Association of SMAD4 gene mutation with incidence of peritoneal involvement in unresectable metastatic colorectal cancer

772 Background: Dorsophilia protein, mothers against decapentaplegic homolog 4 (SMAD4) is involved in TGF- β and Bone Morphogenic Protein (BMP) signaling pathways. Dysregulation in these signaling pathways has been associated with carcinogenesis and poor prognosis in colorectal cancer (CRC). Recent evidence suggests that SMAD4 mutations in CRC may be associated ovarian metastasis, however, the link to peritoneal involvement has not been established. Methods: Patients with next generation sequencing of 50 cancer related genes and unresectable metastatic CRC were identified from a prospectively maintained medical oncology department database. Clinicopathological variables, metastatic sites, and genetic mutations were compared between patients with SMAD4 mutant and SMAD4 wild type patients. Multivariable analysis was then performed to evaluate for factors associated with peritoneal involvement. Results: 324 patients with unresectable metastatic CRC were identified and of these 36 (11%) were SMAD4 mutants. Clinicopathologic variables and additional cancer related gene mutations were similar between SMAD4 mutant and wild type patients. Patients with SMAD4 mutations were more likely to present with peritoneal metastatic disease (50% vs. 24%, p = 0.002) and less likely to present with hepatic metastasis (39% vs 59%, p = 0.021). Metastatic rates to the lungs, distant lymph nodes, and multiple metastatic sites at presentation were similar between the two groups. In patients with metachronous metastatic disease (n = 131), SMAD4 mutation patients demonstrated a trend towards shorter interval to metastatic recurrence (12 vs. 23 months, p = 0.059). During a median follow up of 26 months, SMAD4 mutation patients were more likely to develop peritoneal involvement at either presentation or in progression of disease (58 vs. 35%, p = 0.010). Multivariable analysis showed that compared to other mutations, only the SMAD4 mutation was associated with a higher risk of peritoneal metastasis (OR 2.5, 195% CI 1.2-5.6, p = 0.025). Conclusions: In patients with unresectable metastatic colorectal cancer, SMAD4 mutation is independently associated with peritoneal metastasis.