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Molecular Cancer Therapeutics
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Serum Signature of Hypoxia-Regulated Factors Is Associated with Progression after Induction Therapy in Head and Neck Squamous Cell Cancer

Lauren Averett Byers, F. Christopher Holsinger, Merrill S. Kies, William N. William, Adel K. El-Naggar, J. Jack Lee, Jianhua Hu, Adriana Lopez, Hai T. Tran, Shaoyu Yan, Zhiqiang Du, K. Kian Ang, Bonnie S. Glisson, Maria Gabriela Raso, Ignacio I. Wistuba, Jeffrey N. Myers, Waun-Ki Hong, Vali Papadimitrakopoulou, Scott M. Lippman and John V. Heymach
Lauren Averett Byers
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F. Christopher Holsinger
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Merrill S. Kies
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William N. William
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Adel K. El-Naggar
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J. Jack Lee
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Jianhua Hu
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Adriana Lopez
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Hai T. Tran
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Shaoyu Yan
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Zhiqiang Du
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K. Kian Ang
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Bonnie S. Glisson
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Maria Gabriela Raso
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Ignacio I. Wistuba
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Jeffrey N. Myers
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Waun-Ki Hong
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Vali Papadimitrakopoulou
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Scott M. Lippman
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John V. Heymach
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DOI: 10.1158/1535-7163.MCT-09-1047 Published June 2010
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  • Figure 1.
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    Figure 1.

    Comparison of baseline CAF levels in patients with and without PD for the eight high-risk markers. NED, no evidence of disease.

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    Figure 2.

    Elevations in ≥6 of 8 high-risk CAFs is associated with PD. The number of high-risk CAFs (VEGF, IL-4, IL-8, Gro-α, SDF-1α, G-CSF, osteopontin, and eotaxin) above the median was plotted for each patient (A). HPV status is indicated by open (HPV-positive) and closed symbols (HPV-negative). Patients with PD are indicated in red. Kaplan-Meier curve is shown for time to progression in patients with 0 to 5 versus 6 to 8 high-risk CAFs above the median (B). PFS, progression-free survival.

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    Figure 3.

    Unsupervised clustering identified two distinct subgroups that correlate with clinical outcome but not with HPV status. Relative serum levels of 38 baseline CAFs are shown (red, high protein levels; green, low protein levels). Each row contains CAF levels for an individual patient. Two distinct patient CAF profiles are identified (clusters 1 and 2), and all six patients with PD are in cluster 2, which is characterized by higher levels of hypoxia-associated factors, as indicated in the figure. There is no association between HPV status and clusters. See Table 1 legend for definitions of abbreviations.

Tables

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  • Table 1.

    Cytokines and angiogenic factors in serum biomarker analysis

    βNGFIL-18MIF
    CTACKIL-1RAMIG
    EotaxinIL-2MIP-1β
    G-CSFIL-2RAOsteopontin
    GRO-αIL-3PDGF-bb
    HGFIL-4RANTES
    ICAM-1IL-6SCF
    IFN-α2IL-7SDF-1α
    IFN-γIL-8TNF-β
    IGF-IIP-10TRAIL
    IL-12(p40)MCP-1VCAM-1
    IL-13MCP-3VEGF
    IL-16M-CSF

    Abbreviations: CTACK, cutaneous T cell-attracting chemokine; G-CSF, granulocyte colony stimulating factor; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; ICAM, intercellular adhesion molecule; IFN, interferon; MIP, macrophage inflammatory protein; MIF, macrophage migration inhibitory factor; MCP, monocyte chemotactic protein; M-CSF, monocyte colony stimulating factor; MIG, monokine induced by IFN-γ; NGF, nerve growth factor; PDGF, platelet-derived growth factor; RANTES, regulated upon activation, normal T-cell expressed and secreted; SCF, stem cell factor; TNF, tumor necrosis factor; TRAIL, tumor necrosis factor-related apoptosis inducing ligand; VCAM, vascular cell adhesion molecule.

    • Table 2.

      Clinicopathologic characteristics in patients with progression

      PDP
      No (n = 26)Yes (n = 6)
      Age, median (range)52 (21–76)59 (52–71)0.049*
      Sex
          Male18 (90%)2 (10%)0.17
          Female8 (66.7%)4 (33.3%)—
      Race
          White24 (82.8%)5 (17.2%)0.48
          Black0 (0%)1 (100%)—
          Hispanic1 (100%)0 (0%)—
          Asian1 (100%)0 (0%)—
      Smoking status
          Never smoker12 (92.3%)1 (7.7%)0.17
          Former smoker8 (88.9%)1 (11.1%)—
          Current smoker6 (60%)4 (40%)—
      Differentiation
          Well1 (100%)0 (0%)0.70
          Moderate7 (87.5%)1 (12.5%)—
          Poorly11 (84.6%)2 (15.4%)—
          Moderately well1 (50%)1 (50%)—
          Poorly moderately2 (100%)0 (0%)—
      T stage
          T1–T218 (86%)3 (14%)0.003
          T3–T48 (73%)3 (27%)—
      N stage
          N2B19 (90.5%)2 (9.5%)0.090
          N2C5 (62.5%)3 (37.5%)—
          N31 (50%)1 (50%)—
      EGFR†
          00 (0%)0 (0%)0.78
          1+4 (100%)0 (0%)
          2+5 (100%)0 (0%)
          3+37 (82.2%)8 (17.8%)
      HPV‡
          HPV positive12 (100%)0 (0%)0.008
          HPV negative8 (57%)6 (43%)
      • ↵*P value from Wilcoxon rank sum test; all other P values were from Fisher's exact test.

      • ↵†Available for 24 patients.

      • ↵‡Available for 26 patients.

    • Table 3.

      Baseline CAFs associated with PD

      CovariateProgressionnMean ± SD*Median (min, max)*P†
      EotaxinYes64.8 ± 0.65.1 (4.1, 5.4)0.016
      No262.6 ± 2.02.6 (0, 5.9)
      OsteopontinYes64.0 ± 2.14.5 (0, 6.2)0.021
      No262.0 ± 1.82.3 (0, 5.3)
      G-CSFYes66.4 ± 1.55.9 (5.3, 9.2)0.039
      No264.2 ± 2.13.6 (2.3, 9.8)
      IL-4Yes62.7 ± 0.62.8 (1.9, 3.6)0.040
      No261.8 ± 0.91.7 (0.4, 3.4)
      SDF-1αYes68.6 ± 0.28.6 (8.4, 8.9)0.044
      No268.0 ± 0.98.0 (6.5, 9.9)
      VEGFYes66.0 ± 2.16.3 (3.7, 9.1)0.049
      No263.6 ± 2.53.2 (0.1, 8.3)
      GRO-αYes67.1 ± 0.76.9 (6.2, 8.2)0.049
      No266.3 ± 0.76.3 (4.5, 7.9)—
      IL-8Yes65.5 ± 2.54.6 (3.2, 10)0.050
      No262.9 ± 2.62.4 (0.5, 9.1)
      • ↵*Values are pg/mL log 2 transformed.

      • ↵†P value from the Wilcoxon rank sum test.

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    Molecular Cancer Therapeutics: 9 (6)
    June 2010
    Volume 9, Issue 6
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    Serum Signature of Hypoxia-Regulated Factors Is Associated with Progression after Induction Therapy in Head and Neck Squamous Cell Cancer
    Lauren Averett Byers, F. Christopher Holsinger, Merrill S. Kies, William N. William, Adel K. El-Naggar, J. Jack Lee, Jianhua Hu, Adriana Lopez, Hai T. Tran, Shaoyu Yan, Zhiqiang Du, K. Kian Ang, Bonnie S. Glisson, Maria Gabriela Raso, Ignacio I. Wistuba, Jeffrey N. Myers, Waun-Ki Hong, Vali Papadimitrakopoulou, Scott M. Lippman and John V. Heymach
    Mol Cancer Ther June 1 2010 (9) (6) 1755-1763; DOI: 10.1158/1535-7163.MCT-09-1047

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    Serum Signature of Hypoxia-Regulated Factors Is Associated with Progression after Induction Therapy in Head and Neck Squamous Cell Cancer
    Lauren Averett Byers, F. Christopher Holsinger, Merrill S. Kies, William N. William, Adel K. El-Naggar, J. Jack Lee, Jianhua Hu, Adriana Lopez, Hai T. Tran, Shaoyu Yan, Zhiqiang Du, K. Kian Ang, Bonnie S. Glisson, Maria Gabriela Raso, Ignacio I. Wistuba, Jeffrey N. Myers, Waun-Ki Hong, Vali Papadimitrakopoulou, Scott M. Lippman and John V. Heymach
    Mol Cancer Ther June 1 2010 (9) (6) 1755-1763; DOI: 10.1158/1535-7163.MCT-09-1047
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