An apoptosis methylation prognostic signature for early lung cancer in the IFCT-0002 trial
©2012 AACR..
PURPOSE: To evaluate prognostic and predictive molecular biomarkers in early-stage non-small cell lung carcinoma (NSCLC) receiving neoadjuvant chemotherapy.
EXPERIMENTAL DESIGN: The IFCT-0002 trial compared two neoadjuvant regimens in 528 stages I to II NSCLC patients. DNA extraction of snap-frozen surgical samples taken from 208 patients receiving gemcitabine-cisplatin or paclitaxel-carboplatin regimens allowed for the identification of 3p allelic imbalance, Ras association domain family 1A (RASSF1A) and death-associated protein kinase 1 (DAPK1) promoter methylation, and epidermal growth factor receptor, K-ras, and TP53 mutations. Multivariate analysis identified prognostic and predictive effects of molecular alterations. A Bootstrapping approach was used to assess stability of the prognostic models generating optimism corrected indexes.
RESULTS: RASSF1A methylation correlated significantly with shorter disease-free survival (DFS; adjusted HR = 1.88, 95% CI: 1.25-2.82, P = 0.0048) and shorter median overall survival (OS; adjusted HR = 2.01, 95% CI: 1.26-3.20, P = 0.020). A computed bootstrap resampling strategy led to a prognostic model, including RASSF1A, DAPK1, and tumor stage, dividing patients into three prognostic groups, with median OS ranging from 34 months for high-risk patients (HR for death = 3.85, 95% CI: 1.79-6.40) to more than 84 months for moderate (HR = 1.85, 95% CI: 0.97-3.52) and low-risk patients (reference group; P = 0.00044). In addition, RASSF1A methylation predicted longer DFS in patients treated with paclitaxel-carboplatin compared with gemcitabine-cisplatin (adjusted HR = 0.47, 95% CI: 0.23-0.97, P(interaction) = 0.042).
CONCLUSIONS: Following neoadjuvant chemotherapy, RASSF1A methylation negatively impacted prognosis of early-stage NSCLC. Along with DAPK1 methylation and tumor stage, RASSF1A methylation allowed definition of three subgroups with strikingly different prognosis. Conversely, significantly longer DFS following paclitaxel-based neoadjuvant chemotherapy for patients whose tumors showed RASSF1A methylation suggested its predictive interest in stages I and II NSCLC.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2012 |
|---|---|
| Erschienen: |
2012 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:18 |
|---|---|
| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 18(2012), 10 vom: 15. Mai, Seite 2976-86 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
de Fraipont, Florence [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 05.11.2012 Date Revised 07.12.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1158/1078-0432.CCR-11-2797 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM216362970 |
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| 100 | 1 | |a de Fraipont, Florence |e verfasserin |4 aut | |
| 245 | 1 | 3 | |a An apoptosis methylation prognostic signature for early lung cancer in the IFCT-0002 trial |
| 264 | 1 | |c 2012 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 05.11.2012 | ||
| 500 | |a Date Revised 07.12.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2012 AACR. | ||
| 520 | |a PURPOSE: To evaluate prognostic and predictive molecular biomarkers in early-stage non-small cell lung carcinoma (NSCLC) receiving neoadjuvant chemotherapy | ||
| 520 | |a EXPERIMENTAL DESIGN: The IFCT-0002 trial compared two neoadjuvant regimens in 528 stages I to II NSCLC patients. DNA extraction of snap-frozen surgical samples taken from 208 patients receiving gemcitabine-cisplatin or paclitaxel-carboplatin regimens allowed for the identification of 3p allelic imbalance, Ras association domain family 1A (RASSF1A) and death-associated protein kinase 1 (DAPK1) promoter methylation, and epidermal growth factor receptor, K-ras, and TP53 mutations. Multivariate analysis identified prognostic and predictive effects of molecular alterations. A Bootstrapping approach was used to assess stability of the prognostic models generating optimism corrected indexes | ||
| 520 | |a RESULTS: RASSF1A methylation correlated significantly with shorter disease-free survival (DFS; adjusted HR = 1.88, 95% CI: 1.25-2.82, P = 0.0048) and shorter median overall survival (OS; adjusted HR = 2.01, 95% CI: 1.26-3.20, P = 0.020). A computed bootstrap resampling strategy led to a prognostic model, including RASSF1A, DAPK1, and tumor stage, dividing patients into three prognostic groups, with median OS ranging from 34 months for high-risk patients (HR for death = 3.85, 95% CI: 1.79-6.40) to more than 84 months for moderate (HR = 1.85, 95% CI: 0.97-3.52) and low-risk patients (reference group; P = 0.00044). In addition, RASSF1A methylation predicted longer DFS in patients treated with paclitaxel-carboplatin compared with gemcitabine-cisplatin (adjusted HR = 0.47, 95% CI: 0.23-0.97, P(interaction) = 0.042) | ||
| 520 | |a CONCLUSIONS: Following neoadjuvant chemotherapy, RASSF1A methylation negatively impacted prognosis of early-stage NSCLC. Along with DAPK1 methylation and tumor stage, RASSF1A methylation allowed definition of three subgroups with strikingly different prognosis. Conversely, significantly longer DFS following paclitaxel-based neoadjuvant chemotherapy for patients whose tumors showed RASSF1A methylation suggested its predictive interest in stages I and II NSCLC | ||
| 650 | 4 | |a Clinical Trial, Phase III | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Apoptosis Regulatory Proteins |2 NLM | |
| 650 | 7 | |a Biomarkers, Tumor |2 NLM | |
| 650 | 7 | |a RASSF1 protein, human |2 NLM | |
| 650 | 7 | |a RNA, Small Interfering |2 NLM | |
| 650 | 7 | |a TP53 protein, human |2 NLM | |
| 650 | 7 | |a Tumor Suppressor Protein p53 |2 NLM | |
| 650 | 7 | |a Tumor Suppressor Proteins |2 NLM | |
| 650 | 7 | |a Deoxycytidine |2 NLM | |
| 650 | 7 | |a 0W860991D6 |2 NLM | |
| 650 | 7 | |a Carboplatin |2 NLM | |
| 650 | 7 | |a BG3F62OND5 |2 NLM | |
| 650 | 7 | |a ErbB Receptors |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a DAPK1 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Death-Associated Protein Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a Calcium-Calmodulin-Dependent Protein Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.17 |2 NLM | |
| 650 | 7 | |a Paclitaxel |2 NLM | |
| 650 | 7 | |a P88XT4IS4D |2 NLM | |
| 650 | 7 | |a Cisplatin |2 NLM | |
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| 650 | 7 | |a Gemcitabine |2 NLM | |
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| 700 | 1 | |a Creveuil, Christian |e verfasserin |4 aut | |
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| 700 | 1 | |a Beau-Faller, Michèle |e verfasserin |4 aut | |
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| 700 | 0 | |a Intergroupe Francophone de Cancérologie Thoracique |e verfasserin |4 aut | |
| 700 | 1 | |a Ranfaing, E |e investigator |4 oth | |
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| 700 | 1 | |a Breton, J-L |e investigator |4 oth | |
| 700 | 1 | |a Debieuvre, D |e investigator |4 oth | |
| 700 | 1 | |a Clément, F |e investigator |4 oth | |
| 700 | 1 | |a Falcoz, P-E |e investigator |4 oth | |
| 700 | 1 | |a Antoine, M |e investigator |4 oth | |
| 700 | 1 | |a Milleron, B |e investigator |4 oth | |
| 700 | 1 | |a Herman, D |e investigator |4 oth | |
| 700 | 1 | |a Bazelly, B |e investigator |4 oth | |
| 700 | 1 | |a Neuville, A |e investigator |4 oth | |
| 700 | 1 | |a Quoix, E |e investigator |4 oth | |
| 700 | 1 | |a Ducoloné, A |e investigator |4 oth | |
| 700 | 1 | |a Oster, J-P |e investigator |4 oth | |
| 700 | 1 | |a Ducrocq, X |e investigator |4 oth | |
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| 700 | 1 | |a Rivière, A |e investigator |4 oth | |
| 700 | 1 | |a Zalcman, G |e investigator |4 oth | |
| 700 | 1 | |a Le Rochais, J-P |e investigator |4 oth | |
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