Higher SMAD4 expression tracked with fewer distant failures after resected pancreatic cancer

KEY POINTS

• This exploratory translational analysis used archived tumor tissue from NRG Oncology/RTOG 9704, a phase III trial of resected pancreatic ductal adenocarcinoma. Quantitative SMAD4 protein expression was successfully measured in 141 of 451 eligible patients.
• All trial patients received postoperative chemoradiotherapy with 50.4 Gy in 28 fractions plus continuous-infusion 5-FU. Systemic treatment before and after CRT consisted of either 5-FU or gemcitabine.
• High versus low SMAD4 was defined using the median expression level. In univariable analysis, high SMAD4 was associated with a 32% lower risk of disease-free survival failure (HR 0.68; p=0.03) and a 31% lower risk of death (HR 0.69; p=0.04).
• Estimated 3-year outcomes separated substantially: overall survival was 26.3% with high versus 14.5% with low SMAD4, while disease-free survival was 17.7% versus 7.3%.
• High SMAD4 was also associated with fewer distant failures, with HR 0.69 (p=0.048). By contrast, SMAD4 expression was not significantly associated with locoregional recurrence.
• After multivariable adjustment, the association with disease-free survival persisted (HR 0.66; p=0.028). The distant-metastasis association became borderline (HR 0.68; p=0.052), while the overall-survival association was no longer independently significant.
• Clinical translation remains premature. Roughly two-thirds of the original trial population lacked analyzable tissue, the samples came from patients treated more than two decades ago, contemporary systemic regimens have changed, and the SMAD4 assay has no validated CAP/CLIA-certified clinical cut-off.

CLINICAL TAKEAWAY

SOURCE

International Journal of Radiation Oncology, Biology, Physics