| Summary: | The prognosis of pancreatic adenocarcinoma (PDAC) remains poor, with a 5-year survival rate of 12%. Although radiotherapy is effective for the locoregional control of PDAC, it does not have survival benefits compared with systemic chemotherapy. Most patients with localized PDAC develop distant metastasis shortly after diagnosis. Upfront chemotherapy has been suggested so that patients with localized PDAC with early distant metastasis do not have to undergo radical local therapy. Several potential tissue markers have been identified for selecting patients who may benefit from local radiotherapy, thereby prolonging their survival. This review summarizes these biomarkers including <i>SMAD4</i>, which is significantly associated with PDAC failure patterns and survival. In particular, Krüppel-like factor 10 (<i>KLF10</i>) is an early response transcription factor of transforming growth factor (<i>TGF</i>)<i>-β</i>. Unlike <i>TGF-β</i> in advanced cancers, <i>KLF10</i> loss in two-thirds of patients with PDAC was associated with rapid distant metastasis and radioresistance; thus, <i>KLF10</i> can serve as a predictive and therapeutic marker for PDAC. For patients with resectable PDAC, a combination of <i>KLF10</i> and <i>SMAD4</i> expression in tumor tissues may help select those who may benefit the most from additional radiotherapy. Future trials should consider upfront systemic therapy or include molecular biomarker-enriched patients without early distant metastasis.
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