Beyond Khorana score 2: Molecular correlates of venous thromboembolism in pancreatic cancer.

751 Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with a hypercoagulable state leading to thrombosis. Risk models such as the Khorana score automatically classify PDAC as intermediate-high risk, and recent guidelines recommend consideration of thromboprophylaxis. However, little is known about the molecular correlates of PDAC for venous thromboembolism (VTE). Methods: We examined clinical and genomic data from the prospective multi-institution COMPASS trial (NCT02750657), which enrolled patients with treatment-naïve metastatic PDAC who underwent a fresh tumor biopsy for real-time whole genome and transcriptome sequencing. Laser capture microdissection was performed. Patients underwent restaging scans at 8-week intervals. Detailed chart review was conducted to focus on VTE risk factors, timing of VTE diagnosis, and anticoagulation. We also compared clinical and molecular factors based on timing of VTE diagnosis. Overall survival was defined as time from VTE to death. Results: Of 268 patients enrolled in the COMPASS trial, 166 patients had detailed clinical data available regarding VTE status. 82 patients (49%) developed a VTE, where 16 (20%) had breakthrough clots. Baseline epidemiological variables were similar for those with and without VTE, including no differences between age, sex, BMI, and baseline CA 19-9. No patients were on routine prophylactic anticoagulation. SMAD4 mutations were more frequently seen in the VTE subgroup (57% vs. 40%, p= 0.04), but no differences were seen in other driver genes (KRAS, TP53, CDKN2A), Moffitt subtype, or homologous recombination deficiency status. Patients who developed an early VTE (within 3 months) had a higher baseline CA 19-9 (median 4015 vs. 891, p= 0.02), and none were port-associated. A higher incidence of KRAS wildtype cases (10%) were observed in the early vs. later VTE groups (p= 0.03), but no differences in KRAS allelic status. There were no differences in burden of SNVs, indels, or SVs. Early VTE occurred in 46% of all basal cases, which are typically more aggressive, and only in 37% of classical subtypes. Overall survival was shorter with early VTE (HR 1.74, p= 0.02). Conclusions: A higher incidence of SMAD4 alterations were observed among patients with metastatic PDAC who developed VTE. VTE diagnosed earlier were associated with shorter survival, suggesting that early thromboprophylaxis should be considered at the time of diagnosis. Clinical trial information: NCT02750657 .