Sebastiaan Ceuppens, MD
PhD-researcher
University of Pittsburgh
Pittsburgh, Pennsylvania, United States
Eva Verkolf, MD
Erasmus MC
Rotterdam, Zuid-Holland, Netherlands
Jacob C. Hodges, MS (he/him/his)
Biostatistician
University of Pittsburgh
Pittsburgh, Pennsylvania, United States
Shahzaib Ahmad, MD (he/him/his)
Visiting Scholar
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States
Aatur Singhi, MD PhD
Associate Professor of Anatomic Pathology
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States
Ester Dekker, MD
Erasmus MC
Rotterdam, Zuid-Holland, Netherlands
Marc Besselink, MD, PhD
Amsterdam UMC
Amsterdam, Noord-Holland, Netherlands
Bas Groot Koerkamp, MD, PhD
Attending Surgeon
Erasmus MC Cancer Institute
Rotterdam, Zuid-Holland, Netherlands
Ching-Wei D. Tzeng, MD MS (he/him/his)
Professor
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Amer H. Zureikat, MD
Professor and Chief, Division of Surgical Oncology
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States
Alice C. Wei, MD (she/her/hers)
Attending Surgeon
MEMORIAL SLOAN KETTERING CANCER CENTER
New York, New York, United States
Alessandro Paniccia, MD
Assistant Professor of Surgery
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States
While KRAS mutations occur in ~90% of pancreatic ductal adenocarcinomas (PDAC), alterations in other major oncogenic pathways may hold greater prognostic and therapeutic relevance. This study examines the association between key driver pathway mutations and overall survival in PDAC, and evaluates differential chemotherapy response by mutational profile.
Methods:
This retrospective study included consecutive patients from 5 referral centers in the Unites States and the Netherlands, who were diagnosed with localized PDAC and received at least one cycle of (m)FOLFIRINOX or Gemcitabine-based chemotherapy as initial treatment (2012-2022). Patients were included if targeted next-generation sequencing (NGS) was performed on pre-treatment biopsy, resected specimen or biopsy of a metastatic lesion. The primary outcome was overall survival (OS), defined as the time between date of diagnosis until date of death or last follow-up.
Results:
Out of 2834 patients with localized PDAC, 805 (28.4%) had NGS performed. Overall, 87.7% (n=706) of tumors harbored oncogenic alterations in RTK/RAS pathway, 66.2% in the TP53 pathway, 26.5% in the Cell Cycle Regulation (CCR) pathway, 12.5% in the TGF-β/SMAD pathway, and 7.0% in the HRD pathway.
Overall, 64.7% (n=521) underwent pancreatic resection. In this cohort, KRAS G12D had worse survival outcomes regardless of CCR status (HR: 1.6 (95%CI: 1.1 – 1.8)), compared to KRAS wildtype (WT). In patients with other KRAS mutations without CCR pathway mutation, survival was comparable to KRAS WT (HR: 1.2 (95%CI: 0.8 – 1.9)). However, if patients had other KRAS mutations with a concomitant CCR pathway mutation, their survival was worse compared with no CCR pathway mutation (HR: 2.0 (95%CI: 1.2 – 3.2)).
Patients with no mutation in the HRD pathway receiving gemcitabine-based regimen had worse survival compared to FOLFIRINOX (HR: 1.6 (95%CI: 1.3 – 2.1)). Similarly, patients with a HRD pathway mutation had worse survival outcomes when receiving gemcitabine-based regimen compared to FOLFIRINOX (HR: 3.2 (95%CI: 1.2 - 8.6)).
Conclusions:
This international cohort of patients starting FOLFIRINOX or gemcitabine-based neoadjuvant chemotherapy for localized PDAC showed that specific genomic alterations, particularly in KRAS G12D and CCR pathways, were independently associated with overall survival. HRD mutation status also influenced response to neoadjuvant therapy, with FOLFIRINOX tied to better outcomes. These findings support genomic profiling to guide treatment selection in localized PDAC.