Rates of metachronous colorectal cancer or secondary Lynch syndrome–related cancers in patients with non-metastatic colorectal cancer.

3648 Background: Lynch syndrome (LS) increases metachronous colorectal cancer (CRC) risk up to 5-fold, while extended resection surgery after initial CRC can reduce this risk. Prior work showed that pre-surgical germline genetic testing (GGT) was more likely to result in extended resections, especially for MLH1 / MSH2 carriers. We evaluated the rates of metachronous CRC following surgery, along with rates of other LS cancers following CRC diagnosis. Methods: GGT and insurance claims (Komodo Healthcare Map) data for adults with non-metastatic colon (CC) or rectal (RC) cancer and CRC surgery from 2015-25, ≥6 months of cancer-free claims pre-CRC diagnosis, ≥6 months of claims post-CRC surgery, and EPCAM / MLH1 / MSH2 / MSH6 / PMS2 GGT. Statistical tests compared metachronous CRC rates (new CRC ≥6 months post-surgery) following partial (partial/segmental colectomy or proctectomy) or extended (total colectomy or total proctocolectomy) resections by GGT result. Multivariable logistic regression modeled variables associated with metachronous CRC or other LS cancers. Results: Of 4,050 CRC patients (3,905 CC, 145 RC), 530 (13.1%) were LS-positive. 3,860 (95.3%) had partial (12.2% LS-positive) and 190 (4.7%) had extended resections (32.1% LS-positive). Post-surgery claims were available for a mean (standard deviation) of 47.7 (28.0) months. 251 (6.2%) patients with CRC had metachronous CRC post-surgery (6.1% partial vs. 8.9% extended resection, p=0.145). 282 (7.0%) patients with CRC were diagnosed with other LS cancers (54 10.2% LS-positive vs. 228 6.5% negative/variant of unknown significance (LS-negative), p=0.002). Patients with other LS cancers were diagnosed an average of 31.6 (23.9) months after initial CRC diagnosis (LS-positive: 29.0 26.7, LS-negative: 32.2 23.2). The most common other LS cancer was prostate for men (80/1,822, 4.4%) and endometrial/uterine for women (55/2,228, 2.5%). Increased odds of metachronous CRC were associated with RC (compared to CC) (odds ratio OR: 5.1, 95% confidence interval CI: 3.3-8.0) and more months of available post-surgery claims (OR: 1.02, CI: 1.01-1.02). Increased odds of other LS cancers were associated with MLH1/MSH2/EPCAM carriers (compared to LS-negative) (OR: 2.0, CI: 1.3-3.1), older age (1.04, 1.03-1.05), male sex (1.6, 1.3-2.1), physician-reported Black race (1.6, 1.0-2.4) (compared to White), and more months of available post-surgery claims (1.02, 1.02-1.03). Conclusions: Patients with pathogenic variants in MLH1 / MSH2 / EPCAM had 2x higher odds of a second LS cancer diagnosis. 1 out of 10 patients with CRC and LS had a second LS cancer, and more than half (55.6%) of second diagnoses were within 2 years of initial CRC diagnosis. These findings highlight the importance of integrating genetic testing and comprehensive Lynch syndrome surveillance into patient care at the time of initial CRC diagnosis.