39: Multi-omic Characterization Reveals a Distinct Molecular Landscape in Young-onset Pancreatic Cancer

Thursday, March 10, 2022

2:49 PM – 2:57 PM CST

Location: Trinity Ballroom

Abstract Presenter(s)

Ifeanyichukwu Ogobuiro, MD, MHS

T32 Surgical Oncology Research Fellow
University of Miami School of Medicine, Sylvester Comprehensive Cancer Center
Miami, Florida, United States

Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.

Participants should be aware of the following financial/non-financial relationships:

Ifeanyichukwu Ogobuiro, MD, MHS: I do not have any relevant financial / non-financial relationships with any proprietary interests.

Introduction:

Young-onset pancreatic cancer (YOPC; < 50 yrs) has been associated with male preponderance, extensive smoking history, and a trend towards improved survival compared with average-onset pancreatic cancer (AOPC; ≥70 yrs). Using a large matched genomic-transcriptomic next-generation sequencing (NGS) dataset, we sought to characterize the molecular landscape underlying these clinical differences between YOPC and AOPC patients.

Methods: A total of 2430 NGS samples (YOPC n=292; AOPC n=2138) with matched whole-transcriptome (NovaSeq) and DNA (NextSeq, 592-gene or NovaSeq, whole-exome) sequencing data were analyzed (Caris Life Sciences, Phoenix, AZ). Limited clinical data precluded stage- and treatment-stratified comparisons. Overall survival (OS) was obtained from insurance claims, and Kaplan-Meier estimates were calculated for age- and molecularly-defined cohorts. Significance was designated as FDR-corrected P-values (Q) < 0.05.

Results: Of 2430 patients, YOPC patients (median 46 yrs) were more likely to be male (65% vs 52%;P < 0.001) and current smokers (32% vs 11%;P=0.02) compared with AOPC patients (median 75 yrs). YOPC patients had higher proportions of mismatch repair-deficient (2.8% vs 0.8%;P=0.001), BRCA2-mutant (4.7% vs 2.1%;P=0.009), and PALB2-mutant (1.4% vs 0.5%;P=0.04) tumors compared with AOPC patients, while tumors in AOPC patients had more frequent SMAD4 (20.1% vs 14.7%;P=0.03), RNF43 (6.3% vs 2.5%; P=0.012), CDKN2A (24.8% vs 19.2%;P=0.04), and SF3B1 (2.7% vs. 0.7%;P=0.04) mutations. YOPC patients demonstrated lower HLA-DPA1 homozygosity (55% vs 64%;Q < 0.05) vs. AOPC patients. Notably, YOPC patients demonstrated significantly lower incidence of KRAS-mutant (81.3% vs 90.9%;Q < 0.01) tumors compared with AOPC patients. In the KRAS-wildtype subset (n=225), YOPC tumors were more likely to be driven by NRG1 and MET fusions, while BRAF fusions were exclusively observed in AOPC patients. There was an association with improved OS in YOPC patients with KRAS-wildtype (median 22.4 [YOPC-KRAS^WT] vs 15.1 [AOPC-KRAS^WT] months; P=0.02) but not KRAS-mutant (P=0.28), tumors compared with AOPC patients.

Conclusions:

YOPC is associated with a distinct molecular landscape compared with AOPC, revealing molecular features with prognostic and therapeutic implications.

Learning Objectives:

Upon completion, participants will be able to describe distinct genomic markers associated with young-onset pancreatic cancer (YOPC) compared to average onset pancreatic cancer (AOPC).
Upon completion, participants will be able to understand the differences in KRAS mutational status between YOPC and AOPC and it’s prognostic implications.
Upon completion, participants will be able to engage in discussions on the prognostic and therapeutic potential of the unique molecular characteristics associated with YOPC and AOPC.