41: Combination of tumor and CAF subtypes better predict response to neoadjuvant therapy in pancreatic cancer

Friday, March 22, 2024

2:42pm – 2:54pm ET

Location: Georgia Ballroom

Abstract Presenter(s)

Jaewon Lee, MD

Surgical Oncology Fellow
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States

Submitter(s)

Jaewon Lee, MD

Surgical Oncology Fellow
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States

Author(s)

Jaewon Lee, MD

Surgical Oncology Fellow
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States
Joseph Kearney, M.D.

Surgery resident, Clinical research fellow
UNC Hospitals- General Surgery
Durham, North Carolina, United States
PC

Priscilla Chan, n/a

Research Technician
UNC Chapel Hill, United States
EK

Elena Kharitonova, n/a

Graduate Student
University of North Carolina at Chapel Hill, United States
AH

Arthi Hariharan, n/a

Graduate Research Assistant
University of North Carolina at Chapel Hill, United States
ML

Michelle LaBella, MD

Resident
University of North Carolina, United States
AM

Ashley Morrison, n/a

Research Technician
University of North Carolina at Chapel Hill, United States
AC

Ashley Cliff, PhD

Research Associate
University of North Carolina at Chapel Hill, United States
MM

Michael Meyers, MD

Professor
University of North Carolina at Chapel Hill, United States
Hong Jin Kim, MD

Professor
University of North Carolina at Chapel Hill
Chapel Hill, NC, United States
NR

Naim Rashid, PhD

Associate Professor
University of North Carolina at Chapel Hill, United States
XP

Xianlu Peng, PhD

Assistant Professor
University of North Carolina at Chapel Hill, United States
Jen Jen Yeh, MD

Professor
University of North Carolina at Chapel Hill

Disclosure(s):

Jaewon Lee, MD: No financial relationships to disclose

Jen Jen Yeh, MD: Focal Medical: Ownership Interest (Ongoing)

Introduction: The biology of the tumor and the microenvironment plays an important role in disease progression in pancreatic ductal adenocarcinoma (PDAC). RNA-based tumor-intrinsic subtypes (classical and basal-like) and stromal subtypes (normal and activated) of PDAC have been shown to independently predict outcomes. In addition to our previously described single-sample classifier (SSC) for tumor-intrinsic subtypes, we have now developed a SSC for cancer-associated fibroblast (CAF) subtype that we call DeCAF. Here, we demonstrate even more robust correlations with clinical outcomes and determine their association with clinical variables and treatment outcome.

Methods: 191 deidentified resected PDAC tumors underwent RNA-sequencing. PurIST was used to determine tumor subtypes and a newly developed method DeCAF was used to determine CAF subtypes. Mann-Whitney U test and Fisher's exact test were used for numeric and categorical variables, respectively. Survival was analyzed using logrank test.

Results: 119 patients (62.3%) did not receive neoadjuvant therapy, and 72 (37.7%) received neoadjuvant FOLFIRINOX. 18 tumors (9.4%) were basal-like, and 173 (90.6%) were classical. In classical tumors, there was a decreased proportion of T3 tumors and increased proportion of T1 tumors with neoadjuvant FOLFIRINOX (p = 0.002), whereas there was no difference in T stage for basal-like tumors. Nodal stage was also decreased with therapy in classical tumors (p = 0.043), whereas it remained similar in basal-like tumors. There was no statistically significant difference in overall survival (OS) in basal-like tumors with and without neoadjuvant FOLFIRINOX, whereas there was improved OS with therapy in classical tumors (p = 0.030). DeCAF was used to determine tumor permissive (perm) vs tumor restraining (rest) CAF subtypes. 51 (26.7%) tumors were permCAF, and 140 (73.3%) were restCAF. restCAF tumors were lower T stage with neoadjuvant therapy (p = 0.0005). When tumor and CAF subtypes were evaluated together, the CAF subtypes demonstrated an additive effect over tumor subtype, where the classical-restCAF subtype demonstrated best OS after systemic therapy (p < 0.0001).

Conclusions: Classical and restCAF subtypes are associated with the most favorable response to neoadjuvant FOLFIRINOX as evidenced by lower T and N stages with treatment. Better locoregional response to systemic therapy may lead to better overall survival in these subtypes. Molecular subtyping of PDAC for both the tumor and tumor microenvironment may be important steps in selecting first-line therapy for patients with this deadly disease.

Learning Objectives:

Upon completion, participant will be able to distinguish differences between tumor and tumor microenvironment subtypes in pancreatic cancer.
Upon completion, participant will be able to describe the utility of molecular subtyping in pancreatic cancer.
Upon completion, participant will be able to list clinical and tumor characteristics that are different between the different molecular subtypes of pancreatic cancer.