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TP53 mutations predict sensitivity to adjuvant gemcitabine in patients with pancreatic ductal adenocarcinoma: next-generation sequencing results from the CONKO-001 trial

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TP53 mutations predict sensitivity to adjuvant gemcitabine in patients with pancreatic ductal adenocarcinoma: next-generation sequencing results from the CONKO-001 trial. / Sinn, Marianne; Sinn, Bruno V; Treue, Denise; Keilholz, Ulrich; Damm, Frederik; Schmuck, Rosa Bianca; Lohneis, Philipp; Klauschen, Frederick; Striefler, Jana K; Bahra, Marcus; Bläker, Hendrik; Bischoff, Sven; Pelzer, Uwe; Oettle, Helmut; Riess, Hanno; Budczies, Jan; Denkert, Carsten.

In: CLIN CANCER RES, Vol. 26, No. 14, 15.07.2020, p. 3732-3739.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Sinn, M, Sinn, BV, Treue, D, Keilholz, U, Damm, F, Schmuck, RB, Lohneis, P, Klauschen, F, Striefler, JK, Bahra, M, Bläker, H, Bischoff, S, Pelzer, U, Oettle, H, Riess, H, Budczies, J & Denkert, C 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, vol. 26, no. 14, pp. 3732-3739. https://doi.org/10.1158/1078-0432.CCR-19-3034

APA

Sinn, M., Sinn, B. V., Treue, D., Keilholz, U., Damm, F., Schmuck, R. B., Lohneis, P., Klauschen, F., Striefler, J. K., Bahra, M., Bläker, H., Bischoff, S., Pelzer, U., Oettle, H., Riess, H., Budczies, J., & Denkert, C. (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), 3732-3739. https://doi.org/10.1158/1078-0432.CCR-19-3034

Vancouver

Sinn M, Sinn BV, Treue D, Keilholz U, Damm F, Schmuck RB et al. 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. 2020 Jul 15;26(14):3732-3739. https://doi.org/10.1158/1078-0432.CCR-19-3034

Bibtex

@article{d50fd552f9fa4cd9b3d443b85ec49b79,
title = "TP53 mutations predict sensitivity to adjuvant gemcitabine in patients with pancreatic ductal adenocarcinoma: next-generation sequencing results from the CONKO-001 trial",
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.",
author = "Marianne Sinn and Sinn, {Bruno V} and Denise Treue and Ulrich Keilholz and Frederik Damm and Schmuck, {Rosa Bianca} and Philipp Lohneis and Frederick Klauschen and Striefler, {Jana K} and Marcus Bahra and Hendrik Bl{\"a}ker and Sven Bischoff and Uwe Pelzer and Helmut Oettle and Hanno Riess and Jan Budczies and Carsten Denkert",
note = "{\textcopyright}2020 American Association for Cancer Research.",
year = "2020",
month = jul,
day = "15",
doi = "10.1158/1078-0432.CCR-19-3034",
language = "English",
volume = "26",
pages = "3732--3739",
journal = "CLIN CANCER RES",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "14",

}

RIS

TY - JOUR

T1 - TP53 mutations predict sensitivity to adjuvant gemcitabine in patients with pancreatic ductal adenocarcinoma: next-generation sequencing results from the CONKO-001 trial

AU - Sinn, Marianne

AU - Sinn, Bruno V

AU - Treue, Denise

AU - Keilholz, Ulrich

AU - Damm, Frederik

AU - Schmuck, Rosa Bianca

AU - Lohneis, Philipp

AU - Klauschen, Frederick

AU - Striefler, Jana K

AU - Bahra, Marcus

AU - Bläker, Hendrik

AU - Bischoff, Sven

AU - Pelzer, Uwe

AU - Oettle, Helmut

AU - Riess, Hanno

AU - Budczies, Jan

AU - Denkert, Carsten

N1 - ©2020 American Association for Cancer Research.

PY - 2020/7/15

Y1 - 2020/7/15

N2 - 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.

AB - 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.

U2 - 10.1158/1078-0432.CCR-19-3034

DO - 10.1158/1078-0432.CCR-19-3034

M3 - SCORING: Journal article

C2 - 32234756

VL - 26

SP - 3732

EP - 3739

JO - CLIN CANCER RES

JF - CLIN CANCER RES

SN - 1078-0432

IS - 14

ER -