KN026 is a novel bispecific HER2-targeting antibody for HER2-positive recurrent or metastatic breast cancer that showed prolonged median PFS and lessened distinction of PFS regarding the HR subgroup in our phase II clinical trial, compared with PUFFIN study of first-line trastuzumab combined with pertuzumab therapy. A more detailed discovery of its peculiarity is needed for optimal application of KN026 treatment. We performed whole-transcriptome sequencing of digital spatial profiling (DSP) on 8 pre/post-treatment tumor samples. Mechanistic explorations were conducted by plasmid transfection, co-culture, CCK8 proliferation assay and flow cytometry. Compared to the tumor regions with non-objective response (OR), those with OR had high expression of CALML5, TFAP2B, and ERBB2, and relatively low expression of ESR1 in tumor cells at baseline. The expression of ESR1 had a tentative association with PI3K/AKT and NOTCH signaling pathways which were downstream or interactive pathways of HER2 target and also acted as interactive pathways of ER-mediated signaling. The co-expression of ERBB2 and CDK12 emerged as a distinctive signature of OR. KN026 treatment also reshaped intratumoral activated T- and B-cell subtypes in hot-tumor regions, regardless of myeloid-derived cells. Both HER2 and ESR1 are determinant of KN026 efficacy in advanced HER2-positive breast cancer, implying the potential of KN026 combined with endocrine therapy in HER2- and ER-positive breast cancer.
{"title":"Spatial molecular analyses reveal key features associated with response to KN026 in advanced HER2-positive breast cancer","authors":"Jianli Ma, Shengnan Sun, Xiaowen Tang, Jingxuan Wang, Wenhui Zhao, Dabei Tang, Ying Song, Liru Li, Haitao Luo, Xuhui Liu, Yuwei Deng, Qingyuan Zhang","doi":"10.1038/s41416-025-03287-9","DOIUrl":"10.1038/s41416-025-03287-9","url":null,"abstract":"KN026 is a novel bispecific HER2-targeting antibody for HER2-positive recurrent or metastatic breast cancer that showed prolonged median PFS and lessened distinction of PFS regarding the HR subgroup in our phase II clinical trial, compared with PUFFIN study of first-line trastuzumab combined with pertuzumab therapy. A more detailed discovery of its peculiarity is needed for optimal application of KN026 treatment. We performed whole-transcriptome sequencing of digital spatial profiling (DSP) on 8 pre/post-treatment tumor samples. Mechanistic explorations were conducted by plasmid transfection, co-culture, CCK8 proliferation assay and flow cytometry. Compared to the tumor regions with non-objective response (OR), those with OR had high expression of CALML5, TFAP2B, and ERBB2, and relatively low expression of ESR1 in tumor cells at baseline. The expression of ESR1 had a tentative association with PI3K/AKT and NOTCH signaling pathways which were downstream or interactive pathways of HER2 target and also acted as interactive pathways of ER-mediated signaling. The co-expression of ERBB2 and CDK12 emerged as a distinctive signature of OR. KN026 treatment also reshaped intratumoral activated T- and B-cell subtypes in hot-tumor regions, regardless of myeloid-derived cells. Both HER2 and ESR1 are determinant of KN026 efficacy in advanced HER2-positive breast cancer, implying the potential of KN026 combined with endocrine therapy in HER2- and ER-positive breast cancer.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 4","pages":"685-696"},"PeriodicalIF":6.8,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-025-03287-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145713240","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}
HER2-positive or ERBB2 amplified (ERBB2 amp+) metastatic colorectal cancer (mCRC) is an important subgroup due to emerging HER2-targeted therapies. Although ERBB2 amplification is associated with anti-EGFR antibody resistance, optimal first-line treatment remains unclear. We analysed data from the Flatiron Health-Foundation Medicine CRC clinico-genomic database, including patients with stage IV or recurrent mCRC diagnosed between January 2012 and March 2022 who underwent tissue-based comprehensive genomic profiling. ERBB2 amp+ was defined as an ERBB2 copy number ≥+3 of the tumour base ploidy. Among 5545 patients, 144 (3.1%) had ERBB2 amp+ mCRC. These patients showed significantly worse real-world progression-free survival (rwPFS) than ERBB2 amp− patients (median 7.6 vs. 8.7 months; hazard ratio [HR]: 1.20, 95% confidence interval [CI]: 1.01–1.43, p = 0.04). This trend persisted in patients with left-sided RAS/BRAF V600E wild-type and non-MSI-H mCRC treated with chemotherapy plus anti-EGFR antibody (median 8.7 vs. 12.5 months; HR: 2.18, p = 0.02; adjusted HR: 2.33, p = 0.046) or chemotherapy plus bevacizumab (median 8.9 vs. 10.5 months; HR: 1.65, p = 0.04; adjusted HR: 1.75, p = 0.04). Real-world overall survival did not differ significantly. ERBB2 amp+ mCRC is a small but clinically relevant subgroup with inferior rwPFS across current first-line treatments, highlighting the need for better strategies.
背景：由于her2靶向治疗的出现，her2阳性或ERBB2扩增（ERBB2 amp+）转移性结直肠癌（mCRC）是一个重要的亚组。尽管ERBB2扩增与抗egfr抗体耐药相关，但最佳一线治疗仍不清楚。方法：我们分析了来自Flatiron Health-Foundation Medicine CRC临床基因组数据库的数据，包括2012年1月至2022年3月诊断的IV期或复发性mCRC患者，他们接受了基于组织的综合基因组分析。ERBB2 amp+定义为肿瘤碱基倍体的ERBB2拷贝数≥+3。结果：5545例患者中，144例（3.1%）为ERBB2 amp+ mCRC。这些患者的真实世界无进展生存期（rwPFS）明显低于ERBB2 amp患者（中位7.6个月vs. 8.7个月；风险比[HR]: 1.20, 95%可信区间[CI]: 1.01-1.43, p = 0.04）。这种趋势在左侧RAS/BRAF V600E野生型和非msi - h型mCRC患者中持续存在，化疗加抗egfr抗体（中位8.7 vs 12.5个月；HR: 2.18, p = 0.02；校正HR: 2.33, p = 0.046）或化疗加贝伐单抗（中位8.9 vs 10.5个月；HR: 1.65, p = 0.04；校正HR: 1.75, p = 0.04）。真实世界的总生存率没有显著差异。结论：ERBB2 amp+ mCRC是目前一线治疗中rwPFS较差的一个小但临床相关的亚组，强调需要更好的策略。
{"title":"Survival outcomes of ERBB2-amplified metastatic colorectal cancer treated with first-line chemotherapy","authors":"Yuki Matsubara, Hideaki Bando, Yoshiaki Nakamura, Toshihiro Misumi, Dionne Ng, Eri Tajima, Harlan Pittell, Atsushi Ohtsu, Takayuki Yoshino","doi":"10.1038/s41416-025-03270-4","DOIUrl":"10.1038/s41416-025-03270-4","url":null,"abstract":"HER2-positive or ERBB2 amplified (ERBB2 amp+) metastatic colorectal cancer (mCRC) is an important subgroup due to emerging HER2-targeted therapies. Although ERBB2 amplification is associated with anti-EGFR antibody resistance, optimal first-line treatment remains unclear. We analysed data from the Flatiron Health-Foundation Medicine CRC clinico-genomic database, including patients with stage IV or recurrent mCRC diagnosed between January 2012 and March 2022 who underwent tissue-based comprehensive genomic profiling. ERBB2 amp+ was defined as an ERBB2 copy number ≥+3 of the tumour base ploidy. Among 5545 patients, 144 (3.1%) had ERBB2 amp+ mCRC. These patients showed significantly worse real-world progression-free survival (rwPFS) than ERBB2 amp− patients (median 7.6 vs. 8.7 months; hazard ratio [HR]: 1.20, 95% confidence interval [CI]: 1.01–1.43, p = 0.04). This trend persisted in patients with left-sided RAS/BRAF V600E wild-type and non-MSI-H mCRC treated with chemotherapy plus anti-EGFR antibody (median 8.7 vs. 12.5 months; HR: 2.18, p = 0.02; adjusted HR: 2.33, p = 0.046) or chemotherapy plus bevacizumab (median 8.9 vs. 10.5 months; HR: 1.65, p = 0.04; adjusted HR: 1.75, p = 0.04). Real-world overall survival did not differ significantly. ERBB2 amp+ mCRC is a small but clinically relevant subgroup with inferior rwPFS across current first-line treatments, highlighting the need for better strategies.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 3","pages":"463-468"},"PeriodicalIF":6.8,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-025-03270-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707369","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}
Garsorasib (D-1553), a highly selective, oral KRASG12C inhibitor, has shown clinical efficacy in NSCLC and CRC and is under evaluation in pancreatic cancer. Pancreatic cancer patients with KRAS G12C mutation were enroled and received garsorasib 600 mg twice daily treatment in two international, multicenter, open-label phase 1/2 trials (NCT04585035 and NCT05383898) with similar eligibility criteria. Their data were pooled for analyses of efficacy and safety endpoints. As of April 30, 2024, 24 KRAS G12C–mutated pancreatic cancer patients were enroled with a median follow-up of 8.9 months (range 1.1–22.9). Among 22 evaluable patients, the confirmed objective response rate (ORR) was 45.5% (95% CI, 24.4 to 67.8) with a median duration of response (DOR) of 6.4 months (95% CI, 4.2 to 16.4). The median progression-free survival (PFS) was 7.6 months (95% CI, 3.3 to 8.5) and the 6-month OS rate was 79.2% (95% CI, 57.0, 90.8). Treatment-related adverse events (TRAEs) occurred in 18 (75.0%) patients, including 6 (25.0%) with grade ≥3 events. No TRAEs led to treatment discontinuation. The safety profile was consistent with previous reports of garsorasib. Garsorasib demonstrated encouraging antitumor activity and a tolerable safety profile in patients with KRAS G12C-mutated advanced pancreatic cancer.
{"title":"Efficacy and safety of garsorasib in patients with KRAS G12C-mutated advanced pancreatic cancer","authors":"Noboru Yamamoto, Dong Yan, Vinod Ganju, Xinfang Hou, Hongming Pan, Jianzhen Shan, Liwei Wang, Sang-We Kim, Gary Richardson, Rachel E. Sanborn, Jingdong Zhang, Ziyong Xiang, Wenjia Wang, Zhe Shi, Ling Zhang, Yaolin Wang, Rui-Hua Xu","doi":"10.1038/s41416-025-03286-w","DOIUrl":"10.1038/s41416-025-03286-w","url":null,"abstract":"Garsorasib (D-1553), a highly selective, oral KRASG12C inhibitor, has shown clinical efficacy in NSCLC and CRC and is under evaluation in pancreatic cancer. Pancreatic cancer patients with KRAS G12C mutation were enroled and received garsorasib 600 mg twice daily treatment in two international, multicenter, open-label phase 1/2 trials (NCT04585035 and NCT05383898) with similar eligibility criteria. Their data were pooled for analyses of efficacy and safety endpoints. As of April 30, 2024, 24 KRAS G12C–mutated pancreatic cancer patients were enroled with a median follow-up of 8.9 months (range 1.1–22.9). Among 22 evaluable patients, the confirmed objective response rate (ORR) was 45.5% (95% CI, 24.4 to 67.8) with a median duration of response (DOR) of 6.4 months (95% CI, 4.2 to 16.4). The median progression-free survival (PFS) was 7.6 months (95% CI, 3.3 to 8.5) and the 6-month OS rate was 79.2% (95% CI, 57.0, 90.8). Treatment-related adverse events (TRAEs) occurred in 18 (75.0%) patients, including 6 (25.0%) with grade ≥3 events. No TRAEs led to treatment discontinuation. The safety profile was consistent with previous reports of garsorasib. Garsorasib demonstrated encouraging antitumor activity and a tolerable safety profile in patients with KRAS G12C-mutated advanced pancreatic cancer.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 3","pages":"457-462"},"PeriodicalIF":6.8,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145676374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-04DOI: 10.1038/s41416-025-03295-9
Christoph Springfeld, Thilo Hackert, Daniel H. Palmer, Daniel Öhlund, Teresa Peccerella, Thomas Hank, Markus W. Büchler, Christoph W. Michalski, John P. Neoptolemos
The biggest impact on increasing survival for pancreatic cancer has come about by combining surgical resection with systemic chemotherapy. This groundbreaking paradigm has come under increasing scrutiny relating to the choice of adding chemoradiotherapy to chemotherapy versus chemotherapy alone, neoadjuvant versus adjuvant therapy and the optimal regimens. The paradigm has also been challenged in that a distinction needs to be made between ‘resected’ with ‘resectable’ pancreatic cancer, since if only the former is considered, this leads to a biased prognostically favourable patient group being analysed. Moreover, the distinction between resectable, borderline resectable and unresectable cancers is claimed to be so unreliable that this classification should be discouraged in favour of upfront chemotherapy for all patients and not necessarily using either FOLFIRINOX or gemcitabine-capecitabine. The results of a series of recent trials including the RTOG0848 trial of adjuvant chemotherapy with or without chemoradiation and the NORPACT-1 trial of neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic cancer have significantly contributed to the clarification of some these questions. The results of long-term follow-up studies of the adjuvant PRODIGE24 trial comparing FOLFIRINOX with gemcitabine and the ESPAC4 trial of gemcitabine-capecitabine versus gemcitabine have also consolidated and expanded the applicability of adjuvant chemotherapy.
{"title":"New implications from long-term outcomes of perioperative therapy in resectable pancreatic cancer","authors":"Christoph Springfeld, Thilo Hackert, Daniel H. Palmer, Daniel Öhlund, Teresa Peccerella, Thomas Hank, Markus W. Büchler, Christoph W. Michalski, John P. Neoptolemos","doi":"10.1038/s41416-025-03295-9","DOIUrl":"10.1038/s41416-025-03295-9","url":null,"abstract":"The biggest impact on increasing survival for pancreatic cancer has come about by combining surgical resection with systemic chemotherapy. This groundbreaking paradigm has come under increasing scrutiny relating to the choice of adding chemoradiotherapy to chemotherapy versus chemotherapy alone, neoadjuvant versus adjuvant therapy and the optimal regimens. The paradigm has also been challenged in that a distinction needs to be made between ‘resected’ with ‘resectable’ pancreatic cancer, since if only the former is considered, this leads to a biased prognostically favourable patient group being analysed. Moreover, the distinction between resectable, borderline resectable and unresectable cancers is claimed to be so unreliable that this classification should be discouraged in favour of upfront chemotherapy for all patients and not necessarily using either FOLFIRINOX or gemcitabine-capecitabine. The results of a series of recent trials including the RTOG0848 trial of adjuvant chemotherapy with or without chemoradiation and the NORPACT-1 trial of neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic cancer have significantly contributed to the clarification of some these questions. The results of long-term follow-up studies of the adjuvant PRODIGE24 trial comparing FOLFIRINOX with gemcitabine and the ESPAC4 trial of gemcitabine-capecitabine versus gemcitabine have also consolidated and expanded the applicability of adjuvant chemotherapy.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 4","pages":"531-542"},"PeriodicalIF":6.8,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-025-03295-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145676547","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}
Pub Date : 2025-12-03DOI: 10.1038/s41416-025-03288-8
Jeppe Lyngbye Widding, Hein Vincent Stroomberg, Susanne Oksbjerg Dalton, Klaus Brasso, Andreas Røder, Signe Benzon Larsen
We investigated how lower urinary tract symptoms (LUTS) and urinary tract infections (UTIs) affect prostate-specific antigen (PSA) testing and prostate cancer (PCa) workup. Furthermore, we examined the likelihood of high-grade PCa (Gleason score ≥7) and risk factors of high-grade PCa in men with LUTS/UTIs. We identified all men having a first prostate biopsy in Denmark between 2010–2021 and matched with five age-matched controls without a biopsy. LUTS/UTIs was assessed in the year preceding biopsy based on diagnoses and prescriptions obtained from national health registers. Odds ratios (OR) were calculated using crude and multivariable logistic regression models. In 63,931 men with a first biopsy, 42% had LUTS/UTIs, compared to 16% of controls. For men with LUTS/UTIs the OR of biopsy was 4.30 (95% CI: 4.22–4.38) and 0.56 (95% CI: 0.54–0.58) for high-grade PCa at biopsy after adjustments, compared to men without LUTS/UTIs. The likelihood of high-grade PCa was significantly higher in men with increasing age, and a Charlson Comorbidity Index ≥2, but not with a known family history of PCa. PSA testing in men with LUTS/UTIs increases diagnostic PCa workup, but LUTS/UTIs are not associated with an increased likelihood of high-grade PCa at first biopsy.
{"title":"The association between lower urinary tract symptoms and urinary tract infections, and subsequent prostate cancer workup: a nationwide population-based case-control study","authors":"Jeppe Lyngbye Widding, Hein Vincent Stroomberg, Susanne Oksbjerg Dalton, Klaus Brasso, Andreas Røder, Signe Benzon Larsen","doi":"10.1038/s41416-025-03288-8","DOIUrl":"10.1038/s41416-025-03288-8","url":null,"abstract":"We investigated how lower urinary tract symptoms (LUTS) and urinary tract infections (UTIs) affect prostate-specific antigen (PSA) testing and prostate cancer (PCa) workup. Furthermore, we examined the likelihood of high-grade PCa (Gleason score ≥7) and risk factors of high-grade PCa in men with LUTS/UTIs. We identified all men having a first prostate biopsy in Denmark between 2010–2021 and matched with five age-matched controls without a biopsy. LUTS/UTIs was assessed in the year preceding biopsy based on diagnoses and prescriptions obtained from national health registers. Odds ratios (OR) were calculated using crude and multivariable logistic regression models. In 63,931 men with a first biopsy, 42% had LUTS/UTIs, compared to 16% of controls. For men with LUTS/UTIs the OR of biopsy was 4.30 (95% CI: 4.22–4.38) and 0.56 (95% CI: 0.54–0.58) for high-grade PCa at biopsy after adjustments, compared to men without LUTS/UTIs. The likelihood of high-grade PCa was significantly higher in men with increasing age, and a Charlson Comorbidity Index ≥2, but not with a known family history of PCa. PSA testing in men with LUTS/UTIs increases diagnostic PCa workup, but LUTS/UTIs are not associated with an increased likelihood of high-grade PCa at first biopsy.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 3","pages":"486-492"},"PeriodicalIF":6.8,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145667096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01DOI: 10.1038/s41416-025-03213-z
John Buckell, Nomalanga Madyiwa, Gail Hayward, Mark R. Middleton, FD Richard Hobbs, James Buchanan, Apostolos Tsiachristas, Brian D. Nicholson
{"title":"Correction: Preferences for multi-cancer tests (MCTs) in primary care: discrete choice experiments of general practitioners and the general public in England","authors":"John Buckell, Nomalanga Madyiwa, Gail Hayward, Mark R. Middleton, FD Richard Hobbs, James Buchanan, Apostolos Tsiachristas, Brian D. Nicholson","doi":"10.1038/s41416-025-03213-z","DOIUrl":"10.1038/s41416-025-03213-z","url":null,"abstract":"","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 1","pages":"175-176"},"PeriodicalIF":6.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-025-03213-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145653935","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}
Pub Date : 2025-12-01DOI: 10.1038/s41416-025-03226-8
Konstantina Dimopoulou, Aris Spathis, Christina Papamichail, Aikaterini Athanasiadou, Abraham Pouliakis, Christakis Risilia, Despoina Myoteri, Panayiotis Kokoropoulos, Manousos Konstantoulakis, Ioannis G. Panayiotides, Nikolaos Arkadopoulos, Dina Tiniakos, Periklis G. Foukas
Tumour antigen-specific CD8+CD39+ T cells (TSTs) are crucial components of anti-tumour adaptive immunity, which in tumour microenvironment (TME) may be found at various differentiation stages, from early stem-like states to terminal stages of exhaustion. Our aim was the evaluation of TSTs quantitative and qualitative characteristics in hepatocellular carcinoma (HCC) TME, depending on whether they exhibit stem-like or exhaustion features. We analyzed 100 HCC patients undergoing curative hepatectomy. Multiplex immunohistochemistry (CD8/CD39/TCF1, CD8/CD39/TOX) was applied on tissue microarray sections with digital imaging used to evaluate T cell infiltration in tumour center, periphery and adjacent non-neoplastic liver. Tertiary lymphoid structures (TLS) were assessed on H&E-stained slides. In HCC TME, 72% of CD8+ T cells co-express CD39, while 44% of CD8+CD39+ TSTs co-express TCF1 (stem-like) and over 50% co-express TOX (exhausted). High CD8+CD39+ T cell density in tumour periphery was linked to longer overall survival (p = 0.016). Increased CD8+CD39-TCF1+ T cell infiltration in tumour center and periphery correlated with worse prognosis (p = 0.009). TLS presence was associated with high TST density (p < 0.001). Patients with HCC and high CD8+CD39+ TSTs density exhibiting a tumour-reactive phenotype have improved survival, suggesting the potential role of CD8/CD39 immunohistochemistry as a prognostic tool for personalised therapeutic strategies.
{"title":"Antigen-specific CD8+CD39+ cytotoxic T cell density in the microenvironment of hepatocellular carcinoma predicts patient survival","authors":"Konstantina Dimopoulou, Aris Spathis, Christina Papamichail, Aikaterini Athanasiadou, Abraham Pouliakis, Christakis Risilia, Despoina Myoteri, Panayiotis Kokoropoulos, Manousos Konstantoulakis, Ioannis G. Panayiotides, Nikolaos Arkadopoulos, Dina Tiniakos, Periklis G. Foukas","doi":"10.1038/s41416-025-03226-8","DOIUrl":"10.1038/s41416-025-03226-8","url":null,"abstract":"Tumour antigen-specific CD8+CD39+ T cells (TSTs) are crucial components of anti-tumour adaptive immunity, which in tumour microenvironment (TME) may be found at various differentiation stages, from early stem-like states to terminal stages of exhaustion. Our aim was the evaluation of TSTs quantitative and qualitative characteristics in hepatocellular carcinoma (HCC) TME, depending on whether they exhibit stem-like or exhaustion features. We analyzed 100 HCC patients undergoing curative hepatectomy. Multiplex immunohistochemistry (CD8/CD39/TCF1, CD8/CD39/TOX) was applied on tissue microarray sections with digital imaging used to evaluate T cell infiltration in tumour center, periphery and adjacent non-neoplastic liver. Tertiary lymphoid structures (TLS) were assessed on H&E-stained slides. In HCC TME, 72% of CD8+ T cells co-express CD39, while 44% of CD8+CD39+ TSTs co-express TCF1 (stem-like) and over 50% co-express TOX (exhausted). High CD8+CD39+ T cell density in tumour periphery was linked to longer overall survival (p = 0.016). Increased CD8+CD39-TCF1+ T cell infiltration in tumour center and periphery correlated with worse prognosis (p = 0.009). TLS presence was associated with high TST density (p < 0.001). Patients with HCC and high CD8+CD39+ TSTs density exhibiting a tumour-reactive phenotype have improved survival, suggesting the potential role of CD8/CD39 immunohistochemistry as a prognostic tool for personalised therapeutic strategies.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 3","pages":"447-456"},"PeriodicalIF":6.8,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145653785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-29DOI: 10.1038/s41416-025-03289-7
Jiarui Li, Lian Liu, Min Tao, Zihan Han, Mingyang Ma, Lei Jiang, Chang Liu, Dan Liu, Panpan Zhang, Miao Zhang, Ran Xue, Jifang Gong, Xiaotian Zhang, Lin Shen, Changsong Qi
Claudin18.2 (CLDN18.2)-specific CAR-T cell therapy has demonstrated promise in advanced gastric cancer (GC). However, the impact of concomitant medications on the efficacy outcomes remains unclear. We retrospectively analyzed advanced GC patients receiving CLDN18.2-specific CAR-T cell therapy from a phase I trial. Concomitant medications were defined as any drugs administered within 30 days before and after CAR-T cell infusion, including corticosteroids, antibiotics, tocilizumab, granulocyte colony-stimulating factor (G-CSF), thrombopoietin (TPO), and erythropoietin. Metagenomic sequencing was employed to elucidate the differences in gut microbiome signatures between responders and non-responders. Of 72 patients included in the study, 6 (8.3%) received corticosteroids, 49 (68.1%) received tocilizumab, and 22 (30.6%) received antibiotics, 15 (20.8%) received G-CSF, 5 (6.9%) received thrombopoietin, and no patient received erythropoietin. The median progression-free survival (PFS) (2.6 vs. 5.8 months; P < 0.001) and overall survival (OS) (3.9 vs. 9.5 months; P < 0.001) were significantly shorter for patients who received antibiotics for infection compared to those who did not. No significant differences were observed in objective response rate (ORR), PFS, and OS between patients who received corticosteroids, tocilizumab, antibiotics for prophylaxis, G-CSF, or TPO and those who did not. A higher abundance of Fusobacterium nucleatum, Lactobacillus mucosae, Prevotella pallens, and Streptococcus pseudopneumoniae in gut microbiome was associated with a superior treatment response. The study indicates that the use of antibiotics for infection reduces the efficacy outcomes of CLDN18.2-specific CAR-T cell therapy for advanced GC, while other concomitant medications do not affect the outcomes. Further research is needed to clarify the optimal administration of these medications and the underlying mechanisms of the gut microbiome in impacting CAR-T treatment response. NCT03874897
{"title":"Impact of concomitant medications on efficacy of CLDN18.2-specific CAR-T cell therapy in advanced gastric cancer","authors":"Jiarui Li, Lian Liu, Min Tao, Zihan Han, Mingyang Ma, Lei Jiang, Chang Liu, Dan Liu, Panpan Zhang, Miao Zhang, Ran Xue, Jifang Gong, Xiaotian Zhang, Lin Shen, Changsong Qi","doi":"10.1038/s41416-025-03289-7","DOIUrl":"10.1038/s41416-025-03289-7","url":null,"abstract":"Claudin18.2 (CLDN18.2)-specific CAR-T cell therapy has demonstrated promise in advanced gastric cancer (GC). However, the impact of concomitant medications on the efficacy outcomes remains unclear. We retrospectively analyzed advanced GC patients receiving CLDN18.2-specific CAR-T cell therapy from a phase I trial. Concomitant medications were defined as any drugs administered within 30 days before and after CAR-T cell infusion, including corticosteroids, antibiotics, tocilizumab, granulocyte colony-stimulating factor (G-CSF), thrombopoietin (TPO), and erythropoietin. Metagenomic sequencing was employed to elucidate the differences in gut microbiome signatures between responders and non-responders. Of 72 patients included in the study, 6 (8.3%) received corticosteroids, 49 (68.1%) received tocilizumab, and 22 (30.6%) received antibiotics, 15 (20.8%) received G-CSF, 5 (6.9%) received thrombopoietin, and no patient received erythropoietin. The median progression-free survival (PFS) (2.6 vs. 5.8 months; P < 0.001) and overall survival (OS) (3.9 vs. 9.5 months; P < 0.001) were significantly shorter for patients who received antibiotics for infection compared to those who did not. No significant differences were observed in objective response rate (ORR), PFS, and OS between patients who received corticosteroids, tocilizumab, antibiotics for prophylaxis, G-CSF, or TPO and those who did not. A higher abundance of Fusobacterium nucleatum, Lactobacillus mucosae, Prevotella pallens, and Streptococcus pseudopneumoniae in gut microbiome was associated with a superior treatment response. The study indicates that the use of antibiotics for infection reduces the efficacy outcomes of CLDN18.2-specific CAR-T cell therapy for advanced GC, while other concomitant medications do not affect the outcomes. Further research is needed to clarify the optimal administration of these medications and the underlying mechanisms of the gut microbiome in impacting CAR-T treatment response. NCT03874897","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 3","pages":"439-446"},"PeriodicalIF":6.8,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145630264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-28DOI: 10.1038/s41416-025-03269-x
Qing Huang, Juan Zhao, Yang Zhang, Ying Zhou, Xuyang Yang, Xiaoting Chen, Mingtian Wei, Junhong Han, Yaguang Zhang
Background: Translational reprogramming enables cancer cells to drive tumour progression and metastasis. eIF3i is a core component of the translational regulatory machinery, but the underlying mechanisms through which it promotes tumour metastasis remain unclear.
Methods: Proteomic analysis identified eIF3i-regulated targets. Functional validation utilised in vitro and in vivo models, including migration/invasion assays, polysome profiling, RNA-binding assays (RIP and RNA pull-down), and mouse metastatic models. Clinical relevance was assessed in CRC patients with liver metastases.
Results: eIF3i was significantly overexpressed in metastatic CRC. Its knockdown inhibited cell migration, invasion, epithelial-mesenchymal transition (EMT), invadopodia formation in vitro, and lung metastasis in vivo. NELFCD was identified as a key downstream target, whose translation is directly promoted by eIF3i binding to its mRNA, independent of transcription. NELFCD knockdown phenocopied the anti-metastatic effects of eIF3i depletion. Crucially, the pro-metastatic capacity of eIF3i overexpression was abolished by concurrent NELFCD knockdown. eIF3i and NELFCD protein levels showed a significant positive correlation in clinical CRC metastases.
Conclusions: The eIF3i-NELFCD axis drives CRC metastasis by directly upregulating NELFCD translation, thereby facilitating EMT and invadopodia formation. This pathway represents a promising therapeutic target for inhibiting metastatic progression in CRC.
{"title":"eIF3i facilitates NELFCD translation to promote metastasis via regulating EMT and invadopodia.","authors":"Qing Huang, Juan Zhao, Yang Zhang, Ying Zhou, Xuyang Yang, Xiaoting Chen, Mingtian Wei, Junhong Han, Yaguang Zhang","doi":"10.1038/s41416-025-03269-x","DOIUrl":"https://doi.org/10.1038/s41416-025-03269-x","url":null,"abstract":"<p><strong>Background: </strong>Translational reprogramming enables cancer cells to drive tumour progression and metastasis. eIF3i is a core component of the translational regulatory machinery, but the underlying mechanisms through which it promotes tumour metastasis remain unclear.</p><p><strong>Methods: </strong>Proteomic analysis identified eIF3i-regulated targets. Functional validation utilised in vitro and in vivo models, including migration/invasion assays, polysome profiling, RNA-binding assays (RIP and RNA pull-down), and mouse metastatic models. Clinical relevance was assessed in CRC patients with liver metastases.</p><p><strong>Results: </strong>eIF3i was significantly overexpressed in metastatic CRC. Its knockdown inhibited cell migration, invasion, epithelial-mesenchymal transition (EMT), invadopodia formation in vitro, and lung metastasis in vivo. NELFCD was identified as a key downstream target, whose translation is directly promoted by eIF3i binding to its mRNA, independent of transcription. NELFCD knockdown phenocopied the anti-metastatic effects of eIF3i depletion. Crucially, the pro-metastatic capacity of eIF3i overexpression was abolished by concurrent NELFCD knockdown. eIF3i and NELFCD protein levels showed a significant positive correlation in clinical CRC metastases.</p><p><strong>Conclusions: </strong>The eIF3i-NELFCD axis drives CRC metastasis by directly upregulating NELFCD translation, thereby facilitating EMT and invadopodia formation. This pathway represents a promising therapeutic target for inhibiting metastatic progression in CRC.</p>","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":" ","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145630231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-27DOI: 10.1038/s41416-025-03291-z
Mererid Evans, Chris Hurt, Rhian Rhys, Abhishek Mahajan, Andrew McQueen, Joanna Dixon, Max Robinson, Neil Robinson, Keith Hunter, Adam Christian, Adam Jones, Aline Queiroz, Shao Hui Huang, Brian O’Sullivan, Joanna Canham, Christie Heiberg, Terry Jones
Imaging-detected and pathological extranodal extension (iENE, pENE) negatively impact prognosis in Human Papillomavirus (HPV)-positive oropharyngeal cancer (OPSCC), as reflected in future TNM staging updates. Correlation between iENE and pENE in HPV-positive OPSCC is currently unknown yet is vital to determine how iENE should be used to influence treatment decisions. PATHOS is a trial of de-intensified adjuvant treatment after transoral surgery for HPV-positive OPSCC. 291 consecutively recruited patients undergoing surgery at three UK centres were included. Pre-operative cross-sectional imaging (CT and/or MRI) was independently scored for iENE by 2 expert radiologists; pENE was scored by 2 expert pathologists. Inter-rater agreement for iENE was fair in round 1 (Gwet’s AC: 0.34 (95%CI:0.26–0.41)) but improved to very good after second review (Gwet’s AC: 0.88 (95%CI:0.85–0.93), Agreement: 0.91 (95%CI:0.87–0.94)). Sensitivity of iENE for predicting pENE was relatively low (at best: 56.4% (95%CI:42.3–69.7) and specificity was high (at worst: 70.9% (95%CI:65.0–76.3)). Excluding cases with suboptimal image quality and recent core biopsy produced modest improvements in sensitivity (up to 59.4% (95%CI:40.6–76.3)) and specificity (up to 87.8% (95%CI:80.4–93.2)). The high specificity could help select iENE-negative patients for surgery, but higher sensitivity is required before excluding surgery based solely on iENE positivity.
{"title":"Correlation between imaging-detected and pathological extranodal extension in a randomised trial in Human Papillomavirus-positive oropharyngeal cancer","authors":"Mererid Evans, Chris Hurt, Rhian Rhys, Abhishek Mahajan, Andrew McQueen, Joanna Dixon, Max Robinson, Neil Robinson, Keith Hunter, Adam Christian, Adam Jones, Aline Queiroz, Shao Hui Huang, Brian O’Sullivan, Joanna Canham, Christie Heiberg, Terry Jones","doi":"10.1038/s41416-025-03291-z","DOIUrl":"10.1038/s41416-025-03291-z","url":null,"abstract":"Imaging-detected and pathological extranodal extension (iENE, pENE) negatively impact prognosis in Human Papillomavirus (HPV)-positive oropharyngeal cancer (OPSCC), as reflected in future TNM staging updates. Correlation between iENE and pENE in HPV-positive OPSCC is currently unknown yet is vital to determine how iENE should be used to influence treatment decisions. PATHOS is a trial of de-intensified adjuvant treatment after transoral surgery for HPV-positive OPSCC. 291 consecutively recruited patients undergoing surgery at three UK centres were included. Pre-operative cross-sectional imaging (CT and/or MRI) was independently scored for iENE by 2 expert radiologists; pENE was scored by 2 expert pathologists. Inter-rater agreement for iENE was fair in round 1 (Gwet’s AC: 0.34 (95%CI:0.26–0.41)) but improved to very good after second review (Gwet’s AC: 0.88 (95%CI:0.85–0.93), Agreement: 0.91 (95%CI:0.87–0.94)). Sensitivity of iENE for predicting pENE was relatively low (at best: 56.4% (95%CI:42.3–69.7) and specificity was high (at worst: 70.9% (95%CI:65.0–76.3)). Excluding cases with suboptimal image quality and recent core biopsy produced modest improvements in sensitivity (up to 59.4% (95%CI:40.6–76.3)) and specificity (up to 87.8% (95%CI:80.4–93.2)). The high specificity could help select iENE-negative patients for surgery, but higher sensitivity is required before excluding surgery based solely on iENE positivity.","PeriodicalId":9243,"journal":{"name":"British Journal of Cancer","volume":"134 3","pages":"428-438"},"PeriodicalIF":6.8,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41416-025-03291-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145630278","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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