Age-stratified evaluation of subsequent primary malignancy risk in patients with primary Lynch syndrome–spectrum cancers.

10620 Background: Lynch syndrome spectrum cancers (LSSC) include several of the most common cancers in both men and women. Patients with LS are advised to undergo intensive cancer screening and genetic evaluation. However, most at-risk individuals are not assessed by a cancer geneticist, especially those in middle or older age, despite these cancers often appearing late in life. This study evaluates the incidence and timing of LS-related and non-LS–related subsequent primary malignancy (SPMs) in patients diagnosed with LSSCs. Methods: We used SEER data (1992–2021) to identify patients with LSSC — colorectal (CRC), endometrial (EC), gastric, Bladder/GU tract (GUC), Small bowel, ovarian, pancreatic, sebaceous, and brain (BC) by using histology and site code. Demographics, survival data, and SPMs details were extracted. Patient were stratified by age < 40 years, 40-60 years, and > 60 years. We calculated the mortality-related competitive risk-adjusted cumulative incidence (CI) of SPMs at 5 and 10 years for both LSSCs and all cancers. Median follow up were calculated by reverse KM method. We calculated the time to the development of 1 st SPM after the index cancer diagnosis. Proportions were compared using chi-square test. Results: We identified 774955 patients with LSSC (50.4% Female, mean age 66.2 (SD 13.3) with a median follow-up of 149 months. 74331 (9.6%) patients developed a subsequent malignancy, with 30666 (41.3%) of all SPM had at least 1 LSSC. In < 40 year, 40-60-year, and > 60 years groups, 4.5%, 8.1%, and 10.5 % of total patients with LSSCs had a SPM of which 68.2%, and 43.3%, and 39.9 % patient had at least 1 LSSCs (p < 0.001). Median time to cancers and adjusted CI is given in the table. There was significant difference in distribution of primary (p-value < 0.01) and subsequent (p-value < 0.01) LSSC. CRC was the most common primary LSSC across age group, with Brain, and EC, and GU Cancers were the 2 nd most common cancer in < 40, 40-60, and > 60-year age group respectively representing 19.3%, 16.7%, and 22.9% cancers of respective LSSCs. Among SPM, CRC was the most common across all age group (42.8% of LSS SPM) whereas EC was 2 nd most common LSS SPM in < 40 years, and GU cancers in both 40-60 (35%), and > 60 (31.8%) years group. Conclusions: For LSSC patient, likelihood of developing SPM increased with longer survival, and older patients demonstrated the highest SPM burden for both LSSC and non-LSSCs. These findings suggest that cancer genetics evaluation and robust LS-directed surveillance should be extended beyond younger populations, as older patients remain at significant risk for LS-related SPMs. Age group 18-40 Years 41-60 Years >60 Years Median follow up (months) 131 141 155 Median time to any SPM 40 52 28 Median time to subsequent LSSC 22 28 22 Any SPM 5-year CI % 2.8 4.7 7.8 10-year CI % 3.7 7.1 10.6 Subsequent LSSC 5-year CI % 2.3 2.4 3.3 10-year CI % 2.8 3.2 4.3