SMAD4 Alterations are a Predictive Biomarker to Guide First-line Chemotherapy Selection for the Neoadjuvant Treatment of Localized Pancreatic Cancer

Objective: To evaluate the role of SMAD4 mutational status on clinical outcomes in patients with localized pancreatic ductal adenocarcinoma (PDAC) treated with neoadjuvant chemotherapy (NAC). Background: 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. Methods: 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. Results: 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. Conclusion: 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.