Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive epithelial tumors worldwide. In most patients it represents a deadly disease [
1] due to an advanced stage at the time of diagnosis and the difficulties in therapeutic treatment, but also due to genetic heterogeneity [
2]. Surgical resection remains the only curative treatment option for localized PDAC. During the last decade, systemic treatment with single-agent gemcitabine has evolved as standard chemotherapy for the adjuvant and palliative treatment setting [
3,
4]. Gemcitabine offers a median survival of about 5 to 7 months in patients with advanced disease and shows comparatively good tolerability [
5]; more recently, gemcitabine-based combination regimens with the oral epidermal growth factor receptor (EGFR) inhibitor erlotinib or together with nab-paclitaxel [
6] showed a statistically significant improvement in overall survival (OS). The development and progression of PDAC include different genetic alterations in oncogenic activation, loss of tumor-suppressor gene function and overexpression of receptor-ligand systems [
7,
8]. Among these genetic alterations, mutations in the
KRAS gene, which often are already present in precursor lesions, play an important role in tumor development and progression [
8]. Gain of function mutations in the
KRAS gene are detected in about 70 to 90% of PDAC cases [
9], commonly as point mutations in exon 2 (codon 12/13), most frequently as p.G12D (c.35G > A) or p.G12 V (p.35G > T). Several studies showed that constitutively activating
KRAS mutations are associated with worse OS, whereas
KRAS wildtype status is associated with improved OS in PDAC [
7,
10,
11]. Thus, in PDAC,
KRAS mutations may be regarded as prognostic biomarker. The role of
KRAS mutational status as predictive biomarker regarding the use of EGFR-targeting agents like erlotinib in advanced PDAC still remains a matter of debate to date [
12‐
14].
Here, we report the case of a PDAC patient with an unusual clinical course: the tumor of the patient harbored a wildtype KRAS gene at the time of initial PDAC diagnosis; however, upon disease progression 4 years later, a mutation within exon 2 of the KRAS gene was detectable.