Sainamthip, Panot, Somadasan, Meenakshi, Culnane, Leigh, Andrews, Elizabeth, Brais, Lauren, Dodd, Anna, Perez, Kimberly, Yu, Kenneth, Laheru, Daniel, King, Daniel A, O'Kane, Grainne M, Gallinger, Steven, Tuveson, David, Jaffee, Elizabeth, Knox, Jennifer J, Notta, Faiyaz, Sperling, Adam S, Aguirre, Andrew J, Wolpin, Brian M, Singh, Harshabad (September 2025) Association between clonal hematopoiesis and survival outcomes in pancreatic ductal adenocarcinoma: Analysis from the PASS-01 trial. In: AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions, 2025 Sep 28-Oct 1, Boston, MA.
Abstract
Clonal hematopoiesis (CH) or presence of expanded hematopoietic clones harboring mutations in leukemia associated genes is associated with a higher risk of cardiovascular disease, myeloid malignancies and shorter overall survival. Incidence of CH increases with age, and CH is often found in patients with epithelial malignancies where it can be associated with worse outcomes. However, the impact of CH in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here we study the impact of CH on outcomes in patients enrolled on the PASS-01 trial. PASS-01 is a randomized control phase 2 trial of patients with previously untreated metastatic PDAC who received either FOLFIRINOX or gemcitabine with nab-paclitaxel. As part of the PASS-01 trial, serial peripheral blood samples were collected. CH was identified using a 25-gene next-generation sequencing (NGS) panel assay on DNA extracted from pre-treatment buffy coat. CH was defined as the presence of a pathogenic mutations in any of the included genes on the panel with a variant allele frequency (VAF) ≥1%. Associations between CH and clinical outcomes including overall survival (OS) and progression-free survival (PFS) were evaluated using Kaplan Meier method and significance was estimated using log-rank test. Cox proportional hazards regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs).Results Of 140 patients included in the per-protocol analysis of PASS01, 137 pre-treatment samples were available, and 125 passed quality control metrics for CH analysis. CH mutations were detected in 46 patients (36.8%). The most frequently mutated genes were DNMT3A (60.9%), TET2 (17.4%), and ASXL1 (6.5%). Baseline characteristics were balanced between CH-positive and CH-negative patients though as expected CH was associated with a trend towards older age (Mean age 64.7 vs. 61.8 years, p = 0.08). In CH-positive versus negative patients, median OS was 9.4 months versus 9.6 months (HR = 0.91; 95% CI: 0.59–1.40; p = 0.67) and median PFS was 4.9 months versus 5.2 months, (HR = 0.97; 95% CI: 0.66–1.41; p = 0.85). Interestingly, in basal-like tumors (n = 23), CH (n = 7) was associated with a numerically shorter median OS (6.2 vs. 10.2 months; HR = 1.37; 95% CI: 0.51–3.69; p = 0.52) and median PFS (2.4 vs. 4.7 months; HR = 2.50; 95% CI: 0.93–6.84; p = 0.06). No such differences were observed in classical tumors (n = 70; 26 with CH). There were no difference in OS and PFS by presence of CH based on type of first line chemotherapy regimen patients received on the trial. Exploratory analyses evaluating only larger clones with VAF ≥ 2% did not change our findings. Presence of CH is not associated with adverse outcomes in PDAC, potentially related to high competing risk of PDAC related morbidity and mortality. We observe a provocative trend of worse outcomes in patients with CH and basal-like tumors which may reflect unique tumor biology. Additional studies interrogating impact of tumor infiltrating CH variants and mechanistic connections between tumor transcriptional subtype and CH are ongoing.
| Item Type: | Conference or Workshop Item (Paper) |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > pancreatic cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Tuveson lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 28 September 2025 |
| Date Deposited: | 21 Oct 2025 12:45 |
| Last Modified: | 21 Oct 2025 12:45 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41986 |
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