(P 198) PERSONALIZED MULTIDISCIPLINARY MANAGEMENT OF SARCOMA IN PATIENTS WITH LYNCH SYNDROME

Objective: Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by a germline loss-of-function mutation in one of the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PSM2). Sarcomas are not classically thought of as Lynch-associated cancers but do occur in patients with Lynch syndrome. This project aimed to assess whether these sarcomas are related to Lynch syndrome and display loss of MMR proteins and/or microsatellite instability (MSI) and to determine the optimal treatment of this unique patient population.

Methods: We included 30 patients with a diagnosis of Lynch syndrome (confirmed by germline genetic testing) with a history of sarcoma seen at MD Anderson Cancer Center with sarcoma diagnosis between 1998 and 2022. To assess for MMR deficiency, immunohistochemistry was performed on the sarcoma specimens to assess for expression of MMR proteins. If the staining was normal or intact, we assessed for MSI by PCR assay, as some loss-of-function MMR gene mutants will retain a normal expression pattern. We also extracted and analyzed available clinical data from their medical records.

Results: Among 30 patients with Lynch syndrome and sarcoma, germline mutation in MSH2 was most common (50%), followed by MSH6 (20%), PMS2 (16.7%), and MLH1 (13.3%). The most common sarcoma subtypes in this cohort were undifferentiated pleomorphic sarcoma (40%) and leiomyosarcoma (26.7%). Median age at diagnosis was 49.2 years (range 11.2-79.3). Tissue was available for MMR/MSI testing in 10 cases. Deficient MMR or MSI was demonstrated in 4 of these 10 (40%); One case had intact MMR and stable microsatellite (case 8); MSI testing will be performed on the remaining 5 with intact MMR protein expression. Three patients were treated with immunotherapy. One patient treated with ipilimumab and nivolumab, had a partial response, and was on therapy for 31 months until death from an unrelated cause. The second patient has been on pembrolizumab monotherapy for 44 months and has had a complete response. The third patient treated with pembrolizumab monotherapy developed progressive disease after 4 months. With a median follow-up time of 68.2 months since sarcoma diagnosis (range 2.5-262.7 months), median overall survival and progression-free survival have not been reached.

Conclusion: While rare, Lynch syndrome can be associated with sarcoma. This is most commonly seen with germline MSH2 mutation and undifferentiated pleomorphic sarcoma and leiomyosarcoma subtypes. Immunotherapy has the potential for robust and durable responses and the potential to minimize or obviate surgery in Lynch-associated sarcomas. This is important to consider in this unique patient population that has had or potentially will require treatment for additional malignancies.