated its translocation into exosomes and subsequent delivery to MDMs to induce the formation of SPP1<sup>+</sup> MDMs, which in turn maintained the MES-GBM cell status and induced T-cell dysfunction via the SPP1-ITGA5 pathway, ultimately promoting GBM immune escape. Importantly, our findings demonstrated that antibody-mediated ITGA5 blockade enhanced anti-PD-1-mediated antitumor immunity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This work elucidated the potential tissue adaptation mechanism of intratumoral dynamic interactions between MES-GBM cells, MDMs and T cells in anti-PD-1 non-responders and identified the therapeutic potential of target","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 6","pages":"677-701"},"PeriodicalIF":20.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623806","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}
Anna Petrackova, Jirina Manakova, Romana Nesnadna, Zuzana Kubova, Tomas Papajik, Eva Kriegova
<p>Chronic lymphocytic leukaemia (CLL) has one of the strongest familial risks of all cancers, as evidenced by the eight-fold increased risk seen in relatives of CLL patients, yet much of the heritable risk remains unexplained [<span>1</span>]. Patients with CLL also have a high rate of secondary cancer, i.e., the development of second primary malignancy, compared to the general population, which may be explained by immune dysregulation due to CLL and/or its treatment, but also by environmental and genetic risk factors [<span>2</span>]. The development of second cancer in patients with CLL contributes to higher morbidity in these patients [<span>2</span>]. As the population of long-term CLL survivors expands due to novel agents used in therapy, the identification of patients with risk of developing the second cancer may help to improve longevity of CLL patients.</p><p>In this monocentric study, we aimed to assess whether patients with CLL carrying rare germline variants in <i>ATM</i> have a higher risk of familial CLL or a higher risk of cancer in first-degree relatives than patients without these variants. Next, we aimed to assess whether patients carrying rare <i>ATM</i> variants develop secondary cancer or develop CLL at an earlier age than patients without these variants, and whether these variants influence the time to first treatment (TTFT) and overall survival (OS) in patients with CLL. In this large cohort, we also sought to confirm our previous observation that rare variants in <i>ATM</i> are associated with the development of IGHV-unmutated CLL [<span>3</span>], which has a worse prognosis compared to IGHV-mutated disease.</p><p>A total of 629 patients with CLL were included in the study with a median follow-up of 6 years (range, 0.08-37.80; Supplementary Materials and Methods, Supplementary Table S1). Ten (1.6%) of these patients carried rare pathogenic (P) or likely pathogenic (LP) variants in <i>ATM</i> and 18 (2.9%) carried rare variant of uncertain significance (VUS) in <i>ATM</i>, all heterozygous (Supplementary Table S2, Figure 1). Patients harbouring P/LP <i>ATM</i> variants had a higher risk of secondary cancer (50.0% of patients; relative risk [RR], 2.88; 95% confidence interval [CI], 1.51-5.47; <i>P</i> = 0.001) than those without these variants (17.0%). Similarly, patients harbouring rare VUSes in <i>ATM</i> had a higher risk of secondary cancer (46.0% of patients; RR, 2.56; 95% CI, 1.48-4.41; <i>P</i> = 0.001) than those without these variants (17.0%). Half (7/14) of patients who carried these germline <i>ATM</i> variants and had secondary cancer were first diagnosed with CLL, while the other half (5/9) were first diagnosed with another malignancy. Secondary cancers were always of a different type, with the exception of prostate cancer, which occurred in 2 patients.</p><p>Regarding age at diagnosis of first malignancy in patients with secondary cancer, there was no significant difference between patients carrying rare P/LP
{"title":"Rare germline ATM variants predispose to secondary cancer in chronic lymphocytic leukaemia patients","authors":"Anna Petrackova, Jirina Manakova, Romana Nesnadna, Zuzana Kubova, Tomas Papajik, Eva Kriegova","doi":"10.1002/cac2.70010","DOIUrl":"10.1002/cac2.70010","url":null,"abstract":"<p>Chronic lymphocytic leukaemia (CLL) has one of the strongest familial risks of all cancers, as evidenced by the eight-fold increased risk seen in relatives of CLL patients, yet much of the heritable risk remains unexplained [<span>1</span>]. Patients with CLL also have a high rate of secondary cancer, i.e., the development of second primary malignancy, compared to the general population, which may be explained by immune dysregulation due to CLL and/or its treatment, but also by environmental and genetic risk factors [<span>2</span>]. The development of second cancer in patients with CLL contributes to higher morbidity in these patients [<span>2</span>]. As the population of long-term CLL survivors expands due to novel agents used in therapy, the identification of patients with risk of developing the second cancer may help to improve longevity of CLL patients.</p><p>In this monocentric study, we aimed to assess whether patients with CLL carrying rare germline variants in <i>ATM</i> have a higher risk of familial CLL or a higher risk of cancer in first-degree relatives than patients without these variants. Next, we aimed to assess whether patients carrying rare <i>ATM</i> variants develop secondary cancer or develop CLL at an earlier age than patients without these variants, and whether these variants influence the time to first treatment (TTFT) and overall survival (OS) in patients with CLL. In this large cohort, we also sought to confirm our previous observation that rare variants in <i>ATM</i> are associated with the development of IGHV-unmutated CLL [<span>3</span>], which has a worse prognosis compared to IGHV-mutated disease.</p><p>A total of 629 patients with CLL were included in the study with a median follow-up of 6 years (range, 0.08-37.80; Supplementary Materials and Methods, Supplementary Table S1). Ten (1.6%) of these patients carried rare pathogenic (P) or likely pathogenic (LP) variants in <i>ATM</i> and 18 (2.9%) carried rare variant of uncertain significance (VUS) in <i>ATM</i>, all heterozygous (Supplementary Table S2, Figure 1). Patients harbouring P/LP <i>ATM</i> variants had a higher risk of secondary cancer (50.0% of patients; relative risk [RR], 2.88; 95% confidence interval [CI], 1.51-5.47; <i>P</i> = 0.001) than those without these variants (17.0%). Similarly, patients harbouring rare VUSes in <i>ATM</i> had a higher risk of secondary cancer (46.0% of patients; RR, 2.56; 95% CI, 1.48-4.41; <i>P</i> = 0.001) than those without these variants (17.0%). Half (7/14) of patients who carried these germline <i>ATM</i> variants and had secondary cancer were first diagnosed with CLL, while the other half (5/9) were first diagnosed with another malignancy. Secondary cancers were always of a different type, with the exception of prostate cancer, which occurred in 2 patients.</p><p>Regarding age at diagnosis of first malignancy in patients with secondary cancer, there was no significant difference between patients carrying rare P/LP ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 6","pages":"669-672"},"PeriodicalIF":20.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603972","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}
<p>Trial eligibility criteria, which define an appropriate evaluable population through inclusion and exclusion criteria, are fundamental for reliable evidence and should be tailored to the question that the trial sets out to answer [<span>1</span>]. However, exclusion criteria for cancer trials have become increasingly restrictive over the years, with the median number increased from 21 in 1986 to 46 in 2016 [<span>2, 3</span>]. These restrictive exclusion criteria have created substantial barriers to patient access to novel therapies, hindered trial recruitment and limited the generalizability of trial results, presenting not only practical and scientific problem, but also raises important issues of equity that affect everyone [<span>4</span>].</p><p>While this longstanding issue has garnered widespread attention in the United States (US), research on the severity of restrictive criteria and efforts to modernize them in China remain scarce [<span>5</span>]. Our limited study revealed that the restriction rate for older patients aged over 75 years in cancer trials in China was 56.5%, which is more than 10 times higher than that of the US [<span>5</span>]. Meanwhile, significant shifts in patterns of exclusion criteria, such as brain metastases from conditionally excluded to not excluded, have been observed in the US since a joint recommendation on broadening cancer eligibility criteria was made in 2017 [<span>6</span>]. The above observations inspire us to understand the potential drivers behind the evolution of overly restrictive exclusion criteria, and provide insights into best practice towards modernizing eligibility criteria in China and beyond.</p><p>Regarding to the evolution of overly restrictive eligibility criteria, several fundamental factors should be emphasized. The fundamental consideration about who should be recruited is the future application of the results. Logically, those eligible for a trial should be those who are deemed beneficial from using the treatment in the future. However, when the approved indications are not impacted, sponsors and researchers tend to exclude weaker patients and recruit healthier ones due to excessive concerns about vulnerable populations and drug risk-benefit profiles. This tendency is evident in the fact that most cancer trials in the US enroll healthier patients, such as those with no brain metastases (77.4%), better performance status (PS) (65%) [<span>7</span>].</p><p>Exclusion criteria are often applied in series, meaning that participants meeting any one of the criteria are eliminated. However, many common criteria, when used alone may not represent manifestations of the underlying malignancy or the potential risk-benefit profiles. For instance, if a therapy does not undergo hepatic metabolism and is not expected to cause hepatic toxicity, strict hepatic function eligibility criteria may not be necessary, or there should be very broad entry criteria. Therefore, it is essential to consider the
{"title":"Reflections and insights into the evolution of restrictive eligibility criteria for cancer clinical trials in China and beyond","authors":"Huiyao Huang, Huilei Miao, Jinling Tang, Ning Li","doi":"10.1002/cac2.70007","DOIUrl":"10.1002/cac2.70007","url":null,"abstract":"<p>Trial eligibility criteria, which define an appropriate evaluable population through inclusion and exclusion criteria, are fundamental for reliable evidence and should be tailored to the question that the trial sets out to answer [<span>1</span>]. However, exclusion criteria for cancer trials have become increasingly restrictive over the years, with the median number increased from 21 in 1986 to 46 in 2016 [<span>2, 3</span>]. These restrictive exclusion criteria have created substantial barriers to patient access to novel therapies, hindered trial recruitment and limited the generalizability of trial results, presenting not only practical and scientific problem, but also raises important issues of equity that affect everyone [<span>4</span>].</p><p>While this longstanding issue has garnered widespread attention in the United States (US), research on the severity of restrictive criteria and efforts to modernize them in China remain scarce [<span>5</span>]. Our limited study revealed that the restriction rate for older patients aged over 75 years in cancer trials in China was 56.5%, which is more than 10 times higher than that of the US [<span>5</span>]. Meanwhile, significant shifts in patterns of exclusion criteria, such as brain metastases from conditionally excluded to not excluded, have been observed in the US since a joint recommendation on broadening cancer eligibility criteria was made in 2017 [<span>6</span>]. The above observations inspire us to understand the potential drivers behind the evolution of overly restrictive exclusion criteria, and provide insights into best practice towards modernizing eligibility criteria in China and beyond.</p><p>Regarding to the evolution of overly restrictive eligibility criteria, several fundamental factors should be emphasized. The fundamental consideration about who should be recruited is the future application of the results. Logically, those eligible for a trial should be those who are deemed beneficial from using the treatment in the future. However, when the approved indications are not impacted, sponsors and researchers tend to exclude weaker patients and recruit healthier ones due to excessive concerns about vulnerable populations and drug risk-benefit profiles. This tendency is evident in the fact that most cancer trials in the US enroll healthier patients, such as those with no brain metastases (77.4%), better performance status (PS) (65%) [<span>7</span>].</p><p>Exclusion criteria are often applied in series, meaning that participants meeting any one of the criteria are eliminated. However, many common criteria, when used alone may not represent manifestations of the underlying malignancy or the potential risk-benefit profiles. For instance, if a therapy does not undergo hepatic metabolism and is not expected to cause hepatic toxicity, strict hepatic function eligibility criteria may not be necessary, or there should be very broad entry criteria. Therefore, it is essential to consider the","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 6","pages":"673-676"},"PeriodicalIF":20.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613073","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}
Katia Mariniello, James F. H. Pittaway, Barbara Altieri, Kleiton Silva Borges, Irene Hadjidemetriou, Claudio Ribeiro, Gerard Ruiz-Babot, David S. Tourigny, Jiang A. Lim, Julie Foster, Julie Cleaver, Jane Sosabowski, Nafis Rahman, Milena Doroszko, Constanze Hantel, Sandra Sigala, Andrea Abate, Mariangela Tamburello, Katja Kiseljak-Vassiliades, Margaret Wierman, Charlotte Hall, Laila Parvanta, Tarek E. Abdel-Aziz, Teng-Teng Chung, Aimee Di Marco, Fausto Palazzo, Celso E. Gomez-Sanchez, David R. Taylor, Oliver Rayner, Cristina L. Ronchi, Carles Gaston-Massuet, Silviu Sbiera, William M. Drake, Emanuel Rognoni, Matthias Kroiss, David T. Breault, Martin Fassnacht, Leonardo Guasti
<p>Adrenocortical carcinoma (ACC) is a rare malignancy with no widely available biomarkers and commonly presents at later stages with a bleak prognosis [<span>1</span>]. Dysregulation of signaling pathways involved in the organogenesis and homeostasis of the adrenal cortex is implicated in its pathogenesis [<span>2</span>]. The paternally expressed, cleavable protein delta-like non-canonical Notch ligand 1 (DLK1) is expressed in rat adrenocortical progenitor cells [<span>3</span>] and in clusters of relatively undifferentiated cells in the human adrenal gland [<span>4</span>]. Its expression is rare in most adult human tissues but has been reported across various cancers, often associated with worse survival [<span>5</span>]. Here we define the role of DLK1 in adrenocortical development, self-renewal, and the development and progression of ACC.</p><p>Dlk1<sup>+</sup> cells were present in both the capsule and cortex during embryonic development but became restricted to the capsule postnatally in both male and female mice (Supplementary Figure S1), with minimal overlap in expression with Axin-2 (Wnt-active) cells, their early descendants, and platelet-derived growth factor receptor alpha (PDGFRα), a marker of mesenchymal stem/fibroblastic cells (Supplementary Figure S2). Dlk1 cells were rarely positive for Ki-67, whereas <i>Gli1</i> expression in the capsule, unlike Dlk1, remained high during development and throughout postnatal life (Supplementary Figure S3). Genetic lineage tracing using inducible <i>Dlk1<sup>CreERT2/+</sup></i>; <i>Rosa<sup>tdTomato/+</sup></i> mice showed that Dlk1<sup>+</sup> cells functioned as adrenocortical stem cells during development (Figure 1A-F), but were largely dormant postnatally and inactive during postnatal adrenocortical remodeling (Supplementary Figure S4).</p><p>Capsular-like cells are pathognomonic of subcapsular hyperplasia (SH), a histological hallmark in mouse adrenals that occurs spontaneously in aged females and in certain strains/transgenic models after gonadectomy (GDX) [<span>6</span>]. SH foci are thought to represent a morphological continuum progressing toward adrenocortical tumors. Dlk1 was not expressed in SH or in subsequent tumors in two GDX mouse models (Supplementary Figure S5). Moreover, spontaneous SH foci in aged mice were neither enriched in nor derived from Dlk1-expressing cells (Supplementary Figure S6), supporting the hypothesis that SH results from a de-differentiation event [<span>7</span>]. Interestingly, Dlk1 was re-expressed in an autochthonous mouse model of ACC, in which concomitant inactivation of <i>Trp53</i> and activation of <i>Ctnnb1</i>, driven by the aldosterone synthase promoter (<i>BPCre</i>) [<span>8</span>], leads to ACC formation with high penetrance. In 23 tumor samples from 17 mice (9 female), Dlk1 expression was low or absent in benign and pre-malignant tumors, moderate in localized ACC, and higher in metastatic disease, both in the primary tumors and in lung meta
这些数据表明，ACC的转移潜力可能受到DLK1水平的影响。对DLK1过表达和低表达的ACC细胞系H295R的RNA测序显示，DLK1的高表达与免疫信号基因集的低表达相关，表明DLK1的致癌作用可能在一定程度上通过与衰老诱导的免疫重塑[9]相关的机制介导（Supplementary Figure S9A-E）。DLK1具有可切割的外结构域，可在血清中检测到。BPCre小鼠（与年龄匹配的对照组相比）和两种皮下肿瘤小鼠模型的血清Dlk1水平显著升高：一种使用BPCre肿瘤来源细胞系BCH-ACC3A[10]，另一种注射H295R细胞（图1N-Q）。在所有病例中，肿瘤大小与血清DLK1水平有很强的正相关（Supplementary Figure S10）。在伦敦队列中，人类ACC患者术前血清DLK1水平明显高于良性肾上腺皮质腺瘤患者，可以以高灵敏度和特异性预测ACC的诊断（图1R-S）。这一发现在德国队列中得到了验证，在疾病负担更重的患者中观察到明显更高的血清DLK1水平（图1T，补充表S4）。与组织中一样，血清DLK1水平与其他预后或临床病理特征无关（补充图S11A-F）。术后血液样本显示肿瘤切除后DLK1水平显著降低（图1U）。两组患者术前血清DLK1水平与组织DLK1表达呈正相关（图1V，补充图S11G）。这些发现表明，血清DLK1来源于ACC，其水平反映了原发肿瘤的DLK1表达和疾病的程度。对四个人类acc的DLK1+和DLK1−区域进行空间全转录组分析。令人惊讶的是，类固醇生物合成是DLK1+组中最富集的基因本体途径，与胆固醇合成基因的上调一致，这表明DLK1+区域比DLK1−区域具有更高的类固醇生成潜力（图1W，补充图S12-S13）。在H295R转录组数据中，随着DLK1剂量的增加，肾上腺分化基因的表达增加，进一步支持了这一发现（补充图S9F-H）。为了进一步研究表达一种肾上腺皮质干细胞标记物的ACC细胞中类固醇生成潜能增强这一明显的悖论，我们将四种不同的人ACC细胞系（H295R、muc1、TVBF7和CU-ACC1）和一种小鼠ACC细胞系（BCH-ACC3A）培养成球体。与2D培养相比，H295R、TVBF7和CU-ACC1在3D培养中DLK1表达显著增强，有趣的是，在MUC-1中观察到DLK1蛋白的从头表达（图1X，补充图S14A-F）。液相色谱串联质谱分析显示，与2D细胞相比，H295R、CU-ACC1和BCH-ACC3A中3D球体的类固醇分泌量明显增加，并且在muc1和TVBF7中有增加类固醇生成的趋势（补充表S5）。荧光激活细胞分选显示，培养21天后，DLK1+细胞产生的集落形成单位明显多于DLK1−群体（图1Y，补充图S14G-H）。这些发现表明，表达真正的肾上腺皮质干细胞标记物的ACC细胞在保留一些祖细胞特征的同时具有优越的类固醇生成潜力，这可能解释了DLK1在ACC中的表达对预后的负面影响。这些数据将Dlk1定义为一种新的肾上腺皮质干细胞/祖细胞标志物，在肾上腺皮质器官发生和恶性肿瘤发展中都有作用。小鼠和人ACC的表达数据表明，DLK1与恶性肿瘤和肿瘤侵袭性增加有关。此外，DLK1有望作为ACC患者的诊断、预后和随访的生物标志物，特别是通过使用台式测定法进行血清测量。考虑到DLK1在这种恶性肿瘤中的优先表达，需要进一步更大规模的前瞻性研究来证实这一作用，并研究DLK1作为ACC的潜在治疗靶点。概念化：Leonardo Guasti， James F.H. Pittaway和Katia Mariniello。研究方法：Leonardo Guasti， James F.H. Pittaway, Katia Mariniello, Barbara Altieri, Irene Hadjidemetriou, Silviu Sbiera, Matthias Kroiss, Martin Fassnacht, William M. Drake， Kleiton Silva Borges和David T. breult。验证：Kleiton Silva Borges， Claudio Ribeiro, Katia Mariniello, James F.H. Pittaway, Barabara Altieri, Jiang A. Lim, David T. breult, David S. Tourigny和Charlotte Hall。形式分析：James F.H. Pittaway, Katia Mariniello， Barbara Altieri和Kleiton Silva Borges。调查：Gerard Ruiz-Babot， Oliver Rayner, David R. Taylor, James F.H. Pittaway, Katia Mariniello, Barbara Altieri, Leonardo Guasti, Silviu Sbiera， Carles Gaston-Massuet和Emanuel Rognoni。资源：Sandra Sigala， Andrea Abate, Mariangela Tamburello, Katja kiseljk - vassiliades, Margaret Wierman, Laila Parvanta, Tarek E. Abdel-Aziz, tenteng - teng Chung, Aimee Di Marco, Fausto Palazzo, Celso E. Gomez-Sanchez, Constanze Hantel, Julie Foster, Julie Cleaver, Jane Sosabowski, Nafis Rahman， Milena Doroszko和Cristina L. Ronchi。数据管理：James F.H. Pittaway， Katia Mariniello和Leonardo Guasti。原稿：James F.H. Pittaway， Katia Mariniello和Leonardo Guasti。写作-评审和编辑：所有作者。监督：Leonardo Guasti， William M. Drake, Martin Fassnacht, Matthias Kroiss, David T. breult项目管理：Leonardo Guasti。作者声明在本文的研究、作者身份和/或发表方面没有潜在的利益冲突。这项工作得到了MRC (MR/X021017/1, MR/S022155/1), BBSRC (BB/V007246/1), Barts Charity (MGU0436), Rosetrees Trust (M355-F1)，圣巴塞洛缪医学院医院信托基金，德国研究基金会（Deutsche Forschungsgemeinschaft, 314061271）和美国国立卫生研究院医师-科学家职业发展奖（R01DK123694）的支持。在获得参与者的书面知情同意后，根据研究方案内分泌肿瘤遗传学（REC: 06/Q0104/133），从伦敦圣巴塞洛缪大学学
{"title":"Dlk1 is a novel adrenocortical stem/progenitor cell marker that predicts malignancy in adrenocortical carcinoma","authors":"Katia Mariniello, James F. H. Pittaway, Barbara Altieri, Kleiton Silva Borges, Irene Hadjidemetriou, Claudio Ribeiro, Gerard Ruiz-Babot, David S. Tourigny, Jiang A. Lim, Julie Foster, Julie Cleaver, Jane Sosabowski, Nafis Rahman, Milena Doroszko, Constanze Hantel, Sandra Sigala, Andrea Abate, Mariangela Tamburello, Katja Kiseljak-Vassiliades, Margaret Wierman, Charlotte Hall, Laila Parvanta, Tarek E. Abdel-Aziz, Teng-Teng Chung, Aimee Di Marco, Fausto Palazzo, Celso E. Gomez-Sanchez, David R. Taylor, Oliver Rayner, Cristina L. Ronchi, Carles Gaston-Massuet, Silviu Sbiera, William M. Drake, Emanuel Rognoni, Matthias Kroiss, David T. Breault, Martin Fassnacht, Leonardo Guasti","doi":"10.1002/cac2.70012","DOIUrl":"10.1002/cac2.70012","url":null,"abstract":"<p>Adrenocortical carcinoma (ACC) is a rare malignancy with no widely available biomarkers and commonly presents at later stages with a bleak prognosis [<span>1</span>]. Dysregulation of signaling pathways involved in the organogenesis and homeostasis of the adrenal cortex is implicated in its pathogenesis [<span>2</span>]. The paternally expressed, cleavable protein delta-like non-canonical Notch ligand 1 (DLK1) is expressed in rat adrenocortical progenitor cells [<span>3</span>] and in clusters of relatively undifferentiated cells in the human adrenal gland [<span>4</span>]. Its expression is rare in most adult human tissues but has been reported across various cancers, often associated with worse survival [<span>5</span>]. Here we define the role of DLK1 in adrenocortical development, self-renewal, and the development and progression of ACC.</p><p>Dlk1<sup>+</sup> cells were present in both the capsule and cortex during embryonic development but became restricted to the capsule postnatally in both male and female mice (Supplementary Figure S1), with minimal overlap in expression with Axin-2 (Wnt-active) cells, their early descendants, and platelet-derived growth factor receptor alpha (PDGFRα), a marker of mesenchymal stem/fibroblastic cells (Supplementary Figure S2). Dlk1 cells were rarely positive for Ki-67, whereas <i>Gli1</i> expression in the capsule, unlike Dlk1, remained high during development and throughout postnatal life (Supplementary Figure S3). Genetic lineage tracing using inducible <i>Dlk1<sup>CreERT2/+</sup></i>; <i>Rosa<sup>tdTomato/+</sup></i> mice showed that Dlk1<sup>+</sup> cells functioned as adrenocortical stem cells during development (Figure 1A-F), but were largely dormant postnatally and inactive during postnatal adrenocortical remodeling (Supplementary Figure S4).</p><p>Capsular-like cells are pathognomonic of subcapsular hyperplasia (SH), a histological hallmark in mouse adrenals that occurs spontaneously in aged females and in certain strains/transgenic models after gonadectomy (GDX) [<span>6</span>]. SH foci are thought to represent a morphological continuum progressing toward adrenocortical tumors. Dlk1 was not expressed in SH or in subsequent tumors in two GDX mouse models (Supplementary Figure S5). Moreover, spontaneous SH foci in aged mice were neither enriched in nor derived from Dlk1-expressing cells (Supplementary Figure S6), supporting the hypothesis that SH results from a de-differentiation event [<span>7</span>]. Interestingly, Dlk1 was re-expressed in an autochthonous mouse model of ACC, in which concomitant inactivation of <i>Trp53</i> and activation of <i>Ctnnb1</i>, driven by the aldosterone synthase promoter (<i>BPCre</i>) [<span>8</span>], leads to ACC formation with high penetrance. In 23 tumor samples from 17 mice (9 female), Dlk1 expression was low or absent in benign and pre-malignant tumors, moderate in localized ACC, and higher in metastatic disease, both in the primary tumors and in lung meta","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 6","pages":"663-668"},"PeriodicalIF":20.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540150","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}
Chiwook Chung, Dong Wook Shin, Kyu Na Lee, Sei Won Lee, Kyungdo Han
<p>Low socioeconomic conditions, including low education, low income, manual or unskilled work, and unemployment, have been associated with increased lung cancer risks [<span>1, 2</span>]. Although some studies have identified low household status as a risk factor for lung cancer, they had some limitations in terms of their study design, including limited covariates in multivariate models, and cross-sectional assessment of income status, thereby failing to describe the association between income status change over time and lung cancer [<span>1, 2</span>]. Therefore, we investigated the association between longitudinal low household income status and lung cancer in the South Korean general population. We collected information on income status for 5 years to determine the change in household income status and income volatility. We also designed multivariate regression models with covariates including demographics, lifestyle behaviors, and comorbidities. Consequently, this study investigated the relationship between economic vulnerability, such as income volatility, and lung cancer risk.</p><p>We sampled 40% (4,910,068) of individuals who underwent a national health examination in 2012 (the index year). Among them, we included 3,816,680 individuals aged 30-65 years (economically active population). Thereafter, we excluded individuals with insufficient income information, identified with any cancer (any insurance claim with the International Classification of Diseases 10th Revision [ICD-10] codes for cancer [C00-97] and the critical illness registration code for cancer [V193]) before their health examination (all cancer wash-out), with insufficient medical records, and identified with any cancer within 1 year after the index date (1-year lag period, to exclude over-detection of cancer after the health examination). Finally, the remaining 3,361,091 eligible individuals started follow-up 1 year after the index date, until December 2022. The follow-up was terminated upon lung cancer development, death, or censor.</p><p>Lung cancer was identified using the ICD-10 code (C33 and C34) and matched with the critical illness registration program code (V193). The household income level was estimated based on subscribers’ monthly national health insurance premium, which is a proxy for household income. We categorized household income into quartiles (Q1 = lowest and Q4 = highest). Individuals receiving medical aid benefits (public assistance, the lowest 3% income) were assessed as a separate income category. To evaluate the temporal changes in household income status, we evaluated (1) cumulative number of years receiving medical aid (sustained low-income status) and (2) income volatility, defined as the intraindividual standard deviation (SD) of the percentage change in income (Q1 = the lowest and Q4 = the highest, Supplementary Figure S1), predicts income uncertainty and may limit health behaviors.</p><p>Covariates were collected from the health examination and
低社会经济条件，包括低教育、低收入、体力或非技术工作以及失业，与肺癌风险增加有关[1,2]。虽然一些研究已经确定低家庭状况是肺癌的危险因素，但在研究设计上存在一定的局限性，包括多变量模型协变量有限，收入状况的横断面评估，因此未能描述收入状况随时间变化与肺癌之间的关系[1,2]。因此，我们调查了韩国普通人群中纵向低收入家庭状况与肺癌之间的关系。我们收集了5年的收入状况信息，以确定家庭收入状况的变化和收入波动性。我们还设计了包含人口统计学、生活方式行为和合并症等协变量的多元回归模型。因此，本研究调查了经济脆弱性（如收入波动）与肺癌风险之间的关系。我们对2012年（指标年）接受国家健康检查的40%（4,910,068）个人进行了抽样调查。其中，我们纳入了3816680名年龄在30-65岁（经济活动人口）的个人。之后，我们排除了收入信息不充分的个体，排除了在健康检查前被诊断为任何癌症（任何使用国际疾病分类第十版[ICD-10]癌症代码[C00-97]和癌症重病登记代码[V193]的保险索赔）的个体（所有癌症冲洗），排除了医疗记录不充分的个体，排除了在索引日期后1年内被诊断为任何癌症的个体（1年滞后期）。排除健康检查后过度发现癌症的可能性。最后，剩余的3361091名符合条件的个人在指数日期一年后开始随访，直到2022年12月。随访在肺癌发展、死亡或检查结束。使用ICD-10代码（C33和C34）识别肺癌，并与危重疾病登记程序代码（V193）匹配。家庭收入是根据代表家庭收入的每月国民健康保险费来推算的。我们将家庭收入分成四分位数（Q1 =最低，Q4 =最高）。接受医疗援助福利（公共援助，收入最低的3%）的个人作为一个单独的收入类别进行评估。为了评估家庭收入状况的时间变化，我们评估了(1)接受医疗援助的累计年数（持续低收入状态）和(2)收入波动性，定义为收入百分比变化的个体内标准差（SD） （Q1 =最低，Q4 =最高，补充图S1），预测收入不确定性并可能限制健康行为。从健康检查和保险索赔数据中收集协变量，包括年龄、性别、地区、体重指数、吸烟、饮酒、定期运动、糖尿病、高血压、血脂异常和慢性肾病。数据来源和统计分析见补充资料和方法。在平均9.28±0.78年的随访期间，我们的队列中发现了20,692例新发肺癌患者。参与者平均年龄46.9±9.4岁，男性占56.5%。医疗援助受益人主要是女性（59.0%）和从不吸烟（63.9%），而最高收入群体（Q4）主要是男性（65.5%）和有吸烟史(前者，21.8%；目前，25.6%，补充表S1)。表1给出了家庭收入与肺癌之间的关系。与基线收入状况相比，医疗援助受益人患肺癌的风险最高(调整风险比[aHR]， 1.23；95%可信区间[CI]， 1.12-1.36)。收入越低，患肺癌的风险越高。就持续低收入状况而言，连续5年的医疗援助受益人患肺癌的风险最高(aHR, 1.19；95% ci, 1.07-1.34)。在收入波动方面，收入波动最大的个体（Q4）患肺癌的风险最高(aHR, 1.08；95% ci, 1.04-1.12)。Kaplan-Meier分析显示，肺癌的累积发病率随着经济脆弱性的增加而增加（补充图S2）。在吸烟状况的分层分析中，目前吸烟者患肺癌的风险大约是从不吸烟者或曾经吸烟者的两倍。收入状况与肺癌风险之间的相关性在当前吸烟者中显著，但在从不吸烟者或曾经吸烟者中不显著（补充表S2）。 按年龄分层分析发现，低收入的影响在年龄较大的个体中更为突出。而收入波动的影响在45-55岁的个体中更为突出（补充表S3）。先前的研究已将低收入家庭与肺癌风险增加联系起来[1,2]。在我们的数据中，即使在吸烟调整后，基线低收入和持续低收入都与肺癌风险增加有关。经济脆弱性与肺癌的其他潜在社会经济风险因素有关，包括饮酒和吸烟，这些因素与经济状况不佳导致的情绪压力有关[3,4]。然而，医疗援助受益人中从不吸烟和不饮酒的比例较高。低收入还与空气污染有关，如生物质燃料和环境颗粒物[5]。此外，低收入与不太健康的食物（例如，较少的蔬菜和更多的冷冻甜点）有关。低收入与焦虑和抑郁有关，这可能会加剧经济状况的恶性循环。更重要的是，我们的研究结果表明，收入波动也与肺癌风险增加有关。收入波动最大的个人中，几乎有一半被归类为基线低收入类别(医疗援助，1.6%；第一季度，43.7%)，从而在纵向方面支持经济脆弱性。对于流动性受限的家庭，在24个月内，收入波动性每增加一个标准差，就会导致健康状况恶化的可能性增加1.3%-4.3%。收入波动与健康状况不佳有关，比如抑郁症。此外，心理压力可能导致频繁或大量吸烟和饮酒。家庭收入与肺癌风险之间的关系在当前吸烟者中比从不吸烟者或曾经吸烟者中更为突出。吸烟是肺癌的最重要原因，与其他潜在的肺癌风险因素（如酒精、饮食、职业暴露和空气污染）具有协同效应，这些因素与社会经济地位低下有关，可以通过社会支持计划加以改变[10]。本研究有一定的局限性。首先，订户的国民健康保险费是估算家庭收入的一个代理，而健康保险费的确定因就业类型（雇员投保和自雇）而异，这可能导致收入估算不准确。第二，家庭收入的损失可能反映了先前不良的健康状况（反向因果关系），这可能减轻收入对肺癌的影响。第三，在健康检查中自愿参与和自我报告的问卷回答（特别是关于吸烟和饮酒）可能导致选择偏倚或回忆偏倚。第四，关于潜在风险因素的信息有限，包括空气污染、职业暴露、二手烟和其他与经济脆弱性相关的健康行为。总之，低收入地位，特别是持续低收入和收入不稳定，与肺癌发展风险增加呈剂量反应关系。这些关联在当前吸烟者中更为突出。我们的数据要求公众了解针对经济弱势群体的国家医疗保健政策（例如肺癌筛查或戒烟计划）。社会安全网和稳定的就业机会可以帮助经济弱势群体。Chiwook Chung、Dong Wook Shin、Kyu Na Lee、Sei Won Lee和Kyungdo Han构思并设计了这项研究。Kyu Na Lee和Kyungdo Han对数据收集和分析做出了贡献。这些数据由Chiwook Chung、Dong Wook Shin、Kyu Na Lee、Sei Won Lee和Kyungdo Han负责解释。Chung Chiwook和Dong Wook Shin起草了手稿。所有作者都修改并批准了最终稿件。所有作者对最终稿件内容的准确性负责。作者声明，这项研究是在没有任何商业或财务关系的情况下进行的，这可能被解释为潜在的利益冲突。资助者在研究的设计、数据的收集、分析和解释以及撰写手稿方面没有任何作用。本研究由韩国国家研究基金会（NRF）资助，由韩国政府（MSIT）资助(No。RS-2023-NR077159)，韩国政府资助的国家研究基金（NRF）生物医疗技术发展计划（MSIT） （No. 1）；RS-2022-NR067421RS-2023-00222687)，“美国国立卫生研究院”（NIH）研究项目(编号：
{"title":"Low household income and income volatility increase risk of lung cancer: A nationwide retrospective cohort study","authors":"Chiwook Chung, Dong Wook Shin, Kyu Na Lee, Sei Won Lee, Kyungdo Han","doi":"10.1002/cac2.70011","DOIUrl":"10.1002/cac2.70011","url":null,"abstract":"<p>Low socioeconomic conditions, including low education, low income, manual or unskilled work, and unemployment, have been associated with increased lung cancer risks [<span>1, 2</span>]. Although some studies have identified low household status as a risk factor for lung cancer, they had some limitations in terms of their study design, including limited covariates in multivariate models, and cross-sectional assessment of income status, thereby failing to describe the association between income status change over time and lung cancer [<span>1, 2</span>]. Therefore, we investigated the association between longitudinal low household income status and lung cancer in the South Korean general population. We collected information on income status for 5 years to determine the change in household income status and income volatility. We also designed multivariate regression models with covariates including demographics, lifestyle behaviors, and comorbidities. Consequently, this study investigated the relationship between economic vulnerability, such as income volatility, and lung cancer risk.</p><p>We sampled 40% (4,910,068) of individuals who underwent a national health examination in 2012 (the index year). Among them, we included 3,816,680 individuals aged 30-65 years (economically active population). Thereafter, we excluded individuals with insufficient income information, identified with any cancer (any insurance claim with the International Classification of Diseases 10th Revision [ICD-10] codes for cancer [C00-97] and the critical illness registration code for cancer [V193]) before their health examination (all cancer wash-out), with insufficient medical records, and identified with any cancer within 1 year after the index date (1-year lag period, to exclude over-detection of cancer after the health examination). Finally, the remaining 3,361,091 eligible individuals started follow-up 1 year after the index date, until December 2022. The follow-up was terminated upon lung cancer development, death, or censor.</p><p>Lung cancer was identified using the ICD-10 code (C33 and C34) and matched with the critical illness registration program code (V193). The household income level was estimated based on subscribers’ monthly national health insurance premium, which is a proxy for household income. We categorized household income into quartiles (Q1 = lowest and Q4 = highest). Individuals receiving medical aid benefits (public assistance, the lowest 3% income) were assessed as a separate income category. To evaluate the temporal changes in household income status, we evaluated (1) cumulative number of years receiving medical aid (sustained low-income status) and (2) income volatility, defined as the intraindividual standard deviation (SD) of the percentage change in income (Q1 = the lowest and Q4 = the highest, Supplementary Figure S1), predicts income uncertainty and may limit health behaviors.</p><p>Covariates were collected from the health examination and ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 6","pages":"654-657"},"PeriodicalIF":20.1,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522629","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}
Pojsakorn Danpanichkul, Yanfang Pang, Torlap Inkongngam, Kornnatthanai Namsathimaphorn, Krittameth Rakwong, Chuthathip Kaeosri, Benjamin Nah, Kwanjit Duangsonk, Nicole Shu Ying Tang, Neha Mittal, Donghee Kim, Mazen Noureddin, Michael B. Wallace, Amit G. Singal, Karn Wijarnpreecha, Ju Dong Yang
<p>The global average life expectancy is projected to rise to 80 years by 2040 [<span>1</span>]. Since cancer is closely linked to aging, its prevalence is expected to grow as the population ages. Advancements in cancer diagnosis and treatment have led to an increasing number of cancer survivors. In a 2021 consensus statement, the International Society for Geriatric Oncology updated its top priorities for improving care for older cancer patients [<span>2, 3</span>]. According to the Global Burden of Disease (GBD) study, there were over four million deaths from gastrointestinal (GI) cancer in 2021 [<span>4</span>].</p><p>The aging population, advancements in cancer management, and shifting risk factors are undoubtedly influencing the prevalence of GI cancers in older adults [<span>5</span>]. While aging has increasingly captured the attention of policymakers and stakeholders, epidemiological data on GI cancers in older adults remains limited. Older patients are also underrepresented in GI-specific clinical trials. This study aimed to estimate the global burden of GI cancers in older adults using the most recent GBD 2021 [<span>6</span>].</p><p>The general methods used for estimating disease burden in the GBD 2021 study, including GI cancer, have been detailed in previous publications [<span>4, 6</span>]. Briefly, data were sourced from population-based cancer registries, vital registration systems, and verbal autopsy studies (Supplementary Information S1). This GBD database defines older adults as individuals aged 70 and above. The GBD 2021 study utilized the International Classification of Disease-Tenth and Ninth Revision for GI cancers. We assessed the burden of various GI cancers in older adults, including colorectal, esophageal, liver, biliary tract, pancreatic, and gastric cancers. For liver cancer, we further analyzed the burden by five main etiologies: alcohol, chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, metabolic dysfunction-associated steatohepatitis (MASH), and other causes. Several statistical methods were applied to ensure data consistency, including misclassification correction, garbage code redistribution, and noise reduction algorithms. Mortality rates were evaluated using the Cause of Death Ensemble model (CODEm), which employed Bayesian geospatial regression to account for spatial relationships in the data. The detailed CODEm methodology is listed in Supplementary Information S1. Countries were classified based on their level of development using the sociodemographic index (SDI) (Supplementary Information S2).</p><p>The incidence, prevalence, and disability-adjusted life years (DALYs) (i.e., years of life lost plus years lost due to disability) estimates were reported with a 95% uncertainty interval (UI), calculated as the 2.5th and 97.5th percentiles from a posterior distribution of 1,000 draws. Broader UIs indicate higher uncertainty, typically resulting from limited or lower-quality dat
{"title":"Older adults living with gastrointestinal cancers in 2021","authors":"Pojsakorn Danpanichkul, Yanfang Pang, Torlap Inkongngam, Kornnatthanai Namsathimaphorn, Krittameth Rakwong, Chuthathip Kaeosri, Benjamin Nah, Kwanjit Duangsonk, Nicole Shu Ying Tang, Neha Mittal, Donghee Kim, Mazen Noureddin, Michael B. Wallace, Amit G. Singal, Karn Wijarnpreecha, Ju Dong Yang","doi":"10.1002/cac2.70014","DOIUrl":"10.1002/cac2.70014","url":null,"abstract":"<p>The global average life expectancy is projected to rise to 80 years by 2040 [<span>1</span>]. Since cancer is closely linked to aging, its prevalence is expected to grow as the population ages. Advancements in cancer diagnosis and treatment have led to an increasing number of cancer survivors. In a 2021 consensus statement, the International Society for Geriatric Oncology updated its top priorities for improving care for older cancer patients [<span>2, 3</span>]. According to the Global Burden of Disease (GBD) study, there were over four million deaths from gastrointestinal (GI) cancer in 2021 [<span>4</span>].</p><p>The aging population, advancements in cancer management, and shifting risk factors are undoubtedly influencing the prevalence of GI cancers in older adults [<span>5</span>]. While aging has increasingly captured the attention of policymakers and stakeholders, epidemiological data on GI cancers in older adults remains limited. Older patients are also underrepresented in GI-specific clinical trials. This study aimed to estimate the global burden of GI cancers in older adults using the most recent GBD 2021 [<span>6</span>].</p><p>The general methods used for estimating disease burden in the GBD 2021 study, including GI cancer, have been detailed in previous publications [<span>4, 6</span>]. Briefly, data were sourced from population-based cancer registries, vital registration systems, and verbal autopsy studies (Supplementary Information S1). This GBD database defines older adults as individuals aged 70 and above. The GBD 2021 study utilized the International Classification of Disease-Tenth and Ninth Revision for GI cancers. We assessed the burden of various GI cancers in older adults, including colorectal, esophageal, liver, biliary tract, pancreatic, and gastric cancers. For liver cancer, we further analyzed the burden by five main etiologies: alcohol, chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, metabolic dysfunction-associated steatohepatitis (MASH), and other causes. Several statistical methods were applied to ensure data consistency, including misclassification correction, garbage code redistribution, and noise reduction algorithms. Mortality rates were evaluated using the Cause of Death Ensemble model (CODEm), which employed Bayesian geospatial regression to account for spatial relationships in the data. The detailed CODEm methodology is listed in Supplementary Information S1. Countries were classified based on their level of development using the sociodemographic index (SDI) (Supplementary Information S2).</p><p>The incidence, prevalence, and disability-adjusted life years (DALYs) (i.e., years of life lost plus years lost due to disability) estimates were reported with a 95% uncertainty interval (UI), calculated as the 2.5th and 97.5th percentiles from a posterior distribution of 1,000 draws. Broader UIs indicate higher uncertainty, typically resulting from limited or lower-quality dat","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 6","pages":"658-662"},"PeriodicalIF":20.1,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522631","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}
Bireociclib (XZP-3287) is a novel selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, with a favorable safety profile demonstrated in preclinical and phase I studies. BRIGHT-1 aimed to further explore the efficacy and safety of bireociclib monotherapy in patients with locally advanced, recurrent or metastatic, hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer who had progressed on or after prior chemotherapy and endocrine therapy in advanced settings, without previous exposure to CDK4/6 inhibitors.
Methods
In this open-label phase II trial, eligible patients received bireociclib 480 mg twice daily (BID) until disease progression or intolerable toxicities. The primary endpoint was the confirmed objective response rate (ORR) assessed by an independent review committee (IRC). The secondary endpoints included progression-free survival (PFS), investigator-assessed ORR, disease control rate (DCR), clinical benefit rate (CBR), duration of response (DoR), overall survival (OS), safety and the pharmacokinetic properties of bireociclib.
Results
A total of 131 patients were enrolled. At data cutoff (July 31, 2023), the IRC-assessed ORR was 29.8% (95% confidence interval [CI], 22.1% to 38.4%), with a DCR of 73.3% (95% CI, 64.8% to 80.6%), CBR of 42.0% (95% CI, 33.4% to 50.9%) and a median DoR of 15.2 months (95% CI, 9.5 months to not reached). The median PFS was 11.0 months (95% CI, 7.3 months to 12.9 months) assessed by the IRC, and the median OS was 29.0 months (95% CI, 24.9 months to not reached). The most frequently reported treatment-emergent adverse events (TEAEs) of any grade were diarrhea (93.1%), neutrophil count decreased (87.0%), white blood cell decreased (86.3%), vomiting (78.6%), anemia (72.5%), and platelet count decreased (72.5%). The grade ≥3 TEAEs occurred in 109 (83.2%) patients. The most common grade ≥3 TEAEs were neutrophil count decreased (43.5%), white blood cell decreased (32.8%), hypokalemia (20.6%), and diarrhea (19.1%).
Conclusions
Bireociclib monotherapy at 480 mg BID exhibited promising and sustained clinical activity, with no unexpected and acceptable toxicity in patients with recurrent or metastatic HR+/HER2− breast cancer who had progressed on or after previous therapy.
{"title":"An open-label, single-arm, multicenter, phase II trial of bireociclib as monotherapy for heavily pretreated HR-positive, HER2-negative advanced breast cancer patients: BRIGHT-1 trial","authors":"Jiayu Wang, Qingyuan Zhang, Tao Sun, Huiping Li, Ying Cheng, Zhongsheng Tong, Huihui Li, Wei Li, Jingfen Wang, Yuee Teng, Xinhong Wu, Jing Cheng, Zhendong Chen, Zhengqiu Zhu, Li Wang, Mingming Liu, Xianghui Duan, Lingmei Xu, Binghe Xu","doi":"10.1002/cac2.70009","DOIUrl":"10.1002/cac2.70009","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Bireociclib (XZP-3287) is a novel selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, with a favorable safety profile demonstrated in preclinical and phase I studies. BRIGHT-1 aimed to further explore the efficacy and safety of bireociclib monotherapy in patients with locally advanced, recurrent or metastatic, hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR<sup>+</sup>/HER2<sup>−</sup>) breast cancer who had progressed on or after prior chemotherapy and endocrine therapy in advanced settings, without previous exposure to CDK4/6 inhibitors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this open-label phase II trial, eligible patients received bireociclib 480 mg twice daily (BID) until disease progression or intolerable toxicities. The primary endpoint was the confirmed objective response rate (ORR) assessed by an independent review committee (IRC). The secondary endpoints included progression-free survival (PFS), investigator-assessed ORR, disease control rate (DCR), clinical benefit rate (CBR), duration of response (DoR), overall survival (OS), safety and the pharmacokinetic properties of bireociclib.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 131 patients were enrolled. At data cutoff (July 31, 2023), the IRC-assessed ORR was 29.8% (95% confidence interval [CI], 22.1% to 38.4%), with a DCR of 73.3% (95% CI, 64.8% to 80.6%), CBR of 42.0% (95% CI, 33.4% to 50.9%) and a median DoR of 15.2 months (95% CI, 9.5 months to not reached). The median PFS was 11.0 months (95% CI, 7.3 months to 12.9 months) assessed by the IRC, and the median OS was 29.0 months (95% CI, 24.9 months to not reached). The most frequently reported treatment-emergent adverse events (TEAEs) of any grade were diarrhea (93.1%), neutrophil count decreased (87.0%), white blood cell decreased (86.3%), vomiting (78.6%), anemia (72.5%), and platelet count decreased (72.5%). The grade ≥3 TEAEs occurred in 109 (83.2%) patients. The most common grade ≥3 TEAEs were neutrophil count decreased (43.5%), white blood cell decreased (32.8%), hypokalemia (20.6%), and diarrhea (19.1%).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Bireociclib monotherapy at 480 mg BID exhibited promising and sustained clinical activity, with no unexpected and acceptable toxicity in patients with recurrent or metastatic HR<sup>+</sup>/HER2<sup>−</sup> breast cancer who had progressed on or after previous therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 6","pages":"640-653"},"PeriodicalIF":20.1,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514744","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}
Head and neck squamous cell carcinoma (HNSCC) continues to be a major global health challenge, with limited survival improvements for patients with locally advanced (LA) or recurrent (R) disease [1]. Anlotinib, a novel orally administered small-molecule tyrosine kinase inhibitor (TKI) developed in China, targets a wide range of receptor tyrosine kinases (RTKs) [2]. Our previous studies have also manifested that anlotinib remarkably inhibited the proliferation of HNSCC cells both in vitro and in vivo, and presented promising clinical antitumor efficacy and tolerable safety profile in patients with oral squamous cell carcinoma (OSCC) [3, 4]. This prospective trial was designed to evaluate the clinical efficacy and safety of anlotinib combined with paclitaxel and cisplatin (TP) neoadjuvant therapy in patients with resectable HNSCC. Additionally, the mechanisms underlying the effects of anlotinib and neoadjuvant chemotherapy on HNSCC were investigated through spatial transcriptomics (STs) and multiplex immunohistochemistry (mIHC).
Between October 2022 and May 2023, 20 resectable HNSCC patients were enrolled (median age, 55; range, 27-73). Baseline demographics and disease characteristics are detailed in Supplementary Tables S1-S2. All patients received 3 cycles of neoadjuvant therapy, followed by surgery in 17 and maintenance therapy in 16. No patients were lost to follow-up (study flowchart in Figure 1A). After neoadjuvant therapy, 95.0% (19/20) achieved partial response (PR), and 5.0% (1/20) achieved complete response (CR), with an Objective response rate (ORR) of 100% (95% confidence interval [CI], 83.2-100). Figure 1B shows the waterfall plot of tumor size changes. Surgical resection was performed in 17 patients (LA, 12; R, 5) with a 100% R0 resection rate, one patient declined surgery due to financial constraints and the other two did not want to perform surgery as their tumors had almost regressed. Postoperative pathological efficacy (Supplementary Table S3) showed pathological complete response (pCR) and major pathological response (MPR) in 7 patients each (41.2%; 95% CI, 18.4-67.1). Among 11 with positive cervical lymph nodes, 6 achieved pCR (54.5%; 95% CI, 23.4-83.3). Imaging and pathological data of patient #14 with CR are shown in Figure 1C-D.
All patients were followed for at least one year. Treatment responses and durations are shown in Figure 1E. By May 15, 2024, 17 out of 20 patients were alive. Of the 3 deaths, 1 patient with LA declined further therapy for financial constraints after neoadjuvant treatment and died a year later, another patient with LA refused maintenance therapy after surgery and died within a year, while one patient with LA died in a traffic accident four months post-radiotherapy. Among the all 20 patients, 5 (4 with LA and 1 with R) experienced local recurrence within 1 year. Of the 17 patients with R0 resection, 4 (3 with LA and 1 with R) had a local recurrence
{"title":"Neoadjuvant chemotherapy plus anlotinib in the treatment of resectable head and neck squamous cell carcinoma: A pilot phase II trial","authors":"Qianting He, Shuojin Huang, Dongxiao Tang, Congyuan Cao, Wanhang Zhou, Rongsong Ling, Jie Chen, Bokai Yun, Xin Zheng, Yanchen Li, Anxun Wang, Demeng Chen","doi":"10.1002/cac2.70006","DOIUrl":"10.1002/cac2.70006","url":null,"abstract":"<p>Head and neck squamous cell carcinoma (HNSCC) continues to be a major global health challenge, with limited survival improvements for patients with locally advanced (LA) or recurrent (R) disease [<span>1</span>]. Anlotinib, a novel orally administered small-molecule tyrosine kinase inhibitor (TKI) developed in China, targets a wide range of receptor tyrosine kinases (RTKs) [<span>2</span>]. Our previous studies have also manifested that anlotinib remarkably inhibited the proliferation of HNSCC cells both in vitro and in vivo, and presented promising clinical antitumor efficacy and tolerable safety profile in patients with oral squamous cell carcinoma (OSCC) [<span>3, 4</span>]. This prospective trial was designed to evaluate the clinical efficacy and safety of anlotinib combined with paclitaxel and cisplatin (TP) neoadjuvant therapy in patients with resectable HNSCC. Additionally, the mechanisms underlying the effects of anlotinib and neoadjuvant chemotherapy on HNSCC were investigated through spatial transcriptomics (STs) and multiplex immunohistochemistry (mIHC).</p><p>Between October 2022 and May 2023, 20 resectable HNSCC patients were enrolled (median age, 55; range, 27-73). Baseline demographics and disease characteristics are detailed in Supplementary Tables S1-S2. All patients received 3 cycles of neoadjuvant therapy, followed by surgery in 17 and maintenance therapy in 16. No patients were lost to follow-up (study flowchart in Figure 1A). After neoadjuvant therapy, 95.0% (19/20) achieved partial response (PR), and 5.0% (1/20) achieved complete response (CR), with an Objective response rate (ORR) of 100% (95% confidence interval [CI], 83.2-100). Figure 1B shows the waterfall plot of tumor size changes. Surgical resection was performed in 17 patients (LA, 12; R, 5) with a 100% R0 resection rate, one patient declined surgery due to financial constraints and the other two did not want to perform surgery as their tumors had almost regressed. Postoperative pathological efficacy (Supplementary Table S3) showed pathological complete response (pCR) and major pathological response (MPR) in 7 patients each (41.2%; 95% CI, 18.4-67.1). Among 11 with positive cervical lymph nodes, 6 achieved pCR (54.5%; 95% CI, 23.4-83.3). Imaging and pathological data of patient #14 with CR are shown in Figure 1C-D.</p><p>All patients were followed for at least one year. Treatment responses and durations are shown in Figure 1E. By May 15, 2024, 17 out of 20 patients were alive. Of the 3 deaths, 1 patient with LA declined further therapy for financial constraints after neoadjuvant treatment and died a year later, another patient with LA refused maintenance therapy after surgery and died within a year, while one patient with LA died in a traffic accident four months post-radiotherapy. Among the all 20 patients, 5 (4 with LA and 1 with R) experienced local recurrence within 1 year. Of the 17 patients with R0 resection, 4 (3 with LA and 1 with R) had a local recurrence","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 5","pages":"632-636"},"PeriodicalIF":20.1,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457004","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}
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