A genetically defined signature of responsiveness to erlotinib in early-stage pancreatic cancer patients: results from the CONKO-005 trial

High recurrence rates of up to 75% within 2 years in pancreatic ductal adenocarcinoma (PDAC) patients resected for cure indicate a high medical need for clinical prediction tools and patient specific treatment approaches. Addition of the EGFR inhibitor erlotinib to adjuvant chemotherapy failed to improve outcome but its efficacy in some patients warrants predictors of responsiveness. We analyzed tumor samples from 293 R0-resected patients from the randomized, multicenter phase III CONKO-005 trial (gemcitabine+/-erlotinib) with targeted sequencing, copy number, and RNA expression analyses. This study identified five biologically distinct patient clusters with different actionable lesions and unraveled a previously unappreciated association of SMAD4 alteration status with erlotinib effectiveness. Confirmatory studies and mechanistic experiments are warranted to challenge the hypothesis that SMAD4 status might guide addition of erlotinib treatment in early-stage PDAC patients.