Hoyer, K., Hablesreiter, R., Inoue, Y., Yoshida, K., Briest, F., Christen, F., Kakiuchi, N., Yoshizato, T., Shiozawa, Y., Shiraishi, Y., Striefler, J. K., Bischoff, S., Lohneis, P., Putter, H., Blau, O., Keilholz, U., Bullinger, L., Pelzer, U., Hummel, M., Riess, H., Ogawa, S., Sinn, M. and Damm, F. (2021). A genetically defined signature of responsiveness to erlotinib in early-stage pancreatic cancer patients: Results from the CONKO-005 trial. EBioMedicine, 66. AMSTERDAM: ELSEVIER. ISSN 2352-3964

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Abstract

Background: 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 treat-ment approaches. Addition of the EGFR inhibitor erlotinib to adjuvant chemotherapy failed to improve out-come but its efficacy in some patients warrants predictors of responsiveness. Patients and Methods: we analysed tumour samples from 293 R0-resected patients from the randomized, multicentre phase III CONKO-005 trial (gemcitabine +/- erlotinib) with targeted sequencing, copy number, and RNA expression analyses. Findings: a total of 1086 mutations and 4157 copy-number aberrations (CNAs) with a mean of 17.9 /tumour were identified. Main pathways affected by genetic aberrations were the MAPK-pathway (99%), cell cycle control (92%), TGFb signalling (77%), chromatin remodelling (71%), and the PI3K/AKT pathway (65%). Based on genetic signatures extracted with non-negative matrix factorization we could define five patient clusters, which differed in mutation patterns, gene expression profiles, and survival. In multivariable Cox regression analysis, SMAD4 aberrations were identified as a negative prognostic marker in the gemcitabine arm, an effect that was counteracted when treated with erlotinib (DFS: HR=1.59, p = 0.016, and OS: HR = 1.67, p = 0.014). Integration of differential gene expression analysis established SMAD4 alterations with low MAPK9 expression (n = 91) as a predictive biomarker for longer DFS (HR=0.49; test for interaction, p = 0.02) and OS (HR = 0.32; test for interaction, p = 0.001). Interpretation: this study identified five biologically distinct patient clusters with different actionable lesions and unravelled a previously unappreciated association of SMAD4 alteration status with erlotinib effective-ness. 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. (C) 2021 The Author(s). Published by Elsevier B.V.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Hoyer, K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hablesreiter, R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Inoue, Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yoshida, K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Briest, F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Christen, F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kakiuchi, N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yoshizato, T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shiozawa, Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shiraishi, Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Striefler, J. K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bischoff, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lohneis, P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Putter, H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blau, O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Keilholz, U.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bullinger, L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pelzer, U.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hummel, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riess, H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ogawa, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sinn, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Damm, F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-602400
DOI: 10.1016/j.ebiom.2021.103327
Journal or Publication Title: EBioMedicine
Volume: 66
Date: 2021
Publisher: ELSEVIER
Place of Publication: AMSTERDAM
ISSN: 2352-3964
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MUTATIONS DEFINE; TREATED PATIENTS; GEMCITABINE; PLUS; MULTICENTER; SENSITIVITY; INHIBITOR; LANDSCAPE; SUBGROUP; SUBTYPESMultiple languages
Medicine, General & Internal; Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60240

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