Krüppel-like Factor 10 as a Prognostic and Predictive Biomarker of Radiotherapy in Pancreatic Adenocarcinoma

SIMPLE SUMMARY: Despite recent improvement in chemotherapy regimens for pancreatic adenocarcinoma (PDAC), the clinical outcomes are still unsatisfactory compared to other solid tumors. Radiotherapy was demonstrated to improve locoregional control of PDAC; however, the survival benefit of radiotherapy in localized PDAC is undefined due to early distant progression in the majority of patients. Upfront chemotherapy for localized PDAC was suggested recently to avoid radical local therapy for patients of localized PDAC high risk of distant metastasis. Potential tissue biomarkers were developed to select PDAC patients who will benefit from local radiotherapy. This review summarizes potential tissue biomarkers reported to predict the efficacy and survival benefits of radiotherapy for localized PDAC including SMAD4, a biomarker validated in a prospective clinical trial to correlate with failure pattern of localized PDAC after radiotherapy. In particular, we describe Krüppel-like factor 10 (KLF10), lost in two thirds of PDAC patients, in association with distant metastasis and radio-resistance of PDAC. From tumor tissues of patients with resectable PDAC enrolled to a clinical trial, we demonstrated that the combination of KLF10 and SMAD4 expression in tumor tissues may help select those who may benefit the most from additional radiotherapy. Though promising, these potential biomarkers should be validated in prospective clinical trials. ABSTRACT: 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 SMAD4, which is significantly associated with PDAC failure patterns and survival. In particular, Krüppel-like factor 10 (KLF10) is an early response transcription factor of transforming growth factor (TGF)-β. Unlike TGF-β in advanced cancers, KLF10 loss in two-thirds of patients with PDAC was associated with rapid distant metastasis and radioresistance; thus, KLF10 can serve as a predictive and therapeutic marker for PDAC. For patients with resectable PDAC, a combination of KLF10 and SMAD4 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.