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Background Hypermutated colorectal cancer (CRC) is a molecular subtype characterized by extensive somatic alterations, frequently associated with mismatch repair deficiency (dMMR) and high microsatellite instability (MSI-H). 1 2 These tumors are highly immunogenic and increasingly responsive to immune checkpoint inhibitors.3 However, early recurrence following standard adjuvant chemotherapy remains a clinical challenge, with no established immunotherapy protocols in this setting. We report a case of stage III CRC with early peritoneal recurrence (<3 months) and a hypermutated profile (+190 genes), showing a durable response to pembrolizumab.Methods A 57-year-old male was diagnosed with moderately differentiated CRC (pT3pN1(3/12)-M0, stage IIIB) and underwent left hemicolectomy followed by 12 cycles of adjuvant FOLFOX6M. Three months post-chemotherapy, PET-CT revealed a large peritoneal mass (6.5 x 7.6 x 7.1 cm, SUVmax: 9.4) in the anatomical area of the descending colon ( figure 1). Histology confirmed recurrence. A next-generation sequencing (NGS) panel from liquid biopsy identified somatic mutations in MSH2, MSH6, PMS2, ARID1A (22–30%), in addition to SNVs and insertion/deletion mutations affecting 192 genes, including APC, TP53, and PIK3CA. The tumor lacked KRAS/NRAS/BRAF and POLE mutations but was MSI-H with a tumor mutational burden (TMB) >10 m/Mb. Given the molecular findings and clinical deterioration, pembrolizumab monotherapy (200 mg IV every three weeks) was initiated.Results After four cycles of pembrolizumab, PET-CT showed substantial tumor and metabolic regression (4.1 x 3.7 x 4.8 cm, SUVmax: 4.7). The patient became asymptomatic, discontinued opioids, and resumed normal activities. As of June 2025, he has completed 17 cycles without disease progression or immune-related toxicities. The latest PET-CT (February 2025) showed continued response (1.6 x 2.4 x 2.9 cm, SUVmax: 2.3) ( figure 2).Conclusions This case highlights the potential of checkpoint inhibitor monotherapy in hypermutated, MSI-H CRC with early recurrence post-adjuvant chemotherapy. 3 The patient’s sustained 12-month response aligns with findings from KEYNOTE-177 and meta-analyses supporting PD-1/PD-L1 blockade in metastatic CRC,3 4 even without canonical KRAS, NRAS, BRAF, or POLE mutations. Comprehensive genomic profiling—revealing >190 somatic alterations—combined with MSI and TMB assessment enabled a personalized therapeutic.2 5 Prospective studies are needed to define optimal strategies and guidelines for the use of pembrolizumab in hypermutated CRC.References Jardim DL, Goodman A, de Melo Gagliato D, Kurzrock R. The challenges of tumor mutational burden as an immunotherapy biomarker. Cancer Cell. 2021 Feb 8;39(2):154–173. doi:10.1016/j.ccell.2020.10.001. Epub 2020 Oct 29. PMID: 33125859; PMCID: PMC7878292.Ciepiela I, Szczepaniak M, Ciepiela P, Gorczyca A, Płuciennik E, Bednarek AK. Tumor location matters: next generation sequencing mutation profiling of left-sided, rectal, and right-sided colorectal tumors in 552 patients. Sci Rep. 2024;14:4619. doi:10.1038/s41598-024-55139-w.André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med. 2020 Dec 3;383(23):2207–2218. doi:10.1056/NEJMoa2006401.Rotundo MS, Bagnardi V, Rotundo M, Comandè M, Zampino MG. PD-1/PD-L1 blockade, a novel strategy for targeting metastatic colorectal cancer: a systematic review and meta-analysis of randomized trials. Oncol Lett. 2022;23:134. doi:10.3892/ol.2022.13254.Zhang X, Wu T, Cai X, Dong J, Xia C, Zhou Y, et al. Neoadjuvant immunotherapy for MSI-H/dMMR locally advanced colorectal cancer: new strategies and unveiled opportunities. Front Immunol. 2022 Mar 17;13:795972. doi:10.3389/fimmu.2022.795972. PMID: 35371084; PMCID: PMC8968082.Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.Abstract 471 Figure 1PET-CT post adjuvant treatment (April 2024)Abstract 471 Figure 2PET-CT follow-up (February 2025)