Inna Markovna Chen

In pancreatic ductal adenocarcinoma (PDAC), clinicians often ask whether young age is associated with more aggressive disease or patients more likely to tolerate curative-intent multimodality treatment. The prognostic meaning of age after surgery remains uncertain. We analyzed a retrospective multicenter surgical cohort of patients with resected non-metastatic PDAC. Candidate clinical variables were evaluated in univariable Cox models. The prespecified primary multivariable model included age, sex, N status, T stage, and CA19-9 status. Adjuvant therapy was evaluated in a sensitivity model. The cohort included 696 surgical patients; 70 (10.1%) were aged < 55 years. Median overall survival was 34.4 months in patients aged < 55 years versus 22.0 months in those aged ≥ 55 years (log-rank p = 0.019). In the primary multivariable model, age < 55 years remained independently favorable (HR 0.66, 95% CI 0.49–0.89; p = 0.007). Elevated CA19-9 value independently predicted worse survival (HR 1.39, 95% CI 1.13–1.71; p = 0.002). The sensitivity model confirmed favorable associations for young age and not elevated CA19-9 value. In surgically managed PDAC patients, young age and normal CA19-9 value carried independent favorable prognostic information. Prognosis was also shaped by nodal status, T stage, and receipt of adjuvant therapy.

Transforming growth factor beta (TGFβ) plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) progression by promoting immune suppression, fibrosis, and metastasis. Given its central role in shaping the tumor microenvironment, TGFβ has attracted significant clinical interest as a target for immunotherapy. One promising and innovative approach involves TGFβ-based immune-modulatory vaccines (IMVs). In this study, we explored the immunogenic potential of multiple TGFβ-derived epitopes and assessed the clinical relevance of TGFβ-specific T cells in PDAC patients. We identified T cell responses towards multiple epitopes, TGFβ‑15, TGFβ‑33, and TGFβ‑38, in both healthy donors and PDAC patients, with TGFβ‑33 eliciting particularly robust responses in the patient cohort. These primarily CD4⁺ T cells displayed proinflammatory, as well as notable cytotoxic, properties and recognized target cells in a TGFβ-dependent manner. Moreover, we found that higher baseline frequencies of TGFβ‑33-specific T cells correlated with improved clinical outcomes following combined immune checkpoint inhibitor therapy and radiotherapy. Interestingly, patients with baseline responses to multiple TGFβ-derived epitopes had longer overall and progression-free survival compared to those with responses to none or a single epitope. Using a single mRNA construct encoding multiple TGFβ epitopes, we demonstrated effective activation of T cells specific for distinct TGFβ epitopes. These findings support the potential of a multi-epitope TGFβ-derived immune-modulatory vaccine to enhance anti-tumor immunity, representing a promising strategy to improve therapeutic responses in PDAC.

Description of the quality control of DNA extraction

Multivariate Cox proportional hazards model of progression free survival by ctDNA response.

Overall survival according to baseline ctDNA status

Purpose:Changes in ctDNA levels during systemic treatment may predict treatment efficacy in patients with metastatic pancreatic ductal adenocarcinoma (PDAC), but quantitative response criteria are not yet established. This study evaluates our recently proposed ctDNA-RECIST.Experimental Design:Blood samples were collected before treatment, before the second treatment cycle, and at the time of the first CT evaluation from 220 patients with metastatic PDAC receiving first-line palliative chemotherapy. Plasma ctDNA levels were measured using Droplet Digital PCR with HOXA9 methylation assays. ctDNA response was determined according to ctDNA-RECIST and correlated with overall survival (OS).Results:ctDNA was positive before treatment in 71% of the patients and was related to OS [HR = 1.61; 95% confidence interval (CI), 1.19–2.19; P = 0.002]. Among ctDNA-positive patients, ctDNA maximal response (MR; n = 41) and ctDNA disease control (DC; n = 107) before the second treatment cycle had longer OS compared with ctDNA progressive disease (PD; n = 5; median OS: MR 11.9 months, DC 7.2 months, PD 3.6 months; P = 0.002). In Cox regression, ctDNA DC (HR = 1.55; 95% CI, 1.07–2.26; P = 0.021) and ctDNA PD (HR = 4.50; 95% CI, 1.74–11.6; P = 0.002) showed shorter OS compared with ctDNA MR. The same applied to ctDNA response at the time of the first CT evaluation assessed from the second treatment cycle (P < 0.001) and from treatment start (P < 0.001).Conclusions:ctDNA-RECIST applied to liquid biopsies holds potential for early evaluation of treatment benefit in patients with metastatic PDAC, offering a novel, minimally invasive method to guide early clinical decision-making. Future studies should validate ctDNA-RECIST prospectively, preferably in randomized controlled trials.

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