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Cancer Epidemiology, Biomarkers & Prevention
Cancer Epidemiology, Biomarkers & Prevention
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Prognostic Value of Angiopoietin-2 for Death Risk Stratification in Patients with Metastatic Colorectal Carcinoma

Marine Jary, Dewi Vernerey, Thierry Lecomte, Erion Dobi, François Ghiringhelli, Franck Monnien, Yann Godet, Stefano Kim, Olivier Bouché, Serge Fratte, Anthony Gonçalves, Julie Leger, Lise Queiroz, Olivier Adotevi, Franck Bonnetain and Christophe Borg
Marine Jary
1Department of Medical Oncology, University Hospital, Besançon, France.
2INSERM, Unit 1098, University of Franche-Comté, Besançon, France.
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  • For correspondence: marine.jary@univ-fcomte.fr
Dewi Vernerey
3Methodological and Quality of Life in Oncology Unit, University Hospital of Besançon, Besançon, France.
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Thierry Lecomte
4INSERM, Unit 7292, University François-Rabelais, CNRS, Tours, France.
5Department of Hepatogastroenterology and Digestive Oncology, University Hospital, Tours, France.
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Erion Dobi
1Department of Medical Oncology, University Hospital, Besançon, France.
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François Ghiringhelli
6Department of Medical Oncology, Leclerc Anticancer Center, Dijon, France.
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Franck Monnien
1Department of Medical Oncology, University Hospital, Besançon, France.
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Yann Godet
2INSERM, Unit 1098, University of Franche-Comté, Besançon, France.
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Stefano Kim
1Department of Medical Oncology, University Hospital, Besançon, France.
7Department of Oncology and Radiotherapy, Hospital of Belfort-Montbeliard, Montbeliard, France.
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Olivier Bouché
8Department of Hepatogastroenterology and Digestive Oncology, University Hospital Robert Debré, Reims, France.
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Serge Fratte
9Department of Gastroenterology, Hospital of Belfort-Montbeliard, Montbeliard, France.
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Anthony Gonçalves
10Department of Medical Oncology, Paoli-Calmettes Institute, Marseille, France.
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Julie Leger
11INSERM, Clinical Investigational Center CIC 1415, Tours, France.
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Lise Queiroz
2INSERM, Unit 1098, University of Franche-Comté, Besançon, France.
12Clinical Investigational Center, CIC-Biotherapy-506, University Hospital of Besançon, Besançon, France.
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Olivier Adotevi
1Department of Medical Oncology, University Hospital, Besançon, France.
2INSERM, Unit 1098, University of Franche-Comté, Besançon, France.
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Franck Bonnetain
3Methodological and Quality of Life in Oncology Unit, University Hospital of Besançon, Besançon, France.
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Christophe Borg
1Department of Medical Oncology, University Hospital, Besançon, France.
2INSERM, Unit 1098, University of Franche-Comté, Besançon, France.
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DOI: 10.1158/1055-9965.EPI-14-1059 Published March 2015
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  • Figure 1.
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    Figure 1.

    Flow chart and analysis plan of the study. Population selection during the study is summarized in the flow chart. In the left, the population selection during the study is described. In the right, the derived analysis and their synthetic results are summarized.

  • Figure 2.
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    Figure 2.

    Distribution of Ang-2 measurement value among healthy volunteers (n = 41) and patients with mCRC (n = 109) involved in the final analysis. In our study population, the median value of Ang-2 was 4.045 ng/mL for the 109 patients included in the final analysis. In consequence, to investigate a cutoff value for clinical use, a level of 5 ng/mL seemed to be a relevant choice.

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    Figure 3.

    Kaplan–Meier curves for OS. A, the classic approach based on the GERCOR score in which LDH and PS are key parameters. B, the stratification according to the level of Ang-2. C, the stratification according to the level of Ang-2 in the 45 (41%) patients classified in intermediate risk with the GERCOR score. D, the determination of Ang-2 in the intermediate-risk patients with the GERCOR group (n = 45) reclassified these patients in two groups with similar profiles than low- and high-risk GERCOR groups.

Tables

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  • Table 1.

    Baseline characteristics of patients, according to the cohort set

    Overall population (N = 177)Cohort set-1 (N = 51)Cohort set-2 (N = 126)
    CharacteristicsNNNPc
    Age, yd51126
     ≤6517793 (53%)27 (53%)66 (52%)
     >6584 (47%)24 (47%)60 (48%)0.9461
    Patient male sex, n (%)d17774 (42%)5128 (55%)12646 (37%)0.0246
    PS OMSd167
     0, n (%)91 (55%)4827 (56%)11964 (54%)
     >0, n (%)76 (45%)21 (44%)55 (46%)0.7719
    Primary tumor sited17751126
     Colon, n (%)120 (68%)32 (63%)88 (70%)
     Rectum, n (%)57 (32%)19 (37%)38 (30%)0.3602
    Metastases localizationd17751126
     Liver and other, n (%)98 (55%)17 (33%)81 (64%)
     Liver alone, n (%)68 (39%)23 (45%)45 (36%)
     Other alone, n (%)11 (6%)11 (22%)0 (0%)0.0001
    Timing of metastasesd17348125
     Synchrone, n (%)119 (69%)30 (63%)89 (71%)
     Metachrone, n (%)54 (31%)18 (37%)36 (29%)0.2688
    Surgery of the primary tumor, n (%)d175110 (63%)4928 (57%)12682 (65%)0.3293
    Leucocyte (×106/mL)a1378.1 ± 3.2498.1 ± 3.5888.2 ± 3.00.8926
    Lymphocyte (×106/mL)a1321.5 ± 0.7451.7 ± 0.7871.4 ± 0.60.0550
    LDHd1153382
     ≤350 (ULN)56 (49%)20 (61%)36 (44%)
     >350 (ULN)59 (51%)13 (39%)46 (56%)0.1050
    Ang-2 (ng/mL)b1774.249 (2.683–7.153)512.793 (2.103–4.330)1264.728 (3.298–7.798)0.0001
    Death eventd1775136 (71%)126126 (100%)0.0001
    Median follow-up time in months 95% CI57.9 (53.1–60.3)Max time observed = 64.1
    All patients were follow-up until death

    NOTE: Bold characters represent significative results.

    Abbreviation: ULN, upper limit of normal.

    • ↵aPlus–minus values are means ± SD, and the unpaired t test was used for the comparison of variable among groups.

    • ↵bMedian and interquartile range are described, and the Wilcoxon rank-sum test was used for the comparison of variable among groups.

    • ↵cP values are for the comparison between cohort set-1 and cohort set-2 populations.

    • ↵dχ2 or Fisher's exact tests were used for the comparison of categorical variables.

  • Table 2.

    Univariate and multivariate analyses

    Number of patientsNumber of deathsUnivariate analysisMultivariate analysisMultivariate analysis with bootstrap procedure
    HR (95% CI)PHR (95% CI)P95% percentile CI
    Age, y
     ≤6593841 (—)—
     >6584781.243 (0.912–1.694)0.1689
    Sex
     Male74651
     Female103971.310 (0.955–1.798)0.0941
    PS OMS
     091801
     >076731.274 (0.927–1.751)0.1355
    Primary tumor site
     Colon1201131
     Rectum57490.855 (0.610–1.196)0.3597
    Timing to metastasis
     Metachronous1191111
     Synchronous54471.458 (1.035–2.054)0.0308
    Metastases localization
     Liver alone68591
     Liver and other98951.816 (1.305–2.527)
     Other alone1180.686 (0.326–1.442)0.0003
    Surgery of the primary tumor
     Yes1101011
     No65591.433 (1.035–1.984)0.0304
    Leucocyte (×106/mL)1371221.120 (1.056–1.188)0.0002
    Lymphocyte (×106/mL)1321200.795 (0.589–1.073)0.1339
    LDH
     ≤350 (ULN)564911
     >350 (ULN)59582.026 (1.373–2.988)0.00041.598 (1.040–2.454)0.0323(1.039–2.628)
    Log_Ang-2 (pg/mL)1771621.911 (1.492–2.448)<0.00011.587 (1.138–2.213)0.0065(1.161–2.263)

    NOTE: Bold characters represent significative results.

    Abbreviation: ULN, upper limit of normal.

    • Table 3.

      Baseline characteristics of the patients involved in the multivariate analysis according to the Ang-2 level (n = 109)

      Ang-2 < 5 ng/mLAng-2 ≥ 5 ng/mL
      n(n = 69)(n = 40)Pb
      Age, yc
       ≤655631 (45)25 (63)
       >655338 (55)15(37)0.11
      Sexc
       Male4539 (57)25 (63)
       Female6430 (43)15 (37)0.54
      PS OMSc
       05741 (59)16 (40)
       >05228 (41)24 (60)0.07
      Primary tumor sitec
       Colon7346 (67)27 (68)
       Rectum3623 (33)13 (32)0.93
      Timing to metastasisc
       Synchronous7439 (57)35 (92)
       Metachronous3229 (43)3 (8)<0.0001
      Metastases localizationc
       Liver alone4328 (41)15 (37)
       Liver and other5833 (48)25 (63)
       Other alone88 (12)0 (0)0.04515
      Surgery of the primary tumorc
       No7316 (24)18 (46)
       Yes3452 (76)21 (54)0.0189
      Leucocyte (×106/mL)a897.3713 ± 2.39729.4180 ± 3.82690.0026
      Lymphocyte (×106/mL)a851.6589 ± 0.63551.2187 ± 0.58160.0017
      LDHc
       ≤350 (ULN)5243 (62)9 (23)
       >350 (ULN)5726 (38)31 (77)<0.0001
      GERCOR scorec
       0 Low-risk3229 (42)3 (7)
       1 Intermediate-risk4526 (38)19 (48)
       2 High-risk3214 (20)18 (45)0.0002

      NOTE: Bold characters represent significative results.

      • ↵aPlus–minus values are means ± SD, and the unpaired t test was used for the comparison of variable among groups.

      • ↵bP values are for the comparison between cohort set-1 and cohort set-2 populations.

      • ↵cχ2 or Fisher's exact tests were used for the comparison of categorical variables.

    Additional Files

    • Figures
    • Tables
    • Supplementary Data

      Files in this Data Supplement:

      • Supplementary Methods, Table 1 - Supplementary Methods, Table 1. Supplementary methods: - Ang-2 plasma sample measurement - Statistical analysis interpretation Supplementary table 1: - Cox Univariate analyses for OS prediction with and without the stratified approach (sensitivity analysis) Supplementary references
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    Cancer Epidemiology Biomarkers & Prevention: 24 (3)
    March 2015
    Volume 24, Issue 3
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    Prognostic Value of Angiopoietin-2 for Death Risk Stratification in Patients with Metastatic Colorectal Carcinoma
    Marine Jary, Dewi Vernerey, Thierry Lecomte, Erion Dobi, François Ghiringhelli, Franck Monnien, Yann Godet, Stefano Kim, Olivier Bouché, Serge Fratte, Anthony Gonçalves, Julie Leger, Lise Queiroz, Olivier Adotevi, Franck Bonnetain and Christophe Borg
    Cancer Epidemiol Biomarkers Prev March 1 2015 (24) (3) 603-612; DOI: 10.1158/1055-9965.EPI-14-1059

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    Prognostic Value of Angiopoietin-2 for Death Risk Stratification in Patients with Metastatic Colorectal Carcinoma
    Marine Jary, Dewi Vernerey, Thierry Lecomte, Erion Dobi, François Ghiringhelli, Franck Monnien, Yann Godet, Stefano Kim, Olivier Bouché, Serge Fratte, Anthony Gonçalves, Julie Leger, Lise Queiroz, Olivier Adotevi, Franck Bonnetain and Christophe Borg
    Cancer Epidemiol Biomarkers Prev March 1 2015 (24) (3) 603-612; DOI: 10.1158/1055-9965.EPI-14-1059
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