Abstract B042: Clinical and molecular characterization of Lynch syndrome-associated pancreas adenocarcinoma (PDAC)
Authors: Harrold Emily , O'Connor Catherine A. , Lin David , Gazzo Andrea , Walch Henry , Ranganathan Megha , Catchings Amanda , Kane Sarah , Keane Fergus , Thurtle-Schmidt Deborah M. , Balogun Fiyinfolu , Varghese Anna , Yu Kenneth , Kelsen David , Latham Alicia , Weigelt Britta , Park Wungki , Stadler Zsofia , O'Reilly Eileen M. 
Published: January 2024

Abstract
Background: Lynch syndrome (LS) is a pan-cancer predisposition syndrome caused by pathogenic germline alterations (gPVs) in DNA mismatch repair genes (PMS2, MSH6, MLH1, MSH2, EPCAM). It is characterized by microsatellite instability (MSI)/deficient DNA mismatch repair (dMMR) of associated tumors, which predicts immune checkpoint blockade (ICB) response. Clinical and molecular features of LS-PDAC are not well defined. Herein we sought to describe clinical characteristics, MSI prevalence, and ICB response. Methods: Patients (pts) with LS-associated gPV and PDAC who had consented to IRB-approved protocol of matched tumor-normal sequencing (MSK-IMPACT from which MSIsensor status derivable) were included. MiMSI utilized to assess microsatellite stable (MSS) PDACs to account for low tumor content. MMR status defined with immunohistochemistry (IHC). Composite MSI adjudicated as either loss of MMR protein expression by IHC or MSI by MSISensor or MiMSI. FACETS algorithm assessed biallelic MMR gene alteration status. Mutational signature analysis performed on MSI tumors with deconstructSigs. Results: N=29 pts identified with LS-associated gPVs and PDAC: 10 MSH2 (34%), 9 MSH6 (31%), 7 PMS2 (24%), 2 MLH1 (7%), 1 EPCAM (3%). Majority white (24, 83%) and female (15, 52%). At diagnosis 62% pts early-stage disease (8 stage II, 10 stage III), 11 stage IV. Median age at diagnosis: 68 yrs (range 45-88). Eighteen (62%) had first-degree family history of LS spectrum cancers. Four pts had metachronous cancers (2 CRC, 1 uterine, 1 CRC and uterine). Orthogonal tumor testing feasible in 22 pts (76%). MiMSI (conducted for 16) reclassified 4 as MSI that were indeterminate by MSISensor; IHC (conducted for 15) classified 1/8 tumors as dMMR previously MSS on MSISensor. Whole cohort MSI status: 16 composite MSI (59%), 11 MSS (41%), and 2 MS unknown. gPVs in N= 16 with MSI tumors: 9 MSH2, 4 MSH6, 2 MLH1, and 1 PMS2; amongst N= 11 MSS tumors: 6 gMSH6, 4 gPMS2, and 1 EPCAM. Amongst 24 evaluable pts biallelic loss identified in 6 pts with MSI disease. The dominant mutational signature in 4/6 was Clock/aging and not MSI; 2 of these 4 harbored gMSH2, and 2/4 gMSH6. KRAS and TP53 mutations more common in sporadic MSS PDAC than LS-PDAC (p=0.001, p=0.005 respectively); KRAS G12R was enriched in LS PDAC vs sporadic PDAC (31.6% vs 15.3%, p=0.06). N= 13 (47%) received ICB, inclusive of 4 reclassified by MiMSI and 8 with metastatic disease. In evaluable pts with MSI disease, overall response rate 60% (2 CR, 4 PR, 4 SD). N= 1 MSS PDAC had POD as best response. Median ICB duration: 27.7 months (95% CI 9.0, NR). Conclusion: In this LS PDAC cohort we observed a higher proportion of MSH6, MSH2, PMS2 gPVs relative to other cohorts. LS-PDAC MSI arises frequently in association with gMSH2, gMLH1. MSI status determination with orthogonal testing is critical to appropriately select pts for ICB. Outcome to ICB in LS PDAC MSI comparable to other tumor types highlighting the importance of MSI as a predictive biomarker in PDAC.
Citation Format: Emily Harrold, Catherine A. O'Connor, David Lin, Andrea Gazzo, Henry Walch, Megha Ranganathan, Amanda Catchings, Sarah Kane, Fergus Keane, Deborah M. Thurtle-Schmidt, Fiyinfolu Balogun, Anna Varghese, Kenneth Yu, David Kelsen, Alicia Latham, Britta Weigelt, Wungki Park, Zsofia Stadler, Eileen M. O'Reilly. Clinical and molecular characterization of Lynch syndrome-associated pancreas adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B042.