Pancreatic Cancer Lifestyle Evolution And Resistance

Decoding Environmental Drivers of Adaptive Evolution and Chemotherapy Resistance in Advanced Pancreatic Cancer

Advanced PDAC patients undergo polychemotherapy, yet responses are highly variable. Transcriptome signatures are emerging as key predictors of treatment response. However, PDAC adapts across sites (primary vs. metastases) and evolves under treatment pressure (pre- vs. post-chemotherapy). Moreover, common environmental pollutants, like smoking and microplastics, contribute to carcinogenesis, yet their impact on PDAC evolution and treatment response remains unclear.

To fill these gaps, the CLEAR project aims at investigating:

1. transcriptome patterns linked to treatment response;
2. effects of smoking and microplastic exposure on treatment outcomes;
3. PDAC evolution across organ sites and under chemotherapy. These studies will help uncover biomarkers and factors shaping disease progression, hence paving the ground for personalized therapies.

This study aims at identifying and validating transcriptome signatures in patients with Pancreatic Ductal Adenocarcinoma (PDAC) through EUS-guided biopsies. The study hypothesis is that specific molecular profiles (e.g., "basal-like" vs. "classical" subtypes) obtained at the time of diagnosis can predict primary resistance or sensitivity to standard-of-care first-line chemotherapy regimens (mFOL, NG, or PAXG). By correlating these signatures with clinical outcomes, the study seeks to provide a rationale for personalized therapeutic strategies in advanced PDAC.

This is a prospective, single-center, interventional study. Patients with a cytological diagnosis of PDAC (confirmed via Rapid On-Site Evaluation - ROSE) during a standard-of-care EUS-TA are enrolled at baseline. A part of the citology sample is employed for research purpose (RNA-seq). Following the procedure, patients receive standard-of-care chemotherapy (mFOL, NG, or PAXG). The intervention consists of an additional biopsy pass performed during EUS at the time of re-staging after chemotherapy, exclusively for research purposes (RNA-seq). All patients undergo standard longitudinal clinical monitoring to assess Progression-Free Survival (PFS) and Overall Survival (OS) for a total period of 30 months or until death.

Primary Objective:

To identify baseline transcriptomic signatures associated with treatment response to mFOL, NG, and PAXG in advanced PDAC patients.

Primary Endpoint:

Response to treatment assessed every 3 months by RECIST 1.1 criteria and defined as Disease Control Rate at 6 months (DCR-6); Progression-Free Survival (PFS) and Overall Survival (OS) during the follow-up period.

Secondary Objectives:

To investigate the longitudinal evolution of PDAC signatures during treatment

Secondary Endpoints:

Comparison of transcriptome signatures between baseline EUS-biopsy and repeated biopsy after 6 months of treatment.

To evaluate the impact of active smoking on transcriptomic subtypes and treatment outcomes via correlation between smoking status and the distribution of classical vs. basal-like subtypes and clinical outcomes.

To compare signatures between primary and metastatic sites throughout the comparison of transcriptomic patterns between primary tumor and metastatic biopsy samples.

Inclusion Criteria:

• Age = 18 years
• Willing to sign informed consent
• Patient with CT scan or MRI or EUS with a lesion suspect of PDAC at any clinical stage
• Patients considered fit to receive polychemotherapy with either mFOL, NG or PAXG.
• Patients primarily followed at HSR

Exclusion Criteria:

• Patients not willing to sign informed consent
• Pregnancy and breastfeeding
• Cytology positive for malignancies other than PDAC
• Patients who have not performed biopsy for safety or technical reasons
• Patients unfit for polychemotherapy