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Identifying patients at risk of poor response to neoadjuvant chemoradiotherapy (nCRT) is an emerging clinical need in locally advanced rectal cancer (LARC). SMAD3 is a key player in the chemoradio-resistance phenotype and its expression is both constitutive and locally induced. The aim was to investigate both host (genetic polymorphisms) and tumor SMAD3 profiling to predict response to nCRT. In a group of 76 LARC patients, SMAD3 and phosphorylated-SMAD3 expression was assessed by immunohistochemistry in preoperative tumor tissue. In an expanded study group ( n  = 378), a set of  SMAD3  polymorphisms (rs35874463, rs1065080, rs1061427, rs17228212, rs744910, and rs745103) was analyzed. Association with tumor regression grade (TRG) and patient prognosis (progression-free survival [PFS] and overall survival [OS]) was assessed. Patients with high tumor expression of SMAD3 had a significantly increased risk of poor response (TRG≥2) [cellularity &amp;gt;55% (OR:10.36,  p  = 0.0004), or moderate/high intensity (OR:5.20,  p  = 0.0038), or an H-score≥1 (OR:9.84,  p  = 0.0004)]. Patients carrying the variant SMAD3 rs745103-G allele had a poorer response (OR:0.48,  p  = 0.0093), a longer OS (HR:0.65,  p  = 0.0307), and a trend for longer PFS (HR:0.75,  p  = 0.0944). Patients who carried both high SMAD3 tumor expression and the wild-type rs745103-A allele had an extremely high risk of not achieving a complete response (OR:13.45,  p  = 0.0005). Host and tumor SMAD3 status might be considered to improve risk stratification of LARC patients to facilitate selection for alternative personalized neoadjuvant strategies including intensified regimens.

SMAD3 Host and Tumor Profiling to Identify Locally Advanced Rectal Cancer Patients at High Risk of Poor Response to Neoadjuvant Chemoradiotherapy