MSH2/BRCA1 expression as a DNA-repair signature predicting survival in early-stage lung cancer patients from the IFCT-0002 Phase 3 Trial
INTRODUCTION: DNA repair is a double-edged sword in lung carcinogenesis. When defective, it promotes genetic instability and accumulated genetic alterations. Conversely these defects could sensitize cancer cells to therapeutic agents inducing DNA breaks.
METHODS: We used immunohistochemistry (IHC) to assess MSH2, XRCC5, and BRCA1 expression in 443 post-chemotherapy specimens from patients randomized in a Phase 3 trial, comparing two neoadjuvant regimens in 528 Stage I-II non-small cell lung cancer (NSCLC) patients (IFCT-0002). O6MGMT promoter gene methylation was analyzed in a subset of 208 patients of the same trial with available snap-frozen specimens.
RESULTS: Median follow-up was from 90 months onwards. Only high BRCA1 (n = 221, hazard ratio [HR] = 1.58, 95% confidence interval [CI] [1.07-2.34], p = 0.02) and low MSH2 expression (n = 356, HR = 1.52, 95% CI [1.11-2.08], p = 0.008) significantly predicted better overall survival (OS) in univariate and multivariate analysis. A bootstrap re-sampling strategy distinguished three patient groups at high (n = 55, low BRCA1 and high MSH2, median OS >96 months, HR = 2.5, 95% CI [1.45-4.33], p = 0.001), intermediate (n = 82, median OS = 73.4 p = 0.0596), and low (high BRCA1 and low MSH2, n = 67, median OS = ND, HR = 0.51, 95% CI [0.31-0.83], p = 0.006) risk of death.
INTERPRETATION: DNA repair protein expression assessment identified three different groups of risk of death in early-stage lung cancer patients, according to their tumor MSH2 and BRCA1 expression levels. These results deserve prospective evaluation of MSH2/BRCA1 theranostic value in lung cancer patients treated with combinations of DNA-damaging chemotherapy and drugs targeting DNA repair, such as Poly(ADP-ribose) polymerase (PARP) inhibitors.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2017 |
|---|---|
| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
|---|---|
| Enthalten in: |
Oncotarget - 8(2017), 3 vom: 17. Jan., Seite 4313-4329 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Levallet, Guénaëlle [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 22.02.2018 Date Revised 13.11.2018 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.18632/oncotarget.14025 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM267406770 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM267406770 | ||
| 003 | DE-627 | ||
| 005 | 20231224220620.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2017 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.18632/oncotarget.14025 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0891.xml |
| 035 | |a (DE-627)NLM267406770 | ||
| 035 | |a (NLM)28008145 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Levallet, Guénaëlle |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a MSH2/BRCA1 expression as a DNA-repair signature predicting survival in early-stage lung cancer patients from the IFCT-0002 Phase 3 Trial |
| 264 | 1 | |c 2017 | |
| 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 22.02.2018 | ||
| 500 | |a Date Revised 13.11.2018 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a INTRODUCTION: DNA repair is a double-edged sword in lung carcinogenesis. When defective, it promotes genetic instability and accumulated genetic alterations. Conversely these defects could sensitize cancer cells to therapeutic agents inducing DNA breaks | ||
| 520 | |a METHODS: We used immunohistochemistry (IHC) to assess MSH2, XRCC5, and BRCA1 expression in 443 post-chemotherapy specimens from patients randomized in a Phase 3 trial, comparing two neoadjuvant regimens in 528 Stage I-II non-small cell lung cancer (NSCLC) patients (IFCT-0002). O6MGMT promoter gene methylation was analyzed in a subset of 208 patients of the same trial with available snap-frozen specimens | ||
| 520 | |a RESULTS: Median follow-up was from 90 months onwards. Only high BRCA1 (n = 221, hazard ratio [HR] = 1.58, 95% confidence interval [CI] [1.07-2.34], p = 0.02) and low MSH2 expression (n = 356, HR = 1.52, 95% CI [1.11-2.08], p = 0.008) significantly predicted better overall survival (OS) in univariate and multivariate analysis. A bootstrap re-sampling strategy distinguished three patient groups at high (n = 55, low BRCA1 and high MSH2, median OS >96 months, HR = 2.5, 95% CI [1.45-4.33], p = 0.001), intermediate (n = 82, median OS = 73.4 p = 0.0596), and low (high BRCA1 and low MSH2, n = 67, median OS = ND, HR = 0.51, 95% CI [0.31-0.83], p = 0.006) risk of death | ||
| 520 | |a INTERPRETATION: DNA repair protein expression assessment identified three different groups of risk of death in early-stage lung cancer patients, according to their tumor MSH2 and BRCA1 expression levels. These results deserve prospective evaluation of MSH2/BRCA1 theranostic value in lung cancer patients treated with combinations of DNA-damaging chemotherapy and drugs targeting DNA repair, such as Poly(ADP-ribose) polymerase (PARP) inhibitors | ||
| 650 | 4 | |a Clinical Trial, Phase III | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a BRCA1 | |
| 650 | 4 | |a MGMT | |
| 650 | 4 | |a MSH2 | |
| 650 | 4 | |a neo-adjuvant chemotherapy | |
| 650 | 4 | |a non-small cell lung cancer | |
| 650 | 7 | |a BRCA1 Protein |2 NLM | |
| 650 | 7 | |a BRCA1 protein, human |2 NLM | |
| 650 | 7 | |a Tumor Suppressor Proteins |2 NLM | |
| 650 | 7 | |a DNA Modification Methylases |2 NLM | |
| 650 | 7 | |a EC 2.1.1.- |2 NLM | |
| 650 | 7 | |a MGMT protein, human |2 NLM | |
| 650 | 7 | |a EC 2.1.1.63 |2 NLM | |
| 650 | 7 | |a MSH2 protein, human |2 NLM | |
| 650 | 7 | |a EC 3.6.1.3 |2 NLM | |
| 650 | 7 | |a MutS Homolog 2 Protein |2 NLM | |
| 650 | 7 | |a EC 3.6.1.3 |2 NLM | |
| 650 | 7 | |a XRCC5 protein, human |2 NLM | |
| 650 | 7 | |a EC 3.6.4.12 |2 NLM | |
| 650 | 7 | |a Ku Autoantigen |2 NLM | |
| 650 | 7 | |a EC 4.2.99.- |2 NLM | |
| 650 | 7 | |a DNA Repair Enzymes |2 NLM | |
| 650 | 7 | |a EC 6.5.1.- |2 NLM | |
| 700 | 1 | |a Dubois, Fatéméh |e verfasserin |4 aut | |
| 700 | 1 | |a Fouret, Pierre |e verfasserin |4 aut | |
| 700 | 1 | |a Antoine, Martine |e verfasserin |4 aut | |
| 700 | 1 | |a Brosseau, Solenn |e verfasserin |4 aut | |
| 700 | 1 | |a Bergot, Emmanuel |e verfasserin |4 aut | |
| 700 | 1 | |a Beau-Faller, Michèle |e verfasserin |4 aut | |
| 700 | 1 | |a Gounant, Valérie |e verfasserin |4 aut | |
| 700 | 1 | |a Brambilla, Elisabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Debieuvre, Didier |e verfasserin |4 aut | |
| 700 | 1 | |a Molinier, Olivier |e verfasserin |4 aut | |
| 700 | 1 | |a Galateau-Sallé, Françoise |e verfasserin |4 aut | |
| 700 | 1 | |a Mazieres, Julien |e verfasserin |4 aut | |
| 700 | 1 | |a Quoix, Elisabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Pujol, Jean-Louis |e verfasserin |4 aut | |
| 700 | 1 | |a Moro-Sibilot, Denis |e verfasserin |4 aut | |
| 700 | 1 | |a Langlais, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Morin, Franck |e verfasserin |4 aut | |
| 700 | 1 | |a Westeel, Virginie |e verfasserin |4 aut | |
| 700 | 1 | |a Zalcman, Gérard |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Oncotarget |d 2010 |g 8(2017), 3 vom: 17. Jan., Seite 4313-4329 |w (DE-627)NLM199620113 |x 1949-2553 |7 nnns |
| 773 | 1 | 8 | |g volume:8 |g year:2017 |g number:3 |g day:17 |g month:01 |g pages:4313-4329 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.18632/oncotarget.14025 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 8 |j 2017 |e 3 |b 17 |c 01 |h 4313-4329 | ||