| Summary: | Several molecular biomarkers have been identified to guide induction treatment selection for localized pancreatic ductal adenocarcinoma (PDAC). <i>SMAD4</i> alterations and low <i>GATA6</i> expression/modified “Moffitt” basal-like phenotype have each been associated with inferior survival uniquely for patients receiving 5-FU-based therapies. <i>SMAD4</i> may directly regulate the expression of <i>GATA6</i> in PDAC, pointing to a common predictive biomarker. To evaluate the relationship between <i>SMAD4</i> mutations and <i>GATA6</i> expression in human PDAC tumors, patients with paired <i>SMAD4</i> mutation and <i>GATA6</i> mRNA expression data in the TCGA and CPTAC were identified. In 321 patients (TCGA: n = 180; CPTAC: n = 141), the rate of <i>SMAD4</i> alterations was 26.8%. The rate of <i>SMAD4</i> alteration did not vary per tertile of normalized <i>GATA6</i> expression (TCGA: <i>p</i> = 0.928; CPTAC: <i>p</i> = 0.828). In the TCGA, <i>SMAD4</i> alterations and the basal-like phenotype were each associated with worse survival (log rank <i>p</i> = 0.077 and <i>p</i> = 0.080, respectively), but their combined presence did not identify a subset with uniquely inferior survival (<i>p</i> = 0.943). In the CPTAC, the basal-like phenotype was associated with significantly worse survival (<i>p</i> < 0.001), but the prognostic value was not influenced by the combined presence of <i>SMAD4</i> alterations (<i>p</i> = 0.960). <i>SMAD4</i> alterations were not associated with poor clinico-pathological features such as poor tumor grade, advanced tumor stage, positive lymphovascular invasion (LVI), or positive perineural invasion (PNI), compared with <i>SMAD4</i>-wildtype. Given that <i>SMAD4</i> mutations were not associated with <i>GATA6</i> expression or Moffitt subtype in two independent molecularly characterized PDAC cohorts, distinct biomarker-defined clinical trials are necessary.
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