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Evaluating trastuzumab deruxtecan in patients with gastrooesophageal adenocarcinoma who are ctDNA and HER2 positive: DECIPHER
Pub Date : 2024-12-01 DOI: 10.1016/j.esmogo.2024.100114
E. Smyth , D. Griffiths , K. Cozens , S. Ewings , R. Waugh , R.C. Turkington , K. Foley , R. Roy , S. Ngan , R. Owen , D. Chuter , C. Steele , G. Griffiths
Operable gastrooesophageal adenocarcinoma (GOA) is treated with multimodality therapy which is curative in <50% of patients. Patients in the UK with operable GOA are treated with chemotherapy before and following surgery. Patients who have circulating tumour DNA (ctDNA) present after surgery have worse survival than ctDNA-negative patients. Trastuzumab deruxtecan (T-DXd), a novel human epidermal growth factor receptor 2 (HER2)-targeting antibody–drug conjugate is an effective drug in multiple tumour types and has been licensed to treat advanced HER2-positive GOA that has progressed after chemotherapy and trastuzumab and is European Society for Medical Oncology (ESMO) Guideline recommended. Evaluation of T-DXd in operable but micrometastatic GOA is an attractive option. DECIPHER is a multicentre, phase II trial testing the efficacy of T-DXd in reducing micrometastatic disease burden in HER2-positive GOA patients who are ctDNA positive after neoadjuvant chemotherapy and surgery. Patients will have their resection specimen and plasma analysed to confirm HER2 and ctDNA status post-operatively. Twenty-five ctDNA- and HER2-positive patients will be treated with 6.4 mg/kg T-DXd intravenously every 21 days for a maximum of eight cycles. Study follow-up visits will take place for a maximum of 2 years after treatment, with survival follow-up until the end of the study.
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引用次数: 0
PD-L1 as a response biomarker to chemotherapy plus immune checkpoint inhibitors in operable gastroesophageal adenocarcinoma: a meta-analysis of neoadjuvant clinical trials PD-L1 作为可手术胃食管腺癌化疗加免疫检查点抑制剂的反应生物标记物:新辅助临床试验荟萃分析
Pub Date : 2024-11-27 DOI: 10.1016/j.esmogo.2024.100107
A. Cammarota , S.K. Kamarajah , S. Markar , E.C. Smyth

Background

Perioperative chemoimmunotherapy [i.e. chemotherapy plus immune checkpoint inhibitor (ICI) (ChT–ICI)] is an investigational treatment for operable gastroesophageal adenocarcinoma (GEA) with unclear outcomes in an unselected population. We aimed to assess the cumulative treatment effect of ChT–ICI on pathological response rates, the surrogacy of pathological response rates on overall survival (OS), and the value of programmed death-ligand 1 (PD-L1) as a biomarker of response to ICIs in operable GEA.

Methods

We conducted a systematic review and meta-analysis of randomised clinical trials (RCTs) of ChT with or without ICIs with the primary outcome being pathological response rates [pathological complete response (pCR) and similar metrics]. A weighted linear regression model quantified the relationship between pathological response rates and OS using a determination coefficient (R2). A second meta-regression analysed the predictive effect of PD-L1 on pCR in trials of ICIs with ChT or chemoradiotherapy (CRT).

Results

A total of 18 records from 15 RCTs were included. Of 6624 patients, 5291 received ChT and 1333 ChT–ICI. ChT–ICI significantly improved pathological response rates [pooled odds ratio 3.18, 95% confidence interval (CI) 2.42-4.18, P < 0.0001] compared with ChT (pooled odds ratio 1.66, 95% CI 1.33-2.07, P < 0.0001). The correlation between pathological response and OS was low (R2 = 0.12) but improved in recent trials (R2 = 0.51) and those with ChT–biological agents, including ICIs (R2 = 0.79). In the second analysis (11 studies, 633 patients), PD-L1 ≥5 was a significant predictor of response both individually (estimate: 0.73, 95% CI 0.28-1.18, P = 0.001) and after accounting for the backbone treatment (estimate: 0.80, 95% CI 0.28-1.33, P = 0.003).

Conclusions

Perioperative ChT–ICI improves pathological response rates in operable GEA and PD-L1 ≥5 is a significant biomarker of pCR, supporting stratification by PD-L1 and the design of biomarker-selected trials.
背景围手术期化学免疫疗法[即化疗加免疫检查点抑制剂(ICI)(ChT-ICI)]是一种针对可手术胃食管腺癌(GEA)的研究性治疗方法,但在未入选人群中疗效并不明确。我们旨在评估ChT-ICI对病理反应率的累积治疗效果、病理反应率对总生存期(OS)的替代作用,以及程序性死亡配体1(PD-L1)作为可手术GEA对ICIs反应的生物标志物的价值。方法我们对使用或不使用ICIs的ChT随机临床试验(RCT)进行了系统回顾和荟萃分析,主要结果是病理反应率[病理完全反应(pCR)及类似指标]。加权线性回归模型使用判定系数(R2)量化了病理应答率与OS之间的关系。第二项元回归分析了 ICIs 与 ChT 或化放疗 (CRT) 试验中 PD-L1 对 pCR 的预测作用。在6624例患者中,5291例接受了ChT,1333例接受了ChT-ICI。与 ChT 相比,ChT-ICI 能明显提高病理反应率[汇总几率比 3.18,95% 置信区间 (CI) 2.42-4.18,P <0.0001](汇总几率比 1.66,95% CI 1.33-2.07,P <0.0001)。病理反应与OS之间的相关性较低(R2 = 0.12),但在近期试验(R2 = 0.51)和使用ChT-生物制剂(包括ICIs)的试验(R2 = 0.79)中得到改善。在第二项分析(11 项研究,633 名患者)中,PD-L1 ≥5是预测反应的一个重要指标,无论是单独预测(估计值:0.73,95% CI 0.28-1.18,P = 0.001)还是考虑骨干治疗(估计值:0.80,95% CI 0.结论围手术期 ChT-ICI 可提高可手术 GEA 的病理反应率,PD-L1 ≥5 是 pCR 的重要生物标志物,支持根据 PD-L1 进行分层和设计生物标志物选择试验。
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引用次数: 0
Practical management of oligometastatic gastric cancer 寡转移胃癌的实用治疗方法
Pub Date : 2024-11-21 DOI: 10.1016/j.esmogo.2024.100108
Y. Narita , K. Muro , D. Takahari
Gastric cancer is one of the types of cancer with a high prevalence of morbidity. The frequency of esophagogastric junction cancer, 5-year survival rates, perioperative adjuvant therapy, and standard chemotherapeutic regimens for gastric cancer vary between Asian countries and the West. Although oligometastasis is considered an intermediate state between localized and systemic disease, no standardized definition regarding metastatic organ sites or international consensus in gastric cancer exists. Both local treatment, such as radical surgery and radiotherapy, and systemic chemotherapy can be employed for treating patients with gastric cancer with oligometastatic disease. Recently, evidence for oligometastatic gastric cancer has been accumulated, including findings from several clinical trials conducted in Asian and Western countries, focusing on both organ-specific and non-organ-specific oligometastatic gastric cancer. Here, we review the latest findings on oligometastasis in gastric cancer, including variations in treatment strategies between Western and Asian countries. Further investigation is needed to determine the most favorable practical management strategies for patients with metachronous oligometastasis in gastric cancer, including the use of molecular-targeted agents and immune checkpoint inhibitors. The results of ongoing trials may shed light on the optimal treatment approaches for oligometastatic disease.
胃癌是发病率较高的癌症类型之一。亚洲国家与西方国家在食管胃交界处癌的发病率、5 年生存率、围手术期辅助治疗以及胃癌标准化疗方案方面存在差异。虽然寡转移被认为是介于局部和全身疾病之间的一种中间状态,但目前还没有关于胃癌转移器官部位的标准化定义或国际共识。局部治疗(如根治性手术和放疗)和全身化疗均可用于治疗寡转移性胃癌患者。最近,寡转移性胃癌的证据不断积累,包括在亚洲和西方国家进行的几项临床试验的结果,主要针对器官特异性和非器官特异性寡转移性胃癌。在此,我们回顾了胃癌寡转移的最新研究结果,包括西方国家和亚洲国家在治疗策略上的差异。对于胃癌转移性寡转移患者,包括使用分子靶向药物和免疫检查点抑制剂,需要进一步研究确定最有利的实际治疗策略。正在进行的试验结果可能会为寡转移疾病的最佳治疗方法提供启示。
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引用次数: 0
Risk factor of severe diarrhea and enterocolitis induced by CAPOX: a retrospective multicenter study CAPOX 引发严重腹泻和肠炎的风险因素:一项回顾性多中心研究
Pub Date : 2024-11-20 DOI: 10.1016/j.esmogo.2024.100110
A. Teixeira , T. Felismino , M.D. Donadio , G. Catani , A.L.M. da Silva , R. Weschenfelder , R.D. Peixoto , J.M. O’Connor , A.K. Coutinho , R.P. Riechelmann

Background

We have previously suggested that concurrent use of capecitabine plus oxaliplatin (CAPOX) and angiotensin receptor blockers (ARBs) significantly increased the risk of severe diarrhea and/or enterocolitis. We conducted a multicenter larger study to validate this finding, adjusting for other risk factors.

Patients and methods

This was a retrospective multicenter study of patients with colorectal cancer treated with at least one cycle of CAPOX. The primary endpoint was grade (G) ≥3 diarrhea and/or enterocolitis induced by CAPOX. Unadjusted and adjusted logistic regression models were used to evaluate risk factors for G ≥3 diarrhea and/or enterocolitis. P < 0.05 was deemed significant.

Results

From April 2010 to December 2023, 362 patients were included. In univariate analyses, age ≥65 years, right-sided tumors, use of ARBs or angiotensin-converting enzyme inhibitors (ACEi), age-adjusted Charlson Comorbidity Index, and estimated glomerular filtration rate (eGFR) <60 ml/min were associated with G ≥3 diarrhea and/or enterocolitis. In the multivariable analysis, age ≥65 years [odds ratio (OR) 2.71, 95% confidence interval (CI) 1.38-5.33, P = 0.004] and eGFR <60 ml/min (OR 5.4, 95% CI 2.25-13.8, P < 0.001), but not use of ARBs or ACEi, were significant.

Conclusions

Age ≥65 years and eGFR <60 ml/min were independent risk factors for G ≥3 diarrhea/enterocolitis in patients treated with CAPOX. Concurrent use of ARBs or ACEi was not associated with G ≥3 diarrhea/enterocolitis.
背景我们曾提出,同时使用卡培他滨加奥沙利铂(CAPOX)和血管紧张素受体阻滞剂(ARB)会显著增加严重腹泻和/或肠炎的风险。患者和方法这是一项回顾性多中心研究,研究对象是接受至少一个周期 CAPOX 治疗的结直肠癌患者。主要终点是CAPOX诱发的≥3级腹泻和/或小肠结肠炎。未调整和调整后的逻辑回归模型用于评估G≥3级腹泻和/或肠结肠炎的风险因素。结果从 2010 年 4 月到 2023 年 12 月,共纳入 362 例患者。在单变量分析中,年龄≥65岁、右侧肿瘤、使用ARB或血管紧张素转换酶抑制剂(ACEi)、年龄调整后的Charlson合并症指数和估计肾小球滤过率(eGFR)<60 ml/min与G≥3腹泻和/或小肠结肠炎相关。在多变量分析中,年龄≥65 岁 [odds ratio (OR) 2.71, 95% confidence interval (CI) 1.38-5.33, P = 0.004] 和 eGFR <60 ml/min (OR 5.4, 95% CI 2.25-13.8, P < 0.结论年龄≥65 岁和 eGFR <60 ml/min 是接受 CAPOX 治疗的患者发生 G≥3 腹泻/肠炎的独立危险因素。同时使用 ARBs 或 ACEi 与 G≥3 腹泻/小肠结肠炎无关。
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引用次数: 0
Gastrin-releasing peptide receptor expression in gastrointestinal stromal tumours 胃肠道间质瘤中胃泌素释放肽受体的表达
Pub Date : 2024-11-04 DOI: 10.1016/j.esmogo.2024.100105
M. Berndsen , F. Puls , A. Thornell , Y. Arvidsson , A. Muth , S. Lindskog , E. Elias

Background

There are limited treatment options for patients with advanced or metastatic gastrointestinal stromal tumours (GISTs) that lack mutations targetable by tyrosine kinase inhibitors (TKIs) or that have developed resistance to TKIs. Gastrin-releasing peptide receptor (GRPR) theranostics may offer a viable option in GISTs. However, the expression of the GRPR in GIST has not been extensively studied.

Materials and methods

GRPR expression was evaluated using immunohistochemistry in two separate tissue microarrays from patients treated at Sahlgrenska University Hospital, one from the pre-TKI era (1983-2001) and the other from the post-TKI era (2014-2020). In total, 205 tumour samples were characterized as having low/none or moderate/high expression of the GRPR, and these were correlated with clinical characteristics and survival outcomes.

Results

In total, 80% of the tumour samples exhibited moderate or high expression of GRPR. GRPR expression was not associated with gender, age, tumour location, or risk group, as defined by the modified National Institutes of Health (NIH) consensus criteria. Neoadjuvant treatment with TKI was correlated with low/none GRPR expression (P = 0.04). In patients who underwent surgery with curative intent and did not receive neoadjuvant treatment, GRPR expression was not associated with survival outcomes.

Conclusions

This study is the first to investigate GRPR expression in a large cohort of GIST tumours. Our results demonstrate that most GIST tumours exhibit a moderate to high expression of the receptor, suggesting that GRPR theranostics could be a viable option for TKI-resistant GIST. Interestingly, tumours that were pretreated with TKI showed lower expression levels of GRPR, indicating a need for further studies to explore this finding.
背景对于缺乏酪氨酸激酶抑制剂(TKIs)靶向突变或对TKIs产生耐药性的晚期或转移性胃肠道间质瘤(GISTs)患者,治疗方案十分有限。胃泌素释放肽受体(GRPR)治疗仪可为胃肠道间质瘤提供一种可行的选择。材料与方法采用免疫组织化学方法对胃泌素释放肽受体在两个独立的组织芯片中的表达进行了评估,这两个芯片分别来自在萨赫勒格伦斯卡大学医院接受治疗的患者,一个来自前 TKI 时代(1983-2001 年),另一个来自后 TKI 时代(2014-2020 年)。共有 205 份肿瘤样本被鉴定为 GRPR 低/无表达或中/高表达,并与临床特征和生存结果相关联。根据美国国立卫生研究院(NIH)修改后的共识标准,GRPR的表达与性别、年龄、肿瘤位置或风险组别无关。TKI新辅助治疗与低/无GRPR表达相关(P = 0.04)。在接受根治性手术且未接受新辅助治疗的患者中,GRPR表达与生存结果无关。我们的研究结果表明,大多数 GIST 肿瘤都表现出中度到高度的受体表达,这表明 GRPR 治疗仪可能是治疗 TKI 耐药 GIST 的可行选择。有趣的是,经过TKI预处理的肿瘤显示出较低的GRPR表达水平,这表明需要进一步研究来探索这一发现。
{"title":"Gastrin-releasing peptide receptor expression in gastrointestinal stromal tumours","authors":"M. Berndsen ,&nbsp;F. Puls ,&nbsp;A. Thornell ,&nbsp;Y. Arvidsson ,&nbsp;A. Muth ,&nbsp;S. Lindskog ,&nbsp;E. Elias","doi":"10.1016/j.esmogo.2024.100105","DOIUrl":"10.1016/j.esmogo.2024.100105","url":null,"abstract":"<div><h3>Background</h3><div>There are limited treatment options for patients with advanced or metastatic gastrointestinal stromal tumours (GISTs) that lack mutations targetable by tyrosine kinase inhibitors (TKIs) or that have developed resistance to TKIs. Gastrin-releasing peptide receptor (GRPR) theranostics may offer a viable option in GISTs. However, the expression of the GRPR in GIST has not been extensively studied.</div></div><div><h3>Materials and methods</h3><div>GRPR expression was evaluated using immunohistochemistry in two separate tissue microarrays from patients treated at Sahlgrenska University Hospital, one from the pre-TKI era (1983-2001) and the other from the post-TKI era (2014-2020). In total, 205 tumour samples were characterized as having low/none or moderate/high expression of the GRPR, and these were correlated with clinical characteristics and survival outcomes.</div></div><div><h3>Results</h3><div>In total, 80% of the tumour samples exhibited moderate or high expression of GRPR. GRPR expression was not associated with gender, age, tumour location, or risk group, as defined by the modified National Institutes of Health (NIH) consensus criteria. Neoadjuvant treatment with TKI was correlated with low/none GRPR expression (<em>P</em> = 0.04). In patients who underwent surgery with curative intent and did not receive neoadjuvant treatment, GRPR expression was not associated with survival outcomes.</div></div><div><h3>Conclusions</h3><div>This study is the first to investigate GRPR expression in a large cohort of GIST tumours. Our results demonstrate that most GIST tumours exhibit a moderate to high expression of the receptor, suggesting that GRPR theranostics could be a viable option for TKI-resistant GIST. Interestingly, tumours that were pretreated with TKI showed lower expression levels of GRPR, indicating a need for further studies to explore this finding.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"6 ","pages":"Article 100105"},"PeriodicalIF":0.0,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142578047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Single-cell RNA sequencing of appendiceal adenocarcinoma reveals a low proportion of epithelial cells and a fibroblast enriched tumor microenvironment 阑尾腺癌单细胞 RNA 测序显示上皮细胞比例较低,肿瘤微环境富含成纤维细胞
Pub Date : 2024-10-22 DOI: 10.1016/j.esmogo.2024.100094
B.B. Gunes , N.J. Hornstein , M. Wang , M. Yousef , M.M. Fanaeian , A. Yousef , S. Chowdhury , M.A. Zeineddine , C. Haymaker , B. Helmink , K. Fournier , J.P. Shen

Background

Appendiceal adenocarcinoma (AA) is an understudied gastrointestinal malignancy. Treatment is guided by its proximal counterpart, colorectal cancer (CRC), despite recent studies demonstrating AA’s unique mutational landscape and poor response to CRC chemotherapy. In this study, we describe AA on a single-cell level and uncover features highlighting the contrast between AA and CRC; we believe these findings will support AA as a unique disease entity and encourage further disease-specific focus.

Materials and methods

Three patients with peritoneal metastases from AA and one from CRC profiled with 5′ single-cell RNA sequencing.

Results

Traditional k-means clustering analysis of >30 000 cells revealed three canonical compartments and 11 major cell types. AA samples were mostly comprised of stromal cells (56%), while healthy appendix samples had significantly more immune and epithelial cells. Strikingly, fibroblasts were the most abundant cell type in AA with cancer-associated fibroblasts from the mucinous AA tumors showing a distinct profile from goblet cell AA or CRC. Pseudobulk analysis comparing tumor cells from AA with normal appendiceal epithelial cells demonstrated up-regulation of a diverse range of oncogenic pathways including inflammatory, epithelial–mesenchymal transition, and angiogenesis.

Conclusions

As the first application of single-cell technology to AA these data provide insight into the intratumor heterogeneity of AA and highlight the important contribution of the tumor microenvironment in this orphan disease. These results also reinforce multiple observations that AA is a unique disease entity from CRC and targeting the tumor microenvironment should be considered as a therapeutic strategy.
背景 阑尾腺癌(AA)是一种研究不足的胃肠道恶性肿瘤。尽管最近的研究表明 AA 具有独特的突变特征,且对 CRC 化疗反应不佳,但治疗仍以其近端对应的结肠直肠癌(CRC)为指导。在这项研究中,我们在单细胞水平上描述了 AA,并发现了突出 AA 与 CRC 之间对比的特征;我们相信这些发现将支持 AA 成为一种独特的疾病实体,并鼓励进一步关注特定疾病。AA样本主要由基质细胞组成(56%),而健康阑尾样本中免疫细胞和上皮细胞明显较多。令人震惊的是,成纤维细胞是 AA 中最丰富的细胞类型,来自粘液性 AA 肿瘤的癌症相关成纤维细胞显示出与鹅口疮细胞 AA 或 CRC 截然不同的特征。将 AA 的肿瘤细胞与正常阑尾上皮细胞进行比较的假包块分析表明,包括炎症、上皮-间质转化和血管生成在内的多种致癌通路都出现了上调。结论 作为首次将单细胞技术应用于 AA 的研究,这些数据让人们深入了解了 AA 的瘤内异质性,并强调了肿瘤微环境在这种孤儿病中的重要作用。这些结果还强化了多种观察结果,即 AA 是一种不同于 CRC 的独特疾病实体,应将靶向肿瘤微环境作为一种治疗策略。
{"title":"Single-cell RNA sequencing of appendiceal adenocarcinoma reveals a low proportion of epithelial cells and a fibroblast enriched tumor microenvironment","authors":"B.B. Gunes ,&nbsp;N.J. Hornstein ,&nbsp;M. Wang ,&nbsp;M. Yousef ,&nbsp;M.M. Fanaeian ,&nbsp;A. Yousef ,&nbsp;S. Chowdhury ,&nbsp;M.A. Zeineddine ,&nbsp;C. Haymaker ,&nbsp;B. Helmink ,&nbsp;K. Fournier ,&nbsp;J.P. Shen","doi":"10.1016/j.esmogo.2024.100094","DOIUrl":"10.1016/j.esmogo.2024.100094","url":null,"abstract":"<div><h3>Background</h3><div>Appendiceal adenocarcinoma (AA) is an understudied gastrointestinal malignancy. Treatment is guided by its proximal counterpart, colorectal cancer (CRC), despite recent studies demonstrating AA’s unique mutational landscape and poor response to CRC chemotherapy. In this study, we describe AA on a single-cell level and uncover features highlighting the contrast between AA and CRC; we believe these findings will support AA as a unique disease entity and encourage further disease-specific focus.</div></div><div><h3>Materials and methods</h3><div>Three patients with peritoneal metastases from AA and one from CRC profiled with 5′ single-cell RNA sequencing.</div></div><div><h3>Results</h3><div>Traditional k-means clustering analysis of &gt;30 000 cells revealed three canonical compartments and 11 major cell types. AA samples were mostly comprised of stromal cells (56%), while healthy appendix samples had significantly more immune and epithelial cells. Strikingly, fibroblasts were the most abundant cell type in AA with cancer-associated fibroblasts from the mucinous AA tumors showing a distinct profile from goblet cell AA or CRC. Pseudobulk analysis comparing tumor cells from AA with normal appendiceal epithelial cells demonstrated up-regulation of a diverse range of oncogenic pathways including inflammatory, epithelial–mesenchymal transition, and angiogenesis.</div></div><div><h3>Conclusions</h3><div>As the first application of single-cell technology to AA these data provide insight into the intratumor heterogeneity of AA and highlight the important contribution of the tumor microenvironment in this orphan disease. These results also reinforce multiple observations that AA is a unique disease entity from CRC and targeting the tumor microenvironment should be considered as a therapeutic strategy.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"6 ","pages":"Article 100094"},"PeriodicalIF":0.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142527264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
DNA methylation markers for sensitive detection of circulating tumor DNA in patients with gastroesophageal cancers 用于灵敏检测胃食管癌患者循环肿瘤 DNA 的 DNA 甲基化标记物
Pub Date : 2024-10-16 DOI: 10.1016/j.esmogo.2024.100104
N. Øgaard , C.R. Iden , S.Ø. Jensen , S.M. Mustafa , E. Aagaard , J.B. Bramsen , L.B. Ahlborn , J.P. Hasselby , K.S. Rohrberg , M.P. Achiam , C.L. Andersen , M. Mau-Sørensen

Background

Patients with gastric and gastroesophageal junction adenocarcinomas (G-GEJ ACs) face poor outcomes. Thus sensitive biomarkers for improved clinical management are highly warranted. Detection of circulating tumor DNA (ctDNA) using DNA methylation biomarkers is a highly sensitive approach for cancer detection and management. Here, we explored the potential of a tumor-agnostic test targeting DNA methylation to detect ctDNA in patients with resectable and advanced G-GEJ ACs.

Material and methods

A tumor-agnostic digital PCR test—TriMeth—targeting the gastrointestinal cancer-specific methylated genes C9orf50, KCNQ5, and CLIP4 was carried out on a total of 131 study patients. DNA from surgical tumor specimens of 29 patients with G-GEJ ACs and plasma cell-free DNA from 52 patients with advanced and resectable G-GEJ ACs, and from 50 healthy controls, were analyzed.

Results

Methylated tumor DNA was detected by TriMeth in all of the surgical tumor specimens (29/29, 100%). Furthermore, TriMeth detected ctDNA in plasma from 31/52 (60%) patients with G-GEJ AC, including in 13/17 (76%) advanced cases, and 18/35 (51%) resectable cases. ctDNA was not detected in healthy controls (0/50, 0%).

Conclusions

This study demonstrates that TriMeth may hold potential as a biomarker for identifying ctDNA in patients with G-GEJ ACs. The study sets the scene for ongoing larger clinical studies investigating the performance of TriMeth in different clinical settings.
背景胃癌和胃食管交界腺癌(G-GEJ AC)患者的预后很差。因此非常需要敏感的生物标志物来改善临床管理。利用DNA甲基化生物标志物检测循环肿瘤DNA(ctDNA)是一种高灵敏度的癌症检测和管理方法。在此,我们探讨了以DNA甲基化为靶点的肿瘤诊断测试检测可切除的晚期G-GEJ ACs患者中ctDNA的潜力。结果 TriMeth 在所有手术肿瘤标本中都检测到了甲基化的肿瘤 DNA(29/29,100%)。此外,TriMeth 还在 31/52 例(60%)G-GEJ AC 患者的血浆中检测到了 ctDNA,其中包括 13/17 例(76%)晚期病例和 18/35 例(51%)可切除病例。这项研究为正在进行的更大规模临床研究奠定了基础,这些研究将调查 TriMeth 在不同临床环境中的表现。
{"title":"DNA methylation markers for sensitive detection of circulating tumor DNA in patients with gastroesophageal cancers","authors":"N. Øgaard ,&nbsp;C.R. Iden ,&nbsp;S.Ø. Jensen ,&nbsp;S.M. Mustafa ,&nbsp;E. Aagaard ,&nbsp;J.B. Bramsen ,&nbsp;L.B. Ahlborn ,&nbsp;J.P. Hasselby ,&nbsp;K.S. Rohrberg ,&nbsp;M.P. Achiam ,&nbsp;C.L. Andersen ,&nbsp;M. Mau-Sørensen","doi":"10.1016/j.esmogo.2024.100104","DOIUrl":"10.1016/j.esmogo.2024.100104","url":null,"abstract":"<div><h3>Background</h3><div>Patients with gastric and gastroesophageal junction adenocarcinomas (G-GEJ ACs) face poor outcomes. Thus sensitive biomarkers for improved clinical management are highly warranted. Detection of circulating tumor DNA (ctDNA) using DNA methylation biomarkers is a highly sensitive approach for cancer detection and management. Here, we explored the potential of a tumor-agnostic test targeting DNA methylation to detect ctDNA in patients with resectable and advanced G-GEJ ACs.</div></div><div><h3>Material and methods</h3><div>A tumor-agnostic digital PCR test—TriMeth—targeting the gastrointestinal cancer-specific methylated genes <em>C9orf50</em>, <em>KCNQ5</em>, and <em>CLIP4</em> was carried out on a total of 131 study patients. DNA from surgical tumor specimens of 29 patients with G-GEJ ACs and plasma cell-free DNA from 52 patients with advanced and resectable G-GEJ ACs, and from 50 healthy controls, were analyzed.</div></div><div><h3>Results</h3><div>Methylated tumor DNA was detected by TriMeth in all of the surgical tumor specimens (29/29, 100%). Furthermore, TriMeth detected ctDNA in plasma from 31/52 (60%) patients with G-GEJ AC, including in 13/17 (76%) advanced cases, and 18/35 (51%) resectable cases. ctDNA was not detected in healthy controls (0/50, 0%).</div></div><div><h3>Conclusions</h3><div>This study demonstrates that TriMeth may hold potential as a biomarker for identifying ctDNA in patients with G-GEJ ACs. The study sets the scene for ongoing larger clinical studies investigating the performance of TriMeth in different clinical settings.</div></div>","PeriodicalId":100490,"journal":{"name":"ESMO Gastrointestinal Oncology","volume":"6 ","pages":"Article 100104"},"PeriodicalIF":0.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Prognostic markers in oesophageal and gastric cancer review. Are they ready for clinical practice? 食道癌和胃癌预后标志物回顾。它们准备好用于临床实践了吗?
Pub Date : 2024-10-10 DOI: 10.1016/j.esmogo.2024.100091
V. Kunene , M. Ding , M. Yap , E.A. Griffiths , P. Taniere , D. Fackrell , S. Butler , G. Contino
Oesophageal and gastric cancer outcomes remain poor despite the introduction of new treatments in the past decade. Most patients subjected to chemotherapy or surgery do not, in the long term, benefit from treatment but suffer side-effects. Although next-generation sequencing has accelerated the identification of various genomic aberrations, most have yet to be applied to routine clinical practice. Here, we review published data from systemic reviews and meta-analyses from the past 8 years reporting prognostic markers and why these have not gained traction in clinical practice and how we can improve on this.
尽管在过去十年中引入了新的治疗方法,但食道癌和胃癌的治疗效果仍然不佳。大多数接受化疗或手术的患者从长远来看并不能从治疗中获益,反而会产生副作用。虽然新一代测序技术加快了各种基因组畸变的鉴定,但大多数畸变尚未应用于常规临床实践。在此,我们回顾了过去 8 年中系统综述和荟萃分析中报告预后标志物的已发表数据,以及这些标志物未能在临床实践中得到应用的原因,以及我们该如何改进。
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引用次数: 0
Health-related quality of life with bemarituzumab plus mFOLFOX6 in patients with FGFR2b-overexpressing, advanced gastric or gastroesophageal junction cancer FGFR2b表达过高的晚期胃癌或胃食管交界癌患者使用贝马单抗加mFOLFOX6治疗后的健康相关生活质量
Pub Date : 2024-10-08 DOI: 10.1016/j.esmogo.2024.100095
Z.A. Wainberg , P.C. Enzinger , S. Qin , K. Yamaguchi , J. Wang , X. Zhou , A. Gnanasakthy , K. Taylor , A. Yusuf , I. Majer , A. Jamotte , Y.-K. Kang

Background

In the phase II, randomized, double-blind FIGHT trial (NCT03694522), treatment with bemarituzumab plus mFOLFOX6 resulted in improvements in progression-free survival and overall survival relative to mFOLFOX6 alone in previously untreated locally advanced or metastatic gastric or gastroesophageal junction cancer with fibroblast growth factor receptor 2b overexpression. Using data from the final analysis, we analyzed patient-reported outcomes (PROs) to evaluate the impact of adding bemarituzumab to mFOLFOX6 on health-related quality of life (HRQoL).

Materials and methods

Patients were randomized 1 : 1 to bemarituzumab plus mFOLFOX6 (n = 77) or placebo plus mFOLFOX (n = 78). European Organisation for Research and Treatment of Cancer Core 30-item Quality of Life (EORTC QLQ-C30) and the EuroQol EQ-5D-5L questionnaires were administered at baseline, week 6, every 8 weeks thereafter, and at end-of-treatment visit. Least-squares mean changes from baseline in PRO scale scores were estimated using mixed models for repeated measures; time to deterioration and improvement were assessed using Cox proportional hazards models. Analyses were exploratory post hoc.

Results

PRO scale scores at baseline and compliance rates across PRO assessments over time were similar between the bemarituzumab and placebo arms. Least-squares mean changes from baseline on key EORTC QLQ-C30 scales (global health status/QoL, physical functioning, fatigue, nausea and vomiting, and appetite loss) and the EQ-5D-5L visual analog scale were similar over time between treatment arms. Analyses of time to deterioration, sustained deterioration, and improvement suggested similar HRQoL between treatment arms.

Conclusions

Treatment with bemarituzumab plus mFOLFOX6 was associated with sustained HRQoL relative to mFOLFOX6 alone.
背景在II期随机双盲FIGHT试验(NCT03694522)中,相对于单独使用mFOLFOX6,贝马利珠单抗联合mFOLFOX6治疗既往未经治疗的纤维母细胞生长因子受体2b过表达的局部晚期或转移性胃癌或胃食管交界癌患者的无进展生存期和总生存期均有所改善。利用最终分析的数据,我们分析了患者报告的结果(PROs),以评估在mFOLFOX6基础上加用贝马单抗对健康相关生活质量(HRQoL)的影响。材料与方法患者按1:1随机分配至贝马单抗加mFOLFOX6(n = 77)或安慰剂加mFOLFOX(n = 78)。在基线、第6周、之后的每8周和治疗结束时,对欧洲癌症研究和治疗组织核心30项生活质量(EORTC QLQ-C30)和EuroQol EQ-5D-5L进行问卷调查。使用重复测量混合模型估算PRO评分与基线相比的最小二乘法平均变化;使用Cox比例危险模型评估恶化和改善的时间。结果贝马单抗治疗组和安慰剂治疗组的基线PRO评分和随时间变化的PRO评估达标率相似。各治疗组的主要EORTC QLQ-C30量表(总体健康状况/QoL、身体功能、疲劳、恶心呕吐和食欲不振)和EQ-5D-5L视觉模拟量表与基线相比的最小二乘法平均变化随着时间的推移相似。对恶化时间、持续恶化和改善情况的分析表明,各治疗组之间的 HRQoL 相似。
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引用次数: 0
Gastric cancer hospital-based registry: real-world gastric cancer data from Latin America and Europe 胃癌医院登记:拉丁美洲和欧洲的真实胃癌数据
Pub Date : 2024-09-18 DOI: 10.1016/j.esmogo.2024.100088
B. Freile , T.S. van Schooten , S. Derks , F. Carneiro , C. Figueiredo , R. Barros , C. Gauna , R. Pereira , M. Romero , A. Riquelme , M. Garrido , G. Owen , E. Ruiz-García , E.A. Fernández-Figueroa , A. Hernández-Guerrero , M. Alsina , C. Viaplana , M. Diez , S. Romero-Alcaide , E. Jiménez-Martí , T. Fleitas Kanonnikoff

Background

Gastric cancer has a high incidence and mortality rate worldwide. Epidemiological, clinical, and molecular features significantly impact patient outcomes. In regions lacking a national gastric cancer registry, hospital-based registries can provide crucial data that may aid in planning therapeutic strategies for the disease.

Methods

A retrospective observational cohort design was carried out in European Union (EU) and Latin American (LATAM) countries participating in the LEGACy project. Survival estimates were determined using actuarial Kaplan–Meier curves. Comparison was carried out with the log-rank test, and differences were considered statistically significant for P values ≤0.05.

Results

A total of 689 patients diagnosed with gastric cancer from November 2018 to November 2019 were included. Both cohorts had the body as the most common site reported (34.4% for EU and 51% for LATAM). The most used method for staging was computed tomography for both cohorts, although 6.9% of the LATAM population had positron emission tomography/computed tomography instead. Intestinal histological subtype was the most common (41.9% and 46.3% reported by EU and LATAM), while diffuse subtype was 44.9% for the LATAM and 21.3% for the EU population. Among patients tested for human epidermal growth factor receptor 2 (HER2), 12.5% were positive in the EU cohort and 13.8% in the LATAM cohort. For both cohorts, the most common site of human epidermal growth factor receptor 2 positivity was the gastroesophageal junction. Systemic treatment with curative intention was indicated in 50.7% in the EU cohort and 46.4% of the LATAM cohort. The most frequent scheme indicated for both the localized and the advanced setting was platinum-based (42.6% and 84.8% for EU and LATAM). Considering both cohorts, only 14.4% of the patients received second-line treatment, and 3% received a third-line treatment. After using Cox regression analysis, no difference in overall survival was reported, with a median of 10.9 months.

Conclusions

Despite the limitations of hospital-based registry analysis, our study has provided valuable insights into clinical characteristics and treatment approaches of EU and LATAM populations.

背景胃癌在全世界的发病率和死亡率都很高。流行病学、临床和分子特征对患者的预后有重大影响。在缺乏国家胃癌登记处的地区,以医院为基础的登记处可以提供重要的数据,从而帮助规划该疾病的治疗策略。方法 在参与 LEGACy 项目的欧盟(EU)和拉丁美洲(LATAM)国家开展了回顾性观察队列设计。采用精算卡普兰-梅耶曲线确定生存期估计值。比较采用对数秩检验,P值≤0.05则认为差异具有统计学意义。结果共纳入2018年11月至2019年11月期间确诊的689名胃癌患者。两个队列报告的最常见部位均为身体(欧盟为 34.4%,拉丁美洲和加勒比海地区为 51%)。两个队列中最常用的分期方法都是计算机断层扫描,但拉丁美洲和加勒比海地区有 6.9% 的人使用正电子发射断层扫描/计算机断层扫描。肠组织学亚型最常见(欧盟和拉美及加勒比地区报告的比例分别为 41.9% 和 46.3%),而弥漫亚型在拉美及加勒比地区为 44.9%,在欧盟人群中为 21.3%。在接受人类表皮生长因子受体 2(HER2)检测的患者中,欧盟组有 12.5%呈阳性,拉美和加勒比海地区组有 13.8%呈阳性。在这两个队列中,人表皮生长因子受体 2 阳性最常见的部位是胃食管交界处。在欧盟国家组中,50.7%的患者接受了以治愈为目的的全身治疗,而在拉丁美洲和加勒比海国家组中,46.4%的患者接受了以治愈为目的的全身治疗。无论是局部治疗还是晚期治疗,最常用的方案都是以铂为基础的治疗(欧盟和拉丁美洲分别为42.6%和84.8%)。在两个队列中,只有 14.4% 的患者接受了二线治疗,3% 的患者接受了三线治疗。结论尽管基于医院的登记分析存在局限性,但我们的研究为了解欧盟和拉丁美洲人口的临床特征和治疗方法提供了宝贵的见解。
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引用次数: 0
期刊
ESMO Gastrointestinal Oncology
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