Pub Date : 2026-03-01Epub Date: 2026-01-19DOI: 10.1016/j.esmogo.2025.100295
D. Ciardiello , L. Boscolo Bielo , S. Napolitano , E. Martinelli , T. Troiani , E. Cioli , T.P. Latiano , E. Maiello , P. Parente , A. Avallone , A. De Stefano , R. Bordonaro , A.E. Russo , C. Lotesoriere , S. Vallarelli , S. Pisconti , C. Nisi , E. Tamburini , M.G. Viola , S. Lonardi , G. Martini
Background
Human epidermal growth factor receptor 2 (HER-2) overexpression/amplification is a known prognostic and predictive biomarker in breast and gastric cancer. However, its role in metastatic colorectal cancer (mCRC) is still debated.
Patients and methods
We conducted an exploratory analysis to investigate the role of HER-2 amplifications/mutations in patients with RAS/BRAFV600 wild type (WT), microsatellite stable (MSS) mCRC enrolled in the CAPRI-2 GOIM trial, who received FOLFIRI/cetuximab as first-line therapy. At baseline, plasma and tumor tissue samples were collected for comprehensive genomic profiling using the FoundationOne CDx assay. HER-2 positive tumors were defined in case of HER-2 mutations or gene amplification, defined by using a gene copy number cut-off of ≥4.
Results
Patients with HER-2 negative tumors had numerically higher objective response rates [78% versus 60%; odd-ratio, 1.95, 95% confidence interval (CI): 0.47-8; P = 0.4] compared with HER-2 positive tumors. Patients with HER-2 positive mCRC had worse median progression-free survival (PFS) [(7.54 months; 95% CI:4.99-Not evaluable (NE) versus 13.47 months (95% CI: 11.76-16.3); hazard ratio (HR): 2.47; 95% CI: 1.27-4.65; P = 0.007] as well as worse median overall survival [16.4 months (95% CI:9.4-NE) versus 33.4 (30.36-NE); HR: 2.54; 95% CI: 1.09-5.93; P = 0.031] compared with patients with HER-2 negative tumors. Of note, 6/7 cases with HER-2 mutations exhibited limited benefit from treatment with FOLFIRI plus cetuximab with PFS inferior to 8 months.
Conclusion
Taken together, these results highlight the need to test HER-2 gene alterations for patients with RAS/BRAFV600 WT, MSS mCRC, who are candidates for anti-epidermal growth factor receptor therapies.
{"title":"HER-2 gene alterations as biomarker in patients with metastatic colorectal cancer treated with FOLFIRI + cetuximab: findings from the CAPRI-2 GOIM study","authors":"D. Ciardiello , L. Boscolo Bielo , S. Napolitano , E. Martinelli , T. Troiani , E. Cioli , T.P. Latiano , E. Maiello , P. Parente , A. Avallone , A. De Stefano , R. Bordonaro , A.E. Russo , C. Lotesoriere , S. Vallarelli , S. Pisconti , C. Nisi , E. Tamburini , M.G. Viola , S. Lonardi , G. Martini","doi":"10.1016/j.esmogo.2025.100295","DOIUrl":"10.1016/j.esmogo.2025.100295","url":null,"abstract":"<div><h3>Background</h3><div>Human epidermal growth factor receptor 2 (HER-2) overexpression/amplification is a known prognostic and predictive biomarker in breast and gastric cancer. However, its role in metastatic colorectal cancer (mCRC) is still debated.</div></div><div><h3>Patients and methods</h3><div>We conducted an exploratory analysis to investigate the role of <em>HER-2</em> amplifications/mutations in patients with <em>RAS/BRAF</em><sup><em>V600</em></sup> wild type (WT), microsatellite stable (MSS) mCRC enrolled in the CAPRI-2 GOIM trial, who received FOLFIRI/cetuximab as first-line therapy. At baseline, plasma and tumor tissue samples were collected for comprehensive genomic profiling using the FoundationOne CDx assay. HER-2 positive tumors were defined in case of <em>HER-2</em> mutations or gene amplification, defined by using a gene copy number cut-off of ≥4.</div></div><div><h3>Results</h3><div>Patients with <em>HER-2</em> negative tumors had numerically higher objective response rates [78% versus 60%; odd-ratio, 1.95, 95% confidence interval (CI): 0.47-8; <em>P</em> = 0.4] compared with <em>HER-2</em> positive tumors. Patients with <em>HER-2</em> positive mCRC had worse median progression-free survival (PFS) [(7.54 months; 95% CI:4.99-Not evaluable (NE) versus 13.47 months (95% CI: 11.76-16.3); hazard ratio (HR): 2.47; 95% CI: 1.27-4.65; <em>P</em> = 0.007] as well as worse median overall survival [16.4 months (95% CI:9.4-NE) versus 33.4 (30.36-NE); HR: 2.54; 95% CI: 1.09-5.93; <em>P</em> = 0.031] compared with patients with <em>HER-2</em> negative tumors. Of note, 6/7 cases with <em>HER-2</em> mutations exhibited limited benefit from treatment with FOLFIRI plus cetuximab with PFS inferior to 8 months.</div></div><div><h3>Conclusion</h3><div>Taken together, these results highlight the need to test <em>HER-2</em> gene alterations for patients with <em>RAS/BRAF</em><sup><em>V600</em></sup> WT, MSS mCRC, who are candidates for anti-epidermal growth factor receptor therapies.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"11 ","pages":"Article 100295"},"PeriodicalIF":0.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146038190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-02-02DOI: 10.1016/j.esmogo.2026.100303
V. De Falco , P.P. Vitiello , D. Ciardiello , G. Grasso , E. Mariella , G. Martini , S. Napolitano , C. Cardone , G. Arrichiello , E. Varriale , M. Di Bisceglie , T. Latiano , E. Maiello , A. Reginelli , M.C. Brunese , S. Cappabianca , S. Del Tufo , A. Orlando , A. Nicastro , F. Caraglia , E. Martinelli
Background
Angiogenesis is a key mechanism in metastatic colorectal cancer (mCRC). Novel agents targeting this pathway, like cabozantinib, are of great therapeutic need.
Patients and methods
We conducted an open-label, single-arm phase II trial to assess the antitumor activity of cabozantinib in patients with pretreated mCRC who had progressed following at least two prior lines of therapy. The primary endpoint was the progression-free survival (PFS) rate at 16 weeks, whereas secondary endpoints included median PFS, overall survival (OS), response rate, disease control rate, and safety. DNA- and RNA-based translational analyses were carried out on biological samples.
Results
From October 2019 to January 2023, 33 patients were treated with oral cabozantinib, 60 mg daily. The primary endpoint was met: 11/33 assessable patients (33%) were progression-free at 16 weeks. Median PFS was 2.27 months [95% confidence interval (CI) 1.71-3.65 months], median OS was 6.25 months (95% CI 3.81-10.26 months). Disease control rate was 45.5%. Cabozantinib was generally fairly tolerated. Exploratory analyses investigating the effect of clinical disease features on PFS showed no significant correlation. Comprehensive genomic profiling on 30 patients (tissues and plasma) suggested that absence of TP53 mutations and tumor mutational burden (TMB) ≥4 mutations/Mb positively correlated with response (PFS >16 weeks). Additionally, for a subset of 18 (54.5%) patients, RNA sequencing from archival formalin-fixed paraffin-embedded samples was carried out. Molecular subtypes 4 (CMS4) was the most represented transcriptional subtype (10/18 cases). To verify if other transcriptional features were associated with treatment benefit, for each sample we computed gene set variation analysis. For epithelial-mesenchymal transition (EMT) and angiogenesis gene sets, we identified a trend toward higher scores in tumors from patients with longer PFS.
Conclusion
Within the limitations of a single-arm phase II trial, cabozantinib demonstrates both safety and antitumor activity in mCRC. The observed correlation between specific molecular features, such as EMT activation and angiogenesis, and cabozantinib activity is hypothesis-generating and warrants further investigation.
{"title":"Clinical and translational results from the phase II ABACO trial evaluating the activity of cabozantinib in pretreated patients with metastatic colorectal cancer","authors":"V. De Falco , P.P. Vitiello , D. Ciardiello , G. Grasso , E. Mariella , G. Martini , S. Napolitano , C. Cardone , G. Arrichiello , E. Varriale , M. Di Bisceglie , T. Latiano , E. Maiello , A. Reginelli , M.C. Brunese , S. Cappabianca , S. Del Tufo , A. Orlando , A. Nicastro , F. Caraglia , E. Martinelli","doi":"10.1016/j.esmogo.2026.100303","DOIUrl":"10.1016/j.esmogo.2026.100303","url":null,"abstract":"<div><h3>Background</h3><div>Angiogenesis is a key mechanism in metastatic colorectal cancer (mCRC). Novel agents targeting this pathway, like cabozantinib, are of great therapeutic need.</div></div><div><h3>Patients and methods</h3><div>We conducted an open-label, single-arm phase II trial to assess the antitumor activity of cabozantinib in patients with pretreated mCRC who had progressed following at least two prior lines of therapy. The primary endpoint was the progression-free survival (PFS) rate at 16 weeks, whereas secondary endpoints included median PFS, overall survival (OS), response rate, disease control rate, and safety. DNA- and RNA-based translational analyses were carried out on biological samples.</div></div><div><h3>Results</h3><div>From October 2019 to January 2023, 33 patients were treated with oral cabozantinib, 60 mg daily. The primary endpoint was met: 11/33 assessable patients (33%) were progression-free at 16 weeks. Median PFS was 2.27 months [95% confidence interval (CI) 1.71-3.65 months], median OS was 6.25 months (95% CI 3.81-10.26 months). Disease control rate was 45.5%. Cabozantinib was generally fairly tolerated. Exploratory analyses investigating the effect of clinical disease features on PFS showed no significant correlation. Comprehensive genomic profiling on 30 patients (tissues and plasma) suggested that absence of <em>TP53</em> mutations and tumor mutational burden (TMB) ≥4 mutations/Mb positively correlated with response (PFS >16 weeks). Additionally, for a subset of 18 (54.5%) patients, RNA sequencing from archival formalin-fixed paraffin-embedded samples was carried out. Molecular subtypes 4 (CMS4) was the most represented transcriptional subtype (10/18 cases). To verify if other transcriptional features were associated with treatment benefit, for each sample we computed gene set variation analysis. For epithelial-mesenchymal transition (EMT) and angiogenesis gene sets, we identified a trend toward higher scores in tumors from patients with longer PFS.</div></div><div><h3>Conclusion</h3><div>Within the limitations of a single-arm phase II trial, cabozantinib demonstrates both safety and antitumor activity in mCRC. The observed correlation between specific molecular features, such as EMT activation and angiogenesis, and cabozantinib activity is hypothesis-generating and warrants further investigation.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"11 ","pages":"Article 100303"},"PeriodicalIF":0.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146188606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-22DOI: 10.1016/j.esmogo.2025.100296
R. Fazio, M. Ambrosini, A. Raimondi, C.C. Pircher, C. Leli, C. Sciortino, S. Marchesi, C. Damonte, C. Villa, C. Silvestri, F. Manoni, G. Gronchi, F. Pietrantonio
Gastrointestinal malignancies account for the vast majority of tumours within the microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) phenotype. Over the past decade, evidence on the prognostic and predictive role of MSI-H/dMMR status has steadily accumulated, and immune checkpoint inhibitors (ICIs) are now considered the cornerstone of treatment for all patients with advanced MSI-H/dMMR cancers. However, in non-colorectal tumours the available evidence is less robust, raising important challenges, such as defining the optimal therapeutic regimen across different treatment lines and establishing the appropriate duration of therapy. More recently, the efficacy of ICIs has also been demonstrated in localized disease, prompting new questions regarding their integration into curative-intent strategies, such as the risk of overtreatment given the favourable prognosis of early-stage tumours, the role of nonoperative management, the optimal treatment regimen, and schedule. In this review, we summarize the available literature and the evidence supporting treatment strategies for patients with early- and advanced-stage MSI-H/dMMR non-colorectal cancers.
{"title":"Early- and advanced-stage MSI-H non-colorectal cancers: best management and challenges in 2025","authors":"R. Fazio, M. Ambrosini, A. Raimondi, C.C. Pircher, C. Leli, C. Sciortino, S. Marchesi, C. Damonte, C. Villa, C. Silvestri, F. Manoni, G. Gronchi, F. Pietrantonio","doi":"10.1016/j.esmogo.2025.100296","DOIUrl":"10.1016/j.esmogo.2025.100296","url":null,"abstract":"<div><div>Gastrointestinal malignancies account for the vast majority of tumours within the microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) phenotype. Over the past decade, evidence on the prognostic and predictive role of MSI-H/dMMR status has steadily accumulated, and immune checkpoint inhibitors (ICIs) are now considered the cornerstone of treatment for all patients with advanced MSI-H/dMMR cancers. However, in non-colorectal tumours the available evidence is less robust, raising important challenges, such as defining the optimal therapeutic regimen across different treatment lines and establishing the appropriate duration of therapy. More recently, the efficacy of ICIs has also been demonstrated in localized disease, prompting new questions regarding their integration into curative-intent strategies, such as the risk of overtreatment given the favourable prognosis of early-stage tumours, the role of nonoperative management, the optimal treatment regimen, and schedule. In this review, we summarize the available literature and the evidence supporting treatment strategies for patients with early- and advanced-stage MSI-H/dMMR non-colorectal cancers.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"11 ","pages":"Article 100296"},"PeriodicalIF":0.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146038189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Radiotherapy has traditionally been uncommonly used for hepatocellular carcinoma (HCC) due to concerns of radiation-induced liver damage. However, advancements including stereotactic body radiotherapy have improved target localization and reduced toxicity, leading to its inclusion as a locoregional therapy in recent international guidelines. Newer technologies, such as MR-Linac and particle radiotherapy, have further improved the therapeutic ratio of radiotherapy, showing early promising results. The increasing application of radiotherapy in HCC has led to broadening of its indication to bridging to transplant and palliation. Beyond being a standalone treatment, radiotherapy is increasingly being combined with systemic therapies to enhance treatment response and survival rates. This combination is particularly relevant for patients with portal vein tumour thrombosis, as other locoregional therapies are often unsuitable for them. Furthermore, with the evolving concepts of oligometastatic and oligoprogressive HCC, radiotherapy is being explored as a promising approach to manage these conditions, especially as HCC patients experience longer survival with the introduction of immunotherapy. In this review, we provide an overview of these recent advancements in radiotherapy for HCC.
{"title":"Recent advancements in radiotherapy for hepatocellular carcinoma","authors":"L.L. Chan , K.S.H. Chok , A.Y.H. Ip , D.M.C. Poon , S.L. Chan","doi":"10.1016/j.esmogo.2026.100308","DOIUrl":"10.1016/j.esmogo.2026.100308","url":null,"abstract":"<div><div>Radiotherapy has traditionally been uncommonly used for hepatocellular carcinoma (HCC) due to concerns of radiation-induced liver damage. However, advancements including stereotactic body radiotherapy have improved target localization and reduced toxicity, leading to its inclusion as a locoregional therapy in recent international guidelines. Newer technologies, such as MR-Linac and particle radiotherapy, have further improved the therapeutic ratio of radiotherapy, showing early promising results. The increasing application of radiotherapy in HCC has led to broadening of its indication to bridging to transplant and palliation. Beyond being a standalone treatment, radiotherapy is increasingly being combined with systemic therapies to enhance treatment response and survival rates. This combination is particularly relevant for patients with portal vein tumour thrombosis, as other locoregional therapies are often unsuitable for them. Furthermore, with the evolving concepts of oligometastatic and oligoprogressive HCC, radiotherapy is being explored as a promising approach to manage these conditions, especially as HCC patients experience longer survival with the introduction of immunotherapy. In this review, we provide an overview of these recent advancements in radiotherapy for HCC.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"11 ","pages":"Article 100308"},"PeriodicalIF":0.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146188603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2026-01-27DOI: 10.1016/j.esmogo.2026.100304
A. Ooki , K. Nakano , K. Shimozaki , M. Takamatsu , S. Fukuoka , S. Sakata , H. Osumi , K. Yoshikawa , E. Toyokawa , K. Yoshino , S. Udagawa , T. Wakatsuki , M. Ogura , E. Shinozaki , K. Chin , H. Kawachi , K. Yamaguchi
Background
Zolbetuximab plus chemotherapy improves survival in patients with human epidermal growth factor receptor 2 (HER2)-negative, claudin 18 (CLDN18)-positive advanced gastric cancer (AGC), which is defined as ≥75% of tumor cells with moderate-to-strong membranous staining. Whether semiquantitative expression within this range influences treatment outcomes is unknown.
Patients and methods
This single-center retrospective study evaluated patients with AGC treated with zolbetuximab plus chemotherapy between July 2024 and September 2025. Tumors were independently reviewed by three pathologists and categorized as having moderate (75%-94%) or high (95%-100%) CLDN18 expression. Survival, response, and safety were compared across expression levels.
Results
Fifty-one patients were included in the study. Baseline characteristics were similar across the groups. The median progression-free survival was 6.7 months in both expression groups, and the median overall survival was not reached. The objective response rates were 62.5% and 71.4%, and the disease control rates were 87.5% and 85.7% in the moderate and high expression groups, respectively. The depth of response (−33.6% versus −45.8%) and early tumor shrinkage (43.8% versus 71.4%) differed modestly. The profile of treatment-related adverse events was similar across the expression groups. Specimen type (biopsy or surgical resection) had no apparent impact on treatment outcomes.
Conclusions
Within the approved CLDN18-positive threshold, the semiquantitative staining proportion showed no detectable differences in the efficacy or safety of zolbetuximab plus chemotherapy.
{"title":"Semiquantitative CLDN18 expression and clinical outcomes in patients with CLDN18-positive gastric cancer treated with zolbetuximab plus chemotherapy","authors":"A. Ooki , K. Nakano , K. Shimozaki , M. Takamatsu , S. Fukuoka , S. Sakata , H. Osumi , K. Yoshikawa , E. Toyokawa , K. Yoshino , S. Udagawa , T. Wakatsuki , M. Ogura , E. Shinozaki , K. Chin , H. Kawachi , K. Yamaguchi","doi":"10.1016/j.esmogo.2026.100304","DOIUrl":"10.1016/j.esmogo.2026.100304","url":null,"abstract":"<div><h3>Background</h3><div>Zolbetuximab plus chemotherapy improves survival in patients with human epidermal growth factor receptor 2 (HER2)-negative, claudin 18 (CLDN18)-positive advanced gastric cancer (AGC), which is defined as ≥75% of tumor cells with moderate-to-strong membranous staining. Whether semiquantitative expression within this range influences treatment outcomes is unknown.</div></div><div><h3>Patients and methods</h3><div>This single-center retrospective study evaluated patients with AGC treated with zolbetuximab plus chemotherapy between July 2024 and September 2025. Tumors were independently reviewed by three pathologists and categorized as having moderate (75%-94%) or high (95%-100%) CLDN18 expression. Survival, response, and safety were compared across expression levels.</div></div><div><h3>Results</h3><div>Fifty-one patients were included in the study. Baseline characteristics were similar across the groups. The median progression-free survival was 6.7 months in both expression groups, and the median overall survival was not reached. The objective response rates were 62.5% and 71.4%, and the disease control rates were 87.5% and 85.7% in the moderate and high expression groups, respectively. The depth of response (−33.6% versus −45.8%) and early tumor shrinkage (43.8% versus 71.4%) differed modestly. The profile of treatment-related adverse events was similar across the expression groups. Specimen type (biopsy or surgical resection) had no apparent impact on treatment outcomes.</div></div><div><h3>Conclusions</h3><div>Within the approved CLDN18-positive threshold, the semiquantitative staining proportion showed no detectable differences in the efficacy or safety of zolbetuximab plus chemotherapy.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"11 ","pages":"Article 100304"},"PeriodicalIF":0.0,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146078109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-11-20DOI: 10.1016/j.esmogo.2025.100268
C. Lin , T. Luo , M. Wu , F. Li , L. Nunes , A. Mezheyeuski , K. Hammarström , A. Isaksson , I. Ljuslinder , M. Uhlén , R. Palmqvist , S. Zhu , B. Glimelius , K. Wu , T. Sjöblom
Microsatellite-instable (MSI) tumours constitute one-fifth of colorectal cancers (CRCs). However, the MSI CRCs display substantial tumour microenvironment (TME) heterogeneity and variable responses to immunotherapy, necessitating a refined classification to guide personalized therapy. In this study, we analysed whole-genome and transcriptome sequences from 223 MSI CRC patients from a large prospective longitudinal cancer study in Sweden (Nunes L, Li F, Wu M, et al. Prognostic genome and transcriptome signatures in colorectal cancers. Nature. 2024;633(8028):137-146) and identified three molecular subclasses with distinct TME and genetic features: class 1a (immune-excluded), characterized by prominent stromal activation, transforming growth factor-β signalling, and low tumour neoantigen burdens (TNB); class 1b (immune-infiltrated), marked by intact neoantigen presentation and strong antitumour immunity; and class 2 (immune-cold), exhibiting epithelial features, high tumour mutation burden (TMB) and TNB, chromosomal instability, active metabolism, and a lack of immune activation. We further uncovered a correlation between mutL homolog 1 (MLH1) hypermethylation and the immune-cold phenotype in class 2, where anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) combination immunotherapy demonstrated significantly improved efficacy compared with anti-PD-1 monotherapy. Finally, the molecular features of these subclasses were validated in external MSI CRC cohorts and in MSI tumours from other cancers. Our findings offer a comprehensive understanding of the molecular landscape of MSI CRC, unveiling potential molecular mechanisms underlying different tumour-immune phenotypes and laying the foundation for future development of tailored treatment strategies.
{"title":"Molecular classification of microsatellite-instable colorectal cancers reveals distinct predictors of immunotherapy response","authors":"C. Lin , T. Luo , M. Wu , F. Li , L. Nunes , A. Mezheyeuski , K. Hammarström , A. Isaksson , I. Ljuslinder , M. Uhlén , R. Palmqvist , S. Zhu , B. Glimelius , K. Wu , T. Sjöblom","doi":"10.1016/j.esmogo.2025.100268","DOIUrl":"10.1016/j.esmogo.2025.100268","url":null,"abstract":"<div><div>Microsatellite-instable (MSI) tumours constitute one-fifth of colorectal cancers (CRCs). However, the MSI CRCs display substantial tumour microenvironment (TME) heterogeneity and variable responses to immunotherapy, necessitating a refined classification to guide personalized therapy. In this study, we analysed whole-genome and transcriptome sequences from 223 MSI CRC patients from a large prospective longitudinal cancer study in Sweden (Nunes L, Li F, Wu M, et al. Prognostic genome and transcriptome signatures in colorectal cancers. <em>Nature.</em> 2024;633(8028):137-146) and identified three molecular subclasses with distinct TME and genetic features: class 1a (immune-excluded), characterized by prominent stromal activation, transforming growth factor-β signalling, and low tumour neoantigen burdens (TNB); class 1b (immune-infiltrated), marked by intact neoantigen presentation and strong antitumour immunity; and class 2 (immune-cold), exhibiting epithelial features, high tumour mutation burden (TMB) and TNB, chromosomal instability, active metabolism, and a lack of immune activation. We further uncovered a correlation between mutL homolog 1 (<em>MLH1</em><em>)</em> hypermethylation and the immune-cold phenotype in class 2, where anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) combination immunotherapy demonstrated significantly improved efficacy compared with anti-PD-1 monotherapy. Finally, the molecular features of these subclasses were validated in external MSI CRC cohorts and in MSI tumours from other cancers. Our findings offer a comprehensive understanding of the molecular landscape of MSI CRC, unveiling potential molecular mechanisms underlying different tumour-immune phenotypes and laying the foundation for future development of tailored treatment strategies.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"10 ","pages":"Article 100268"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145578866","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-09-25DOI: 10.1016/j.esmogo.2025.100240
A. Ooki , H. Osumi , K. Shimada , N. Machida , H. Hara , M. Takamatsu , N. Ishizuka , Y. Fukuda , W. Hashimoto , K. Yamaguchi
Background
Human epidermal growth factor receptor 2 (HER2) is overexpressed in ∼20% of advanced gastroesophageal adenocarcinomas (GEAs). Trastuzumab (T-mab) is the standard first-line treatment for HER2-positive GEA, and trastuzumab deruxtecan (T-DXd) has demonstrated clinical efficacy in later-line settings. However, the potential loss of HER2 expression following T-mab treatment raises concerns about the subsequent effectiveness of T-DXd. The temporal dynamics of HER2 expression across treatment lines are not well understood.
Design
We designed a prospective, single-arm, multicenter study to investigate the association between the efficacy of third-line T-DXd and changes in HER2 status in tumor tissue and blood after first-line T-mab treatment in patients with HER2-positive GEA. The aim is to inform the optimal clinical use of T-DXd. Serial tumor and/or blood re-biopsies will be carried out at each line of treatment following first-line therapy. The study consists of two parts. In part 1, we will evaluate biomarker dynamics—specifically HER2 status and circulating tumor DNA alterations—during second-line therapy. In part 2, we will assess the efficacy and safety of third-line T-DXd in relation to these biomarker changes. Approximately 120 patients will be enrolled in part 1 and 50 in part 2.
{"title":"Multicenter prospective EN-MARK study: efficacy of third-line trastuzumab deruxtecan and dynamic changes in biomarkers, including HER2 status","authors":"A. Ooki , H. Osumi , K. Shimada , N. Machida , H. Hara , M. Takamatsu , N. Ishizuka , Y. Fukuda , W. Hashimoto , K. Yamaguchi","doi":"10.1016/j.esmogo.2025.100240","DOIUrl":"10.1016/j.esmogo.2025.100240","url":null,"abstract":"<div><h3>Background</h3><div>Human epidermal growth factor receptor 2 (HER2) is overexpressed in ∼20% of advanced gastroesophageal adenocarcinomas (GEAs). Trastuzumab (T-mab) is the standard first-line treatment for HER2-positive GEA, and trastuzumab deruxtecan (T-DXd) has demonstrated clinical efficacy in later-line settings. However, the potential loss of HER2 expression following T-mab treatment raises concerns about the subsequent effectiveness of T-DXd. The temporal dynamics of HER2 expression across treatment lines are not well understood.</div></div><div><h3>Design</h3><div>We designed a prospective, single-arm, multicenter study to investigate the association between the efficacy of third-line T-DXd and changes in HER2 status in tumor tissue and blood after first-line T-mab treatment in patients with HER2-positive GEA. The aim is to inform the optimal clinical use of T-DXd. Serial tumor and/or blood re-biopsies will be carried out at each line of treatment following first-line therapy. The study consists of two parts. In part 1, we will evaluate biomarker dynamics—specifically HER2 status and circulating tumor DNA alterations—during second-line therapy. In part 2, we will assess the efficacy and safety of third-line T-DXd in relation to these biomarker changes. Approximately 120 patients will be enrolled in part 1 and 50 in part 2.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"10 ","pages":"Article 100240"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145159274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-12-02DOI: 10.1016/j.esmogo.2025.100267
K. Sato , I. Nakayama , M. Yura , A. Sato , M. Suzuki , T. Kadota , M. Nakamura , N. Sakamoto , T. Hashimoto , S. Sakashita , M. Wakabayashi , H. Shoji , T. Hayashi , H. Daiko , K. Kato , T. Yoshino , T. Yano , T. Fujita , T. Kinoshita , K. Shitara
Background
Durvalumab combined with fluorouracil, leucovorin, oxaliplatin, and docetaxel (D-FLOT) has demonstrated significant improvement in event-free survival (EFS) among patients with resectable gastric and gastroesophageal junction adenocarcinoma (GEJA) and is expected to become a new standard of care. Nevertheless, surgical resection remains requisite and is associated with substantial morbidity and deterioration in quality of life for GEJA. Given that D-FLOT achieves a pathological complete response in ∼20% of patients, intensification of total neoadjuvant therapy with short-course radiation (SRT) could further increase clinical CR (cCR) rates and facilitate non-operative management (NOM) in selected GEJA patients.
Trial design
EPOC2301 is a single-arm, phase II study evaluating the efficacy and safety of pembrolizumab with FLOT plus SRT as total neoadjuvant therapy for resectable GEJA. Patients receive two cycles of FLOT and one dose of pembrolizumab, followed by 25 Gy radiotherapy, then two more cycles of FLOT and one dose of pembrolizumab. Response is assessed by computed tomography, positron emission tomography-computed tomography, endoscopy with bite-on-bite biopsy, and whole-genome circulating tumor DNA analysis. Patients achieving cCR or near-cCR continue NOM with pembrolizumab and FLOT, whereas those without adequate response undergo surgery followed by adjuvant pembrolizumab and FLOT. The primary endpoint is 3-year EFS.
{"title":"An open label phase II study of total neoadjuvant therapy (TNT) consisting of FLOT with pembrolizumab and short radiation for patients with locally advanced gastroesophageal junction adenocarcinoma (EPOC2301)","authors":"K. Sato , I. Nakayama , M. Yura , A. Sato , M. Suzuki , T. Kadota , M. Nakamura , N. Sakamoto , T. Hashimoto , S. Sakashita , M. Wakabayashi , H. Shoji , T. Hayashi , H. Daiko , K. Kato , T. Yoshino , T. Yano , T. Fujita , T. Kinoshita , K. Shitara","doi":"10.1016/j.esmogo.2025.100267","DOIUrl":"10.1016/j.esmogo.2025.100267","url":null,"abstract":"<div><h3>Background</h3><div>Durvalumab combined with fluorouracil, leucovorin, oxaliplatin, and docetaxel (D-FLOT) has demonstrated significant improvement in event-free survival (EFS) among patients with resectable gastric and gastroesophageal junction adenocarcinoma (GEJA) and is expected to become a new standard of care. Nevertheless, surgical resection remains requisite and is associated with substantial morbidity and deterioration in quality of life for GEJA. Given that D-FLOT achieves a pathological complete response in ∼20% of patients, intensification of total neoadjuvant therapy with short-course radiation (SRT) could further increase clinical CR (cCR) rates and facilitate non-operative management (NOM) in selected GEJA patients.</div></div><div><h3>Trial design</h3><div>EPOC2301 is a single-arm, phase II study evaluating the efficacy and safety of pembrolizumab with FLOT plus SRT as total neoadjuvant therapy for resectable GEJA. Patients receive two cycles of FLOT and one dose of pembrolizumab, followed by 25 Gy radiotherapy, then two more cycles of FLOT and one dose of pembrolizumab. Response is assessed by computed tomography, positron emission tomography-computed tomography, endoscopy with bite-on-bite biopsy, and whole-genome circulating tumor DNA analysis. Patients achieving cCR or near-cCR continue NOM with pembrolizumab and FLOT, whereas those without adequate response undergo surgery followed by adjuvant pembrolizumab and FLOT. The primary endpoint is 3-year EFS.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"10 ","pages":"Article 100267"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145693513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-09-15DOI: 10.1016/j.esmogo.2025.100237
L.M. Veen , A.P. van der Zalm , D. Blangé , P. Manoukian , M. van Mourik , R.R. de Goeij-de Haas , S.R. Piersma , T.V. Pham , C.R. Jimenez , S.L. Meijer , H.W. van Laarhoven , M.F. Bijlsma
Background
Despite combination therapies, less than half of patients with resectable esophageal cancer (EC) survive beyond 5 years. Previous studies, primarily using transcriptomics, revealed high plasticity in these cancer cells. In other cancer contexts, such plasticity has been demonstrated to also result in aberrant tubulin expression and resistance to taxanes. Given that taxanes are a cornerstone in EC treatment, we established a multi-omics analysis of neoadjuvantly treated EC cells and tissues with a focus on tubulins.
Materials and methods
We applied transcriptomics and proteomics to pretreated EC resection samples and primary cell lines from various treatment settings. RNA-Sequencing and MS-based proteomics data were correlated with clinical outcomes to identify response-associated tubulin genes and proteins. In vitro experiments included lentiviral gene silencing of candidate resistance mediators and pharmacological interventions.
Results
In both the transcriptomics and proteomics datasets, tubulin isoforms that are not typically expressed in the esophagus were found to associate with survival outcome. Specifically, we found that beta-tubulin 3 (TUBB3) was associated with unfavorable outcomes. However, TUBB3 silencing in vitro did not render cells sensitive to taxanes, nor did it prevent transitions to resistant cell states. Pharmacological inhibition did not improve the efficacy of chemoradiation. Instead, we found that TUBB3 is highly correlated with mesenchymal cell states, and that its expression is a consequence of such transitions rather than a cause.
Conclusions
A neuronal tubulin isoform was found to increase in cells undergoing mesenchymal transition and acquiring resistance. These abundant proteins could serve as biomarkers for acquired therapy resistance in EC.
{"title":"Proteome and transcriptome analysis reveals tubulin isotype switching in paclitaxel-treated esophageal cancer","authors":"L.M. Veen , A.P. van der Zalm , D. Blangé , P. Manoukian , M. van Mourik , R.R. de Goeij-de Haas , S.R. Piersma , T.V. Pham , C.R. Jimenez , S.L. Meijer , H.W. van Laarhoven , M.F. Bijlsma","doi":"10.1016/j.esmogo.2025.100237","DOIUrl":"10.1016/j.esmogo.2025.100237","url":null,"abstract":"<div><h3>Background</h3><div>Despite combination therapies, less than half of patients with resectable esophageal cancer (EC) survive beyond 5 years. Previous studies, primarily using transcriptomics, revealed high plasticity in these cancer cells. In other cancer contexts, such plasticity has been demonstrated to also result in aberrant tubulin expression and resistance to taxanes. Given that taxanes are a cornerstone in EC treatment, we established a multi-omics analysis of neoadjuvantly treated EC cells and tissues with a focus on tubulins.</div></div><div><h3>Materials and methods</h3><div>We applied transcriptomics and proteomics to pretreated EC resection samples and primary cell lines from various treatment settings. RNA-Sequencing and MS-based proteomics data were correlated with clinical outcomes to identify response-associated tubulin genes and proteins. <em>In vitro</em> experiments included lentiviral gene silencing of candidate resistance mediators and pharmacological interventions.</div></div><div><h3>Results</h3><div>In both the transcriptomics and proteomics datasets, tubulin isoforms that are not typically expressed in the esophagus were found to associate with survival outcome. Specifically, we found that beta-tubulin 3 (TUBB3) was associated with unfavorable outcomes. However, TUBB3 silencing <em>in vitro</em> did not render cells sensitive to taxanes, nor did it prevent transitions to resistant cell states. Pharmacological inhibition did not improve the efficacy of chemoradiation. Instead, we found that TUBB3 is highly correlated with mesenchymal cell states, and that its expression is a consequence of such transitions rather than a cause.</div></div><div><h3>Conclusions</h3><div>A neuronal tubulin isoform was found to increase in cells undergoing mesenchymal transition and acquiring resistance. These abundant proteins could serve as biomarkers for acquired therapy resistance in EC.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"10 ","pages":"Article 100237"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145061400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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