A durable response to pembrolizumab in a patient with uterine serous carcinoma and Lynch syndrome due to the MSH6 germline mutation.

Abstract

BACKGROUND\nPembrolizumab, a PD-L1 checkpoint inhibitor, has elicited responses in mismatch repair (MMR) deficient advanced solid tumors, leading to its agnostic approval by the U.S Food and Drug Administration in 2017 when no other therapeutic options are available. However, there is still insufficient data on the response to checkpoint inhibitors in advanced endometrial cancer related to Lynch syndrome (LS) and specifically, in uterine serous carcinoma which is uncommon in LS.\n\n\nKEY POINTS\nEven though checkpoint inhibitors are effective in mismatch repair-deficient endometrial cancer, it is unknown whether the response to them differs between women with endometrial cancer due to germline mutations in a mismatch repair gene (Lynch syndrome) and women with sporadic endometrial cancer. In our case, a patient with a Lynch syndrome and recurrent mismatch repair-deficient serous endometrial cancer achieved a durable remission on the first-line therapy with a checkpoint inhibitor pembrolizumab and remains progression-free after more than two years. Based on our observation and the data, suggesting the stronger immune activation in women with Lynch syndrome-associated endometrial cancer, we propose to use checkpoint inhibitor monotherapy early in the course of their treatment and stratify patients for the presence of Lynch syndrome in clinical trials.\n\n\nPATIENT STORY\nHere we report a case of metastatic uterine serous carcinoma due to a germline MSH6 mutation (Lynch syndrome) which was discovered because of her tumor MMR deficiency. The patient was started on first-line pembrolizumab in 2018 and sustained a partial response. She remains asymptomatic and progression-free for more than two years. Tumor sequencing showed a high mutational burden and an upstream somatic mutation in the same gene, p.F1088fs. Immunohistochemical staining was negative for PD-L1 expression. We discuss clinical characteristics of the patient, molecular features of her tumor, and the mechanism of her tumor response. We also discuss the duration of immunotherapy in her case.\n\n\nCONCLUSION\nOur case demonstrated a partial response and a long-term remission from the front-line single-agent pembrolizumab in a woman with metastatic uterine serous carcinoma and Lynch syndrome due to a germline MSH6 gene mutation. Our experience suggests a potential significant clinical benefit of checkpoint inhibitors used as single agents early on in the treatment of MMR-deficient/MSI-H/hypermutated uterine cancers in women with Lynch Syndrome.