AR3 - Genetic Signatures Can Identify Appendiceal Cancer Patients with Poor Outcomes Who Would Less Likely Benefit From Incomplete Cytoreduction/HIPEC

Introduction: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is an accepted treatment for Appendiceal Mucinous Neoplasm (AMN) that could potentially confer long term survival. This major operation should be reserved for appropriate candidates in whom the benefits outweigh the risks. Clinical decision making is more challenging when complete cytoreduction is not feasible. Nevertheless, some patients still benefit from long term survival after incomplete CRS/HIPEC. There is a lack of a robust predictive tool that can assist in clinical decision making.

Methods: We have quantified tumor gene expression with a custom Nanostring 148-gene panel. Using signed non-negative matrix factorization algorithms, we have classified AMN into 3 molecular subtypes with distinct prognostic signatures: Immune Enriched (IE), Mixed (M) and Oncogene Enriched (OE). Expression of Nanostring panel of 82 AMN patients with incomplete CRS/HIPEC (R2 resection) was assessed and genetic signatures were identified. Log-rank test and Kaplan-Meier survival curves were used to compare the overall survivals (OS). Cox proportional hazard models were used to identify the genes associated with OS.

Results: We studied 82 patients with R2 resection. Genes associated with survival were distinct for each pathologic grade. They were involved in various signaling pathways associated with innate and adaptive immunity, carcinogenesis cascades and metastatic pathways including ERBB signaling, Wnt/β-catenin, PI3K/Akt, mitogen-activated protein kinase and Epithelial-mesenchymal transition. Median OS were 4.8yr (IE), 3.5yr (M) and 1.4yr (OE). OE was associated with significantly lower survival compared to others (HR=2.53; 95%CI: 1.40-4.57, p=0.002). This was more prominent in the high-grade subset (Median survival 1yr, HR=2.79; 95%CI 1.22-6.42, p=0.015).

Conclusion: Genetic signatures can identify AMNs with poor outcomes who would less likely benefit from incomplete CRS/HIPEC. This has potential clinical implications as a molecular tool that can be utilized for clinical decision making after prospective validation.