236P - Oncogenic fusions shape the landscape of actionable genomic alterations in pancreatic acinar cell carcinoma

Background

The importance of oncogenic fusions and rearrangements as genetic drivers of acinar cell pancreatic cancer (PACC) has been underestimated in prior studies due to a lack of sensitive detection methods. Identifying these targetable alterations is crucial for treatment stratification and subsequent use of targeted therapies.

Methods

We retrospectively identified patients with PACC across three German tertiary care hospitals and the Germanwide DKFZ/NCT/DKTK MASTER platform trial. Tumors were subject to RNA-based fusion/rearrangement detection by hybrid capture panel sequencing or whole-transcriptome sequencing and expression analysis by 3' RNA-Seq. We collected medical records, including the use and outcome of targeted therapies. Genomic data and clinical outcomes were compared to patients with pancreatic ductal adenocarcinoma (PDAC) from the lead institute.

Results

29 patients with PACC were identified. Molecularly targetable oncogenic fusions/rearrangements (3 ERBB2, 3 FGFR1/2-, 2 NTRK1, 4 RAF1, and 2 BRAF rearrangements) were found in 14 patients (48%). Six tumors (21%) were homologous recombination deficient; one was microsatellite instable, and two tumors harbored BRAF ^V600E variants. Overall, tumors from 21 patients (72%) were amendable to treatment with EMA-approved therapeutics. Eight of these patients (38%) were treated or are undergoing treatment with targeted therapies. In contrast, in 18 KRAS^WT PDAC, three oncogenic fusions (1 FGFR2, 1 BRAF, 1 NRG1; 16%) and six BRAF variants (33%) were identified. In 196 KRAS ^mut PDAC, only one oncogenic fusion (1 FGFR3; 0,005%) was identified.

Conclusions

These findings underscore the high prevalence of targetable fusions and rearrangements in PACC, highlighting the pivotal role of comprehensive RNA-based somatic testing alongside DNA-based sequencing for these patients. When combined with targetable genomic alterations that have been described before, such as homologous recombination deficiency or activating BRAF mutations, actionable genomic biomarkers are found in most pancreatic acinar cell carcinomas.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.