Catherine A O'Connor, Emily Harrold, David Lin, Henry Walch, Andrea Gazzo, Megha Ranganathan, Sarah Kane, Fergus Keane, Joshua Schoenfeld, Drew Moss, Deborah M Thurtle-Schmidt, Sarah P Suehnholz, Debyani Chakravarty, Fiyinfolu Balogun, Anna Varghese, Kenneth Yu, David Kelsen, Alicia Latham, Britta Weigelt, Wungki Park, Zsofia Stadler, Eileen M O'Reilly
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The contribution of somatic oncogenesis to MSI-H in pancreatic cancer (PC) is unknown.</p><p><strong>Objective: </strong>To evaluate an LS-related PC cohort to define clinicogenomic features, describe somatic MSI-H cases (germline negative), characterize response to ICB, and guide preferred MS testing methods.</p><p><strong>Design, setting, and participants: </strong>This single-institution, retrospective analysis was conducted from March 2012 to July 2023 at Memorial Sloan Kettering Cancer Center and included 55 patients with PC and either an LS germline pathogenic variant (gPV) or somatic mismatch repair (MMR) variant.</p><p><strong>Main outcomes and measures: </strong>Composite MMR and MS status determined using orthogonal methods. An artificial intelligence classifier was used to account for low-cellularity specimens. Demographic and clinical data were abstracted from medical record. Zygosity status and somatic comutation landscape analyzed.</p><p><strong>Results: </strong>Fifty-five patients (23 women [42%]) had PC and an MMR variant: 32 (58%) had LS (LS cohort) and 23 (42%) had a somatic MMR variant (no germline pathogenic variant, somatic MMR cohort). In the LS cohort, 10 (31%) had gMSH2, 9 (28%) gMSH6, 8 (25%) gPMS2, 4 (13%) gMLH1, 1 (3%) gEPCAM. The median age at diagnosis was 68 years (range, 45-88 years). For composite MS status, 17 (59%) were MSI-H, 12 (41%) MS stable, and 3 MS unknown. Five cases were reclassified as MSI-H by the artificial intelligence classifier. In the somatic MMR cohort, 11 (48%) had MSH6, 7 (30%) MLH1, 3 (13%) MSH2, and 2 (9%) PMS2. The median age at diagnosis was 72 years (range, 66-85 years). For composite MS status, 10 (43%) were MSI-H, 11 (48%) MS stable, and 2 (9%) MS indeterminate. Six cases were reclassified as MSI-H by the artificial intelligence classifier. For the LS and somatic MMR cohorts, 20 received ICB (n = 17 MSI-H). The median ICB duration was 27.7 months (95% CI, 11.5 to not reached); the disease control rate was 80%.</p><p><strong>Conclusion: </strong>The results of this cross-sectional study suggest that MSI-H occurs due to LS or somatic oncogenesis in PC. Orthogonal MS testing is key in PC; the artificial intelligence classifier reclassified approximately 20% of cases, most of which were low cellularity. 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引用次数: 0
摘要
重要性：微卫星（MS）不稳定性（MSI-H）经常发生在林奇综合征（LS）相关肿瘤中，并与对免疫检查点阻断（ICB）疗法的反应有关。MSI-H 由错配修复基因的种系或体细胞变异引起。体细胞致癌对胰腺癌（PC）MSI-H的影响尚不清楚：评估与LS相关的PC队列，以确定临床基因组学特征，描述体细胞MSI-H病例（种系阴性），描述对ICB的反应，并指导首选的MS检测方法：这项单一机构的回顾性分析于2012年3月至2023年7月在纪念斯隆-凯特琳癌症中心进行，共纳入55例PC患者和LS种系致病变异体（gPV）或体细胞错配修复（MMR）变异体：采用正交方法确定MMR和MS的复合状态。人工智能分类器用于考虑低细胞标本。人口统计学和临床数据摘自病历。对杂合子状态和体细胞变异情况进行分析：55名患者（23名女性[42%]）患有PC和MMR变异：32名（58%）患有LS（LS队列），23名（42%）患有体细胞MMR变异（无种系致病变异，体细胞MMR队列）。在LS队列中，10人（31%）有gMSH2，9人（28%）有gMSH6，8人（25%）有gPMS2，4人（13%）有gMLH1，1人（3%）有gEPCAM。诊断时的中位年龄为 68 岁（45-88 岁）。综合 MS 状态，17 例（59%）为 MSI-H，12 例（41%）为 MS 稳定型，3 例 MS 状态不明。5例被人工智能分类器重新分类为MSI-H。在体细胞MMR队列中，11例（48%）为MSH6，7例（30%）为MLH1，3例（13%）为MSH2，2例（9%）为PMS2。诊断时的中位年龄为 72 岁（66-85 岁）。综合 MS 状态，10 例（43%）为 MSI-H，11 例（48%）为 MS 稳定型，2 例（9%）为 MS 不确定型。人工智能分类器将 6 例重新分类为 MSI-H。在LS和体细胞MMR队列中，20例接受了ICB治疗（n = 17 MSI-H）。中位 ICB 持续时间为 27.7 个月（95% CI，11.5 到未达到）；疾病控制率为 80%：这项横断面研究的结果表明，MSI-H发生于PC的LS或体细胞致癌。人工智能分类器对约20%的病例进行了重新分类，其中大部分为低细胞性病例。对LS或体细胞MSI-H型PC患者进行ICB治疗有显著疗效。
Lynch Syndrome and Somatic Mismatch Repair Variants in Pancreas Cancer.
Importance: Microsatellite (MS) instability (MSI-H) occurs frequently in Lynch syndrome (LS)-associated tumors and is associated with response to immune checkpoint blockade (ICB) therapy. MSI-H is conferred by germline or somatic variants in mismatch repair genes. The contribution of somatic oncogenesis to MSI-H in pancreatic cancer (PC) is unknown.
Objective: To evaluate an LS-related PC cohort to define clinicogenomic features, describe somatic MSI-H cases (germline negative), characterize response to ICB, and guide preferred MS testing methods.
Design, setting, and participants: This single-institution, retrospective analysis was conducted from March 2012 to July 2023 at Memorial Sloan Kettering Cancer Center and included 55 patients with PC and either an LS germline pathogenic variant (gPV) or somatic mismatch repair (MMR) variant.
Main outcomes and measures: Composite MMR and MS status determined using orthogonal methods. An artificial intelligence classifier was used to account for low-cellularity specimens. Demographic and clinical data were abstracted from medical record. Zygosity status and somatic comutation landscape analyzed.
Results: Fifty-five patients (23 women [42%]) had PC and an MMR variant: 32 (58%) had LS (LS cohort) and 23 (42%) had a somatic MMR variant (no germline pathogenic variant, somatic MMR cohort). In the LS cohort, 10 (31%) had gMSH2, 9 (28%) gMSH6, 8 (25%) gPMS2, 4 (13%) gMLH1, 1 (3%) gEPCAM. The median age at diagnosis was 68 years (range, 45-88 years). For composite MS status, 17 (59%) were MSI-H, 12 (41%) MS stable, and 3 MS unknown. Five cases were reclassified as MSI-H by the artificial intelligence classifier. In the somatic MMR cohort, 11 (48%) had MSH6, 7 (30%) MLH1, 3 (13%) MSH2, and 2 (9%) PMS2. The median age at diagnosis was 72 years (range, 66-85 years). For composite MS status, 10 (43%) were MSI-H, 11 (48%) MS stable, and 2 (9%) MS indeterminate. Six cases were reclassified as MSI-H by the artificial intelligence classifier. For the LS and somatic MMR cohorts, 20 received ICB (n = 17 MSI-H). The median ICB duration was 27.7 months (95% CI, 11.5 to not reached); the disease control rate was 80%.
Conclusion: The results of this cross-sectional study suggest that MSI-H occurs due to LS or somatic oncogenesis in PC. Orthogonal MS testing is key in PC; the artificial intelligence classifier reclassified approximately 20% of cases, most of which were low cellularity. ICB for patients with LS or somatic MSI-H PC provided significant benefit.
期刊介绍：
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