SMAD4 Alterations are a Predictive Biomarker to Guide First-line Chemotherapy Selection for the Neoadjuvant Treatment of Localized Pancreatic Cancer : A Multicenter, Retrospective Cohort Study.

Abstract

To evaluate the role of SMAD4 mutational status on clinical outcomes in patients with localized pancreatic ductal adenocarcinoma (PDAC) treated with neoadjuvant chemotherapy (NAC). NAC is increasingly utilized in the management of localized PDAC. In biologically unselected patients, FOLFIRINOX (FFX) and gemcitabine plus nab-paclitaxel (gem/nab-p) demonstrate equivalent oncologic outcomes. SMAD4 has been identified as a potential biomarker of resistance to FFX in single institution studies but validation is needed. A multicenter, retrospective cohort study was conducted of patients with localized PDAC who received neoadjuvant FFX or gem/nab-p. Alterations in SMAD4 were assessed by targeted next-generation sequencing. The association of SMAD4 alterations with rates of metastatic progression and surgical resection were assessed by multivariable logistic regression accounting for resectability status and tumor location. The rate of SMAD4 alterations was 27.3% (85/311). A total of 168 (54.0%) patients underwent surgical resection; there was no difference in rates of surgical resection between FFX vs. gem/nab-p treatment groups (52.0% vs. 59.3%; P =0.248). When stratified by SMAD4 mutational status, SMAD4 alterations were associated with increased likelihood of metastatic progression (OR 1.89, 95% CI 1.01-3.55; P =0.047) and failure to complete surgical resection (OR 0.49, 95% CI 0.26-0.91; P =0.024) uniquely among patients who received FFX. SMAD4 alterations were not associated with metastatic progression ( P =0.804) or surgical resection ( P =0.689) for gem/nab-p treated patients. Alterations in SMAD4 were predictive of treatment failure for patients receiving neoadjuvant FFX. These data warrant prospective evaluation and support future trial designs incorporating SMAD4 as a predictive genomic biomarker.