To identify molecular prognostic factors and potentially actionable mutations in ampulla of Vater cancer (AVC).
The largely variable outcomes of AVCs make clinical decisions difficult regarding the need of postsurgical therapy, which is based on morphological and immunohistochemical classification that do not adequately consider the varying degrees of heterogeneity present in many AVCs. No approved targeted therapies for AVC exist, but some show promising results requiring better molecular characterization to identify potential responders.
We assessed 80 AVCs for the prognostic value of mutations of kirsten rat sarcoma (KRAS), neuroblastoma RAS (NRAS), B rapidly accelerated fibrosarcoma (BRAF), TP53, and 4 membrane erythroblastosis oncogene B (ERBB) receptor tyrosine kinases (EGFR-ERBB1, HER2-ERBB2, HER3-ERBB3, HER4-ERBB4) amenable to pharmacological inhibition. Moreover, we evaluated mutations in 16 key components of rat sarcoma (RAS), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), protein 53 (P53), transforming growth factor beta (TGF-β), and wingless/integrated (WNT) pathways, recently associated to AVC by whole-exome sequencing.
TP53 and KRAS were mutated in 41% and 35% of cases, respectively, and emerged as independent prognostic factors together with tumor stage and regardless of the histotype (TP53: P = 0.0006; KRAS: P = 0.0018; stage IIB: P = 0.0117; stage III–IV: P = 0.0020). ERBB, WNT and PI3K pathway genes were mutated in 37.5% of cases.
KRAS and TP53 mutations are negative predictors of survival in AVCs, regardless of histotype. Potentially actionable mutations in ERBB, WNT, and PI3K signaling pathway genes are present in 37.5% of all cases. These might be amenable to target therapy using available drugs like Everolimus in PI3K-mutated cases or compounds under active screening against ERBB and WNT signaling.
Supplemental Digital Content is available in the text
*ARC-NET Research Centre, University of Verona, Verona, Italy
†Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
‡Department of Surgery, Istituto del Pancreas, University of Verona, Verona, Italy
§Department of Medical Oncology, University of Verona, Verona, Italy.
Reprints: Professor Aldo Scarpa, MD, PhD, ARC-NET Research Centre and Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Piazzale L. A. Scuro 10, 37134 Verona, Italy. E-mail: firstname.lastname@example.org.
AM and EA contributed equally and share the first authorship.
CB and AS contributed equally and share the last authorship.
Funding: This work was supported by: Italian Cancer Genome Project—Ministry of University [FIRB RBAP10AHJB]; Associazione Italiana Ricerca Cancro [grant number: 12182]; FP7 European Community Grant Cam-Pac [no: 602783]; Italian Ministry of Health [FIMP-CUP_J33G13000210001]. The funding agencies had no role in the collection, analysis and interpretation of data and in the writing of the manuscript.
The authors declare no conflicts of interest.
Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.annalsofsurgery.com).