Universität zu Köln

Sinn, Marianne, Sinn, Bruno, V, Treue, Denise, Keilholz, Ulrich, Damm, Frederik, Schmuck, Rosa, Lohneis, Philipp, Klauschen, Frederick, Striefler, Jana K., Bahra, Marcus, Blaeker, Hendrik, Bischoff, Sven, Pelzer, Uwe ORCID: 0000-0001-9213-2737, Oettle, Helmut, Riess, Hanno, Budczies, Jan and Denkert, Carsten (2020). TP53 Mutations Predict Sensitivity to Adjuvant Gemcitabine in Patients with Pancreatic Ductal Adenocarcinoma: Next-Generation Sequencing Results from the CONKO-001 Trial. Clin. Cancer Res., 26 (14). S. 3732 - 3740. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3265

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Abstract

Purpose: We performed next-generation sequencing (NGS) in the CONKO-001 phase III trial to identify clinically relevant prognostic and predictive mutations and conducted a functional validation in The Cancer Genome Atlas (TCGA) sequencing data. Experimental Design: Patients of the CONKO-001 trial received curatively intended surgery for pancreatic adenocarcinoma (PDAC) followed by adjuvant chemotherapy with gemcitabine (Gem) or observation only (Obs). Tissue samples of 101 patients were evaluated by NGS of 37 genes. Cox proportional hazard models were applied for survival analysis. In addition, functional genomic analyses were performed in an NGS and RNA-sequencing dataset of 146 pancreatic tumors from TCGA. Results: The most common mutations in the CONKO cohort were KRAS (75%), TP53 (60%), SMAD4 (10%), CDKNA2 (9%), as well as SWI/SNF (12%) complex alterations. In untreated patients, TP53 mutations were a negative prognostic factor for disease-free survival (DFS; HR mut vs. WT 2.434, P = 0.005). With respect to gemcitabine treatment, TP53 mutations were a positive predictive factor for gemcitabine efficacy [TP53mut: HR for DFS Gem vs. Obs, 0.235 (0.130 - 0.423; P < 0.001); TP53wt: HR for DFS Gem vs. Obs, 0.794 (0.417 - 1.513; P = 0.483)] with a significant test for interaction (P = 0.003). In the TCGA dataset, TP53 mutations were associated with shortened DFS. Conclusions: In CONKO-001, the benefit from adjuvant gemcitabine was confined to the TP53mut patient group. This potentially clinical relevant observation needs to be confirmed in independent prospective studies. The sensitivity of TP53mut PDAC to gemcitabine in CONKO-001 provides a lead for further mechanistic investigations.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Sinn, Marianne UNSPECIFIED UNSPECIFIED UNSPECIFIED Sinn, Bruno, V UNSPECIFIED UNSPECIFIED UNSPECIFIED Treue, Denise UNSPECIFIED UNSPECIFIED UNSPECIFIED Keilholz, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Damm, Frederik UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmuck, Rosa UNSPECIFIED UNSPECIFIED UNSPECIFIED Lohneis, Philipp UNSPECIFIED UNSPECIFIED UNSPECIFIED Klauschen, Frederick UNSPECIFIED UNSPECIFIED UNSPECIFIED Striefler, Jana K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bahra, Marcus UNSPECIFIED UNSPECIFIED UNSPECIFIED Blaeker, Hendrik UNSPECIFIED UNSPECIFIED UNSPECIFIED Bischoff, Sven UNSPECIFIED UNSPECIFIED UNSPECIFIED Pelzer, Uwe UNSPECIFIED orcid.org/0000-0001-9213-2737 UNSPECIFIED Oettle, Helmut UNSPECIFIED UNSPECIFIED UNSPECIFIED Riess, Hanno UNSPECIFIED UNSPECIFIED UNSPECIFIED Budczies, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Denkert, Carsten UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-326336
DOI:	10.1158/1078-0432.CCR-19-3034
Journal or Publication Title:	Clin. Cancer Res.
Volume:	26
Number:	14
Page Range:	S. 3732 - 3740
Date:	2020
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1557-3265
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CLINICAL-TRIALS; CANCER; CHEMOTHERAPY; P53; RESECTION Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/32633