Abstract
Molecular landscape and site of metastasis in PDAC.
Author
person
Shafia Rahman
The Ohio State University Comprehensive Cancer Center, Columbus, OH
info_outline
Shafia Rahman, Yasmine Baca, Harshabad Singh, Joanne Xiu, Atrayee B Mallick, Mark P. Rubinstein, Andrew Aguirre, George W. , Michael J. Pishvaian
Full text
Authors
person
Shafia Rahman
The Ohio State University Comprehensive Cancer Center, Columbus, OH
info_outline
Shafia Rahman, Yasmine Baca, Harshabad Singh, Joanne Xiu, Atrayee B Mallick, Mark P. Rubinstein, Andrew Aguirre, George W. , Michael J. Pishvaian
Organizations
The Ohio State University Comprehensive Cancer Center, Columbus, OH, Caris Life Sciences, Phoenix, AZ, Dana-Farber Cancer Institute, Brookline, MA, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, The Ohio State University, Columbus, OH, Dana-Farber Cancer Institute, Boston, MA, Johns Hopkins University School of Medicine, Washington, DC
Abstract Disclosures
Research Funding
No funding sources reported
Background:
More than 50% of patients with Pancreatic ductal adenocarcinoma (PDAC) have metastatic disease at the time of diagnosis and liver is the most common site of metastatic spread. Liver metastasis (LM) is associated with poor prognosis. Herein we examine the difference in molecular landscape of PDACs with LM versus other metastatic sites (OM).
Methods:
Total of 7,979 PDAC tumors underwent next-generation sequencing of DNA (592-gene/whole exome) and RNA (whole transcriptome) at Caris Life Sciences (Phoenix, AZ). Tumors were then evaluated and divided into LM (N=4988) site vs OM (N=3073) sites based on tissue specimen sites. RNA expression data was used to analyze transcriptional signatures as well as tumor immune microenvironment (TME) using Quantiseq. Real-world overall survival (rwOS) information was obtained from insurance claims data and calculated from time of collection or first treatment to last contact. Hazard ratio (HR) was calculated using Cox proportional hazards model, and P values were calculated using log-rank test.Significance for molecular comparisons was calculated using either chi-square, Fisher’s exact, or Mann-Whitney U test, with p-values adjusted for multiple comparisons (q<0.05).
Results:
Mutations in TP53 (81% vs 67%), KRAS (88% vs 83%), ARID1A (13% vs 11%), KDM6A (4% vs 3%), and BRCA1 (1.3% vs 0.7%) were all significantly higher in LM vs OM (all <0.05). Conversely, TMB-H (3% vs 4%), MSI-H (0.7% vs 1.3%), GNAS (1% vs 3%), STK11 (1% vs 3%), ATM (3% vs 5%), PTPRD (2% vs 9%) and RNF43 (5% vs 6%) mutations were significantly lower in LM vs OM (all q<0.05). In the TME, B cells, Tregs, M1, M2 macrophages, and NK cell infiltration was lower in LM vs OM (FC: 0.62-0.91, q<0.05). However, LM had higher neutrophil infiltration vs OM (FC: 1.1, q<0.05). Both interferon-gamma score (IFG) and T cell inflamed score (TIS) were significantly higher in OM vs LM (q<0.05). OM had better OS than LM (11.4 m vs 6.8 m, HR=0.65 95% CI: 0.62-0.68, p<0.001). This association held for tumors treated with Immune Checkpoint Inhibitors (ICI) (9.6 m vs 4.6 m, HR=0.71 95% CI: 0.52-0.97, p=0.031), Gemcitabine/Nab-paclitaxel treated (15.3 m vs 8.1 m, HR=0.57 95% CI: 0.52-0.61, p<0.001) as well as mFOLFIRINOX treated tumors (20.3 m vs 12.0 m, HR=0.57 95% CI: 0.52-0.63, p<0.001).
Conclusions:
When comparing pancreatic LM to OM sites, our data reinforces the observation that OS is better in OM vs LM and response to ICI was better in OM vs. LM. Significant differences were observed in molecular landscape, TME and signatures that are predictive of immunotherapy response (TIS and IFG scores).
Test
Positive N in LM
Total N - LM
% LM
Positive N in OM
Total N - OM
% OM
q-value
TP53 mut
3391
4195
80.8%
1631
2430
67.1%
0.0
GNAS mut
42
4214
1.0%
82
2451
3.4%
0.0
KRAS mut
3709
4215
88.0%
2048
2456
83.4%
0.0
STK11 mut
51
4211
1.2%
71
2448
2.9%
0.0
PTPRD mut
3
143
2.1%
8
86
9.3%
0.02
BRCA1 mut
56
4187
1.3%
17
2446
0.7%
0.02
RNF43 mut
194
4217
4.6%
144
2456
5.9%
0.04
ARID1A mut
435
3399
12.8%
205
1917
10.7%
0.04
7 organizations
Organization
Caris Life Sciences, Irving, TXOrganization
Dana-Farber Cancer InstituteOrganization
Thomas Jefferson UniversityOrganization
Johns Hopkins University School of Medicine