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, Jahrgang 26, Nr. 14, 15.07.2020, S. 3732-3739.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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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 -