Tumor-intrinsic and Cancer-associated Fibroblast Subtypes Independently Predict Outcomes in Pancreatic Cancer

Abstract

Objective: To assess the utility of tumor-intrinsic and cancer-associated fibroblast (CAF) subtypes of pancreatic ductal adenocarcinoma (PDAC) in predicting response to neoadjuvant therapy (NAT) and overall survival (OS). Background: PDAC remains a deadly disease with limited treatment options, and both the tumor as well as the microenvironment play an important role in pathogenesis. Gene expression–based tumor-intrinsic subtypes (classical and basal-like) have been shown to predict outcomes, but tumor microenvironment subtypes are still evolving. Methods: RNA-sequencing was performed on 114 deidentified resected PDAC tumors. Clinical data were collected by retrospective chart review. Single sample classifiers were used to determine classical and basal-like subtypes as well as tumor-permissive permCAF and tumor-restraining restCAF subtypes. Survival was analyzed using the log-rank test. Results: Patients who received NAT had an increase in OS, with a median survival of 27.9 months compared with 20.1 months for those who did not receive NAT, but the difference did not reach statistical significance (hazard ratio: 0.64, P=0.076). Either tumor-intrinsic or CAF subtypes alone were associated with OS regardless of NAT or no NAT, and patients with classical or restCAF subtypes had the best outcomes. When evaluated together, patients with the classical-restCAF subtype had the best OS and basal-permCAF the worst OS (P<0.0001). Patients undergoing NAT with the classical-restCAF subtype demonstrated the longest OS compared with the other groups (P=0.00041). Conclusions: CAF subtypes have an additive effect over tumor-intrinsic subtypes in predicting survival with or without neoadjuvant FOLFIRINOX in PDAC. Molecular subtyping of both tumor and CAF compartments of PDAC may be important steps in selecting first-line systemic therapy.