Characterization of discordance between mismatch repair deficiency and microsatellite instability testing may prevent inappropriate treatment with immunotherapy

IF 5.6 2区 医学 Q1 ONCOLOGY
Birgit S Geurts, Laurien J Zeverijn, Jade M van Berge Henegouwen, Hanneke van der Wijngaart, Louisa R Hoes, Gijs F de Wit, Ilse AC Spiekman, Thomas W Battaglia, Daphne M van Beek, Paul Roepman, Anne ML Jansen, Wendy WJ de Leng, Annegien Broeks, Mariette Labots, Carla ML van Herpen, Hans Gelderblom, Henk MW Verheul, Petur Snaebjornsson, Emile E Voest
{"title":"Characterization of discordance between mismatch repair deficiency and microsatellite instability testing may prevent inappropriate treatment with immunotherapy","authors":"Birgit S Geurts,&nbsp;Laurien J Zeverijn,&nbsp;Jade M van Berge Henegouwen,&nbsp;Hanneke van der Wijngaart,&nbsp;Louisa R Hoes,&nbsp;Gijs F de Wit,&nbsp;Ilse AC Spiekman,&nbsp;Thomas W Battaglia,&nbsp;Daphne M van Beek,&nbsp;Paul Roepman,&nbsp;Anne ML Jansen,&nbsp;Wendy WJ de Leng,&nbsp;Annegien Broeks,&nbsp;Mariette Labots,&nbsp;Carla ML van Herpen,&nbsp;Hans Gelderblom,&nbsp;Henk MW Verheul,&nbsp;Petur Snaebjornsson,&nbsp;Emile E Voest","doi":"10.1002/path.6279","DOIUrl":null,"url":null,"abstract":"<p>In the Drug Rediscovery Protocol (DRUP), patients with cancer are treated based on their tumor molecular profile with approved targeted and immunotherapies outside the labeled indication. Importantly, patients undergo a tumor biopsy for whole-genome sequencing (WGS) which allows for a WGS-based evaluation of routine diagnostics. Notably, we observed that not all biopsies of patients with dMMR/MSI-positive tumors as determined by routine diagnostics were classified as microsatellite-unstable by subsequent WGS. Therefore, we aimed to evaluate the discordance rate between routine dMMR/MSI diagnostics and WGS and to further characterize discordant cases. We assessed patients enrolled in DRUP with dMMR/MSI-positive tumors identified by routine diagnostics, who were treated with immune checkpoint blockade (ICB) and for whom WGS data were available. Patient and tumor characteristics, study treatment outcomes, and material from routine care were retrieved from the patient medical records and via Palga (the Dutch Pathology Registry), and were compared with WGS results. Initially, discordance between routine dMMR/MSI diagnostics and WGS was observed in 13 patients (13/121; 11%). The majority of these patients did not benefit from ICB (11/13; 85%). After further characterization, we found that in six patients (5%) discordance was caused by dMMR tumors that did not harbor an MSI molecular phenotype by WGS. In six patients (5%), discordance was false due to the presence of multiple primary tumors (<i>n</i> = 3, 2%) and misdiagnosis of dMMR status by immunohistochemistry (<i>n</i> = 3, 2%). In one patient (1%), the exact underlying cause of discordance could not be identified. Thus, in this group of patients limited to those initially diagnosed with dMMR/MSI tumors by current routine diagnostics, the true assay-based discordance rate between routine dMMR/MSI-positive diagnostics and WGS was 5%. To prevent inappropriate ICB treatment, clinicians and pathologists should be aware of the risk of multiple primary tumors and the limitations of different tests. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 3","pages":"288-299"},"PeriodicalIF":5.6000,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Pathology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/path.6279","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

In the Drug Rediscovery Protocol (DRUP), patients with cancer are treated based on their tumor molecular profile with approved targeted and immunotherapies outside the labeled indication. Importantly, patients undergo a tumor biopsy for whole-genome sequencing (WGS) which allows for a WGS-based evaluation of routine diagnostics. Notably, we observed that not all biopsies of patients with dMMR/MSI-positive tumors as determined by routine diagnostics were classified as microsatellite-unstable by subsequent WGS. Therefore, we aimed to evaluate the discordance rate between routine dMMR/MSI diagnostics and WGS and to further characterize discordant cases. We assessed patients enrolled in DRUP with dMMR/MSI-positive tumors identified by routine diagnostics, who were treated with immune checkpoint blockade (ICB) and for whom WGS data were available. Patient and tumor characteristics, study treatment outcomes, and material from routine care were retrieved from the patient medical records and via Palga (the Dutch Pathology Registry), and were compared with WGS results. Initially, discordance between routine dMMR/MSI diagnostics and WGS was observed in 13 patients (13/121; 11%). The majority of these patients did not benefit from ICB (11/13; 85%). After further characterization, we found that in six patients (5%) discordance was caused by dMMR tumors that did not harbor an MSI molecular phenotype by WGS. In six patients (5%), discordance was false due to the presence of multiple primary tumors (n = 3, 2%) and misdiagnosis of dMMR status by immunohistochemistry (n = 3, 2%). In one patient (1%), the exact underlying cause of discordance could not be identified. Thus, in this group of patients limited to those initially diagnosed with dMMR/MSI tumors by current routine diagnostics, the true assay-based discordance rate between routine dMMR/MSI-positive diagnostics and WGS was 5%. To prevent inappropriate ICB treatment, clinicians and pathologists should be aware of the risk of multiple primary tumors and the limitations of different tests. © 2024 The Pathological Society of Great Britain and Ireland.

对错配修复缺陷和微卫星不稳定性检测之间的不一致性进行定性,可防止不适当的免疫疗法。
在 "药物再发现方案"(DRUP)中,癌症患者将根据其肿瘤分子特征接受已获批准的标示适应症之外的靶向治疗和免疫治疗。重要的是,患者要接受肿瘤活检以进行全基因组测序(WGS),从而对常规诊断进行基于 WGS 的评估。值得注意的是,我们观察到,并非所有经常规诊断确定为 dMMR/MSI 阳性的肿瘤患者的活检结果都被随后的 WGS 归类为微卫星不稳定。因此,我们旨在评估常规 dMMR/MSI 诊断和 WGS 之间的不一致率,并进一步描述不一致病例的特征。我们评估了入选 DRUP 的 dMMR/MSI 阳性肿瘤患者,这些患者经常规诊断确定为 dMMR/MSI 阳性,接受了免疫检查点阻断疗法(ICB)治疗,且 WGS 数据可用。患者和肿瘤特征、研究治疗结果以及常规护理材料均来自患者病历和 Palga(荷兰病理登记处),并与 WGS 结果进行了比较。初步观察发现,13 例患者(13/121;11%)的常规 dMMR/MSI 诊断与 WGS 结果不一致。这些患者中的大多数并未从 ICB 中获益(11/13;85%)。经过进一步鉴定,我们发现有 6 名患者(5%)的不一致是由 WGS 检测未发现 MSI 分子表型的 dMMR 肿瘤引起的。在 6 名患者(5%)中,由于存在多个原发性肿瘤(3 人,2%)和免疫组化对 dMMR 状态的误诊(3 人,2%),造成了不一致。有一名患者(1%)无法确定造成不一致的确切原因。因此,在这组仅限于通过当前常规诊断初步确诊为 dMMR/MSI 肿瘤的患者中,常规 dMMR/MSI 阳性诊断与 WGS 之间基于检测的真实不一致率为 5%。为防止不恰当的 ICB 治疗,临床医生和病理学家应了解多原发肿瘤的风险和不同检测方法的局限性。© 2024 大不列颠及爱尔兰病理学会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
The Journal of Pathology
The Journal of Pathology 医学-病理学
CiteScore
14.10
自引率
1.40%
发文量
144
审稿时长
3-8 weeks
期刊介绍: The Journal of Pathology aims to serve as a translational bridge between basic biomedical science and clinical medicine with particular emphasis on, but not restricted to, tissue based studies. The main interests of the Journal lie in publishing studies that further our understanding the pathophysiological and pathogenetic mechanisms of human disease. The Journal of Pathology welcomes investigative studies on human tissues, in vitro and in vivo experimental studies, and investigations based on animal models with a clear relevance to human disease, including transgenic systems. As well as original research papers, the Journal seeks to provide rapid publication in a variety of other formats, including editorials, review articles, commentaries and perspectives and other features, both contributed and solicited.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信