Peritoneal Mesotheliomas Characterized By Less Cell-Cycle Alterations And More Traf7 Alterations Than Malignant Pleural Mesotheliomas.

9059 Background: While peritoneal mesotheliomas (PM) are clinically distinct from malignant pleural mesotheliomas (MPM) it is unknown if genetic alterations reflect these differences. Here we report the molecular alterations and clinicopathologic characteristics of a prospectively collected PM cohort as compared to MPM. Methods: Patients with PM (n = 59) and targeted next generation sequencing (NGS; MSK-IMPACT) from January 2014 to January 2019 were assessed and followed through February 2020. Germline variants were analyzed in consented patients. NGS was compared to patients with MPM (n = 194) assessed in the same time interval. Results: Median age at diagnosis was 61 (range: 20-77), 56% were women (n = 33), and 92% had epithelioid histology (n = 54). 66% had ascites (n = 39) and 24% developed extra-abdominal metastases (n = 14; including lung, pleura, and mediastinum). 68% (n = 40) underwent surgical debulking and 80% (n = 47) had infusional therapy (median lines: 3) including platinum/pemetrexed (n = 38), EPIC (n = 22), HIPEC (n = 15), and immunotherapy (n = 16). The median overall survival (OS) from diagnosis was 5.4 years (median follow up 3.5 years). The median tumor mutation burden (TMB) was 1.8 mut/Mb (range: 0-14.9) in PM vs 2.0 mut/Mb (range: 0-31.5) in MPM (p = 0.049). More patients with PM had TRAF7 alterations than in MPM (5/59 vs 3/194; p = 0.02) while fewer had CDKN2A/ CDKN2B (4 vs 55; p = 0.0004). All patients with TRAF7 altered PM had well-differentiated papillary epithelioid histology. There was no difference in the prevalence of other common alterations such as BAP1 (32 vs 98; p = 0.66), NF2 (12 vs 55, p = 0.24), SETD2 (11 vs 24; p = 0.28), and TP53 (9 vs 28; p = 0.84) in PM vs MPM respectively. Patients with BAP1-altered PM had shorter OS (4.6 vs 9.8 years; HR 2.6, 95% CI 1.1-6.4; p = 0.04) while TRAF7-altered PM had improved OS (not reached vs 4.8 years; HR 0.3, 95% CI 0.1-0.9; p = 0.04) compared to wild type. 13% (4/30) of patients with PM had pathogenic variants on germline NGS ( POT1 I78T, MUTYH R109Y, BAP1 E402*, APC I1037K). Conclusions: NGS confirms the distinct biology of PM compared to MPM. Specifically, the former shows fewer cell cycle ( CDKN2) alterations compared to MPM. In contrast to MPM, BAP1 alteration was associated with shorter survival. As previously described, we found enrichment of TRAF7 in well differentiated papillary epithelioid PM associated with improved survival but notably some TRAF7 alterations were identified in poorly differentiated MPM. Consistent with other reports, the prevalence of germline alterations was 13%.