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Oncol."],"abstract":"<jats:p>Immune checkpoint blockade (ICB) shows remarkable clinical effects in patients with metastatic microsatellite-unstable (MSI) cancer. However, markers identifying potential non-responders are missing. We examined the prevalence of <jats:italic>Beta-2-microglobulin<\/jats:italic> (<jats:italic>B2M)<\/jats:italic> mutations, a common immune evasion mechanism, in stage IV MSI gastrointestinal cancer and its influence on metastatic pattern and patients\u2019 survival under ICB. Twenty-five patients with metastatic, MSI gastrointestinal adenocarcinoma were included. Eighteen patients received ICB with pembrolizumab and one patient with nivolumab\/ipilimumab. Sequencing was performed to determine <jats:italic>B2M<\/jats:italic> mutation status. <jats:italic>B2M<\/jats:italic> mutations and loss of B2M expression were detected in 6 out of 25 stage IV MSI cancers. <jats:italic>B2M<\/jats:italic> mutations were strongly associated with exclusively peritoneal\/peritoneal and lymph node metastases (p=0.0055). However, no significant differences in therapy response (25% <jats:italic>vs<\/jats:italic>. 46.6%, p&amp;gt;0.99) and survival (median PFS: 19.5 <jats:italic>vs<\/jats:italic> 33.0 months, p=0.74; median OS 39 months <jats:italic>vs<\/jats:italic>. not reached, p&amp;gt;0.99) were observed between <jats:italic>B2M<\/jats:italic>-mutant and <jats:italic>B2M<\/jats:italic>-wild type tumor patients. Among metastatic MSI GI cancers, <jats:italic>B2M<\/jats:italic>-mutant tumors represent a biologically distinct disease with distinct metastatic patterns. To assess ICB response in <jats:italic>B2M<\/jats:italic>-mutant MSI cancer patients, future studies need to account for the fact that baseline survival of patients with <jats:italic>B2M<\/jats:italic>-mutant MSI cancer may be longer than of patients with <jats:italic>B2M<\/jats:italic>-wild type MSI cancer.<\/jats:p>","DOI":"10.3389\/fonc.2021.669774","type":"journal-article","created":{"date-parts":[[2021,6,8]],"date-time":"2021-06-08T06:43:57Z","timestamp":1623134637000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Beta-2-microglobulin Mutations Are Linked to a Distinct Metastatic Pattern and a Favorable Outcome in Microsatellite-Unstable Stage IV Gastrointestinal Cancers"],"prefix":"10.3389","volume":"11","author":[{"given":"Elena","family":"Busch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aysel","family":"Ahadova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosima","family":"Kosmalla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Bohaumilitzky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline 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