胰腺癌（PC）的预后差，诊断时无法手术/转移的病例率高，切除后易复发，且系统治疗选择有限。在KEYNOTE-158中，缺乏错配修复（dMMR）/高微卫星不稳定性（MSI-H）的PC表现出不寻常的糟糕结果，评估了帕博利珠单抗在MSI-H固体肿瘤中的疗效。我们的研究汇集了梅奥诊所对dMMR/MSI-H PC的经验，对临床、分子和治疗反应模式进行了表征，重点关注免疫检查点抑制剂（ICI）的疗效。回顾性数据从2009年12月至2023年2月从电子病历中收集。如果患者经过病理学确认为胰腺恶性肿瘤，并具备以下条件，将被纳入研究：（1）瘤体免疫组化结果显示错配修复（MMR）蛋白的表达缺陷，（2）基因组测序显示错误配修复（MMR）基因的致病性突变，（3）聚合酶链反应显示微卫星不稳定（MSI-H）。共鉴定了32名符合条件的患者，涵盖疾病的各个阶段。其中16名患者接受了手术或放化疗。在这些患者中，出现了不寻常的有利反应，仅有19％（n = 3）的复发率，尽管随访中位数为25个月。在姑息治疗中，ICI显示出极好的疗效，总体应答率（ORR）为75％（完全缓解为20％）。尚未达到中位无病进展时间。姑息治疗中的细胞毒性化疗应答率较低，ORR为30％，中位无病进展时间为4个月。我们观察到MMR和MSI检测方法之间的不一致率较高，占整个队列的19％，评估的病例中达到26％。我们的数据表明，在需要全身治疗的任何dMMR/MSI-H PC患者中，包括转移性和辅助/新辅助治疗，优先使用ICI而非细胞毒性化疗。

Pancreatic cancer (PC) carries a poor prognosis with high rates of unresectable/metastatic disease at diagnosis, recurrence after resection, and few systemic therapy options. Deficient mismatch repair (dMMR)/high microsatellite instability (MSI-H) PCs demonstrated uncharacteristically poor outcomes in KEYNOTE-158, evaluating pembrolizumab in MSI-H solid tumors. Our study aggregates the Mayo Clinic experience with dMMR/MSI-H PCs, characterizing the clinical, molecular, and treatment response patterns with a focus on response to immune checkpoint inhibitors (ICIs).Retrospective data were collected from the electronic medical record from December 2009 to February 2023. Patients were included if they had a pathologically confirmed pancreatic malignancy and had (1) deficient expression of mismatch repair (MMR) proteins by tumor immunohistochemistry, (2) pathogenic mutation of MMR genes on genomic sequencing, and/or (3) MSI-H by polymerase chain reaction.Thirty-two patients were identified for inclusion, with all stages of disease represented. Sixteen of these patients underwent surgery or chemoradiotherapy. Of these patients, uncharacteristically favorable responses were seen, with a recurrence rate of only 19% (n = 3) despite a median follow-up of 25 months. In the palliative setting, excellent responses to ICI were seen, with overall response rate (ORR) of 75% (20% complete response). Median time to disease progression was not reached. Response rates to cytotoxic chemotherapy in the palliative setting were poor, with 30% ORR and median time to progression of 4 months. We observed a high rate of discrepancy between MMR and MSI testing methods, representing 19% of the entire cohort and 26% of evaluable cases.Our data argue for the preferential use of ICI over cytotoxic chemotherapy in any patient with dMMR/MSI-H PC requiring systemic therapy, including in the metastatic and adjuvant/neoadjuvant settings.