Hyperprogression after Anti-Programmed Death-1 Therapy in a Case of Sigmoid Colon Cancer with Lynch Syndrome

Lynch syndrome is a hereditary condition caused by germline defects in mismatch repair (MMR) genes, resulting in microsatellite instability-high (MSI-H) tumors. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in the treatment of MSI-H advanced cancers. However, hyperprogressive disease (HPD) following ICI therapy is a rare and paradoxical phenomenon. We report a case of advanced sigmoid colon cancer associated with Lynch syndrome that developed HPD after pembrolizumab treatment.

A 51-year-old woman with advanced sigmoid colon cancer and a history of endometrial cancer presented with severe colonic stenosis, peritoneal dissemination, and suspected liver metastases, necessitating emergency colostomy. Immunohistochemistry revealed loss of MLH1 and PMS2 expression, consistent with suspected Lynch syndrome. Targeted molecular testing identified a KRAS exon 2 mutation (c.38G>A; p.G13D), with wild-type NRAS (exons 2-4) and BRAF (exon 15), and MSI-H status. Pembrolizumab was initiated, but within 3 days, rapid disease progression occurred, including abscess formation, enlargement of liver metastases, and lymphadenopathy, accompanied by clinical deterioration. Pembrolizumab was discontinued, and FOLFOXIRI plus bevacizumab was introduced, resulting in clinical stabilization. Subsequent germline testing confirmed Lynch syndrome with a pathogenic MLH1 variant. At 24 months of chemotherapy, the patient remains alive with a sustained partial response.

This case underscores the importance of early response evaluation in ICI-treated MSI-H tumors. Rapid disease progression requires prompt differentiation between HPD and pseudoprogression, emphasizing the necessity of timely therapeutic modification.