BACKGROUND Transcriptional subtypes of pancreatic ductal adenocarcinoma (PDAC) have prognostic implications and potential predictive functions. This study aimed to determine their clinicopathological impact in large cohorts of advanced and resected PDAC and their evolution during disease progression. METHODS The clinicopathological and prognostic implications of transcriptional subtypes determined by the expression of KRT81, HNF1A and GATA6 were examined using immunohistochemistry in advanced (n=139) and resected (n=411) PDAC samples as well as in 57 matched primary tumors and corresponding metastases. RNAseq data of‭ 316‬ resected PDAC patients was analyzed for validation. ‬‬‬‬‬‬ RESULTS Both subtyping systems were highly interrelated. Subtypes switched during disease progression in up to 31.6% of patients. Transcriptional subtyping had a modest prognostic impact in both unstratified cohorts, but strongly improved outcomes in patients with KRT81 positive / GATA6 negative tumors treated with palliative or adjuvant gemcitabine-based chemotherapy. RNAseq expression data confirmed the findings. CONCLUSIONS Transcriptional subtypes have differential responses on palliative and adjuvant gemcitabine-based chemotherapy, but they may change during disease progression. Both employed subtyping systems are equivalent and can be used to inform clinical therapy decisions. CLINICAL TRIAL REGISTRY The clinical trial registry identifier is NCT00440167.

The authors have declared no competing interest.

This study did not receive any funding

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Each patient gave written informed consent for the use of its tumor material and clinical data for academic research purposes upon study enrollment. Ethical approval by the local ethics committee was given for each study 33,34 and they were carried out according to the Declaration of Helsinki. The non-commercial academic use of anonymized patient data and corresponding tumor material was approved by the ethics committee of the medical faculty of Ludwig-Maximilians-University without obtaining the patients' informed consent (project numbers 554-11, 401-15, 20-081, 23-0222 and 23-0224).

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The expression datasets used for validation are publicly accessible on https://portal.gdc.cancer.gov/ and https://dcc.icgc.org/. Raw data on the patient cohorts employed in this study can be obtained from the corresponding author upon reasonable request.

https://portal.gdc.cancer.gov/

https://dcc.icgc.org/.