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Tumor-Intrinsic and Cancer-Associated Fibroblast Subtypes Independently Predict Outcomes in Pancreatic Cancer
*Jaewon Lee, *Joseph Kearney, *Priscilla Chan, *Elena Kharitonova, *Arthi Hariharan, *Michelle LaBella, *Ashley Morrison, *Ashley Cliff, *Michael Meyers, Hong Jin Kim, *Naim Rashid, *Xianlu Peng, Jen Jen Yeh
UNC Chapel Hill, Chapel Hill, NC

Background: Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease with limited treatment options, and both the tumor as well as the microenvironment play an important role in disease progression and response to therapy. Gene expression-based tumor-intrinsic subtypes (classical and basal-like) and stromal subtypes (normal and activated) of PDAC have been shown to independently predict outcomes. Here, we introduce cancer-associated fibroblast (CAF) subtypes named tumor-permissive permCAF and tumor-restraining restCAF. We applied these subtypes to resected PDAC specimens and correlated them with treatment outcomes. Methods: RNA-sequencing was performed on 112 deidentified resected PDAC tumors. Clinical data of the patients were collected by retrospective chart review. Further refined single sample classifiers (SSCs) were used to determine tumor-intrinsic classical and basal-like subtypes as well as permCAF and restCAF subtypes. Mann-Whitney U test was performed for numeric variables and Fisher’s exact test was used for categorical variables. Survival was analyzed using logrank test. Results: 76 patients (68%) did not receive neoadjuvant systemic therapy (NAT) and 36 (32%) received neoadjuvant FOLFIRINOX. Patients who received NAT trended on improved overall survival (OS), with median survival of 27.9 months compared to 19.8 months for those who did not receive NAT (HR 0.64, p = 0.0757). 99 tumors (88%) were classical and 13 (12%) were basal-like, whereas 79 (71%) were restCAF and 33 (29%) were permCAF subtypes. Both tumor and CAF subtypes affected OS with classical and restCAF subtypes leading to improved survival (p = 0.0014 and 0.00031, respectively). When evaluated together, classical-restCAF subtype had the best OS and basal-permCAF the worst OS (p < 0.0001). With NAT, classical-restCAF subtype demonstrated improved OS compared to the rest (p = 0.0005). Conclusions: CAF subtypes have an additive effect over tumor subtypes in predicting survival with and without neoadjuvant FOLFIRINOX in PDAC. Molecular subtyping of both tumor and microenvironment compartments of PDAC may be important steps in selecting first-line therapy to improve disease outcomes.
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