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Hypoxia-inducible factor 1alpha (HIF-1α)
and carbonic anhydrase IX (CA 9) expressions in glioblastoma multiform
to predict response to radiation therapy
J.-M. Simon, K.
Mokhtari, C. Genestie, A. Bissery, J.-J.
Mazeron and P. Jaillon
Pitie-Salpetriere Univ Hosp, AP-HP,
Paris, France; Pitie-Salpetriere Hosp, Paris, France; Saint Antoine
Univ Hosp, Paris, France
Background. Tumor hypoxia
is known to be associated with resistance to
radiotherapy.
Hypoxia induces the expression of hypoxia-inducible factor-1alpha
(HIF-1α), allowing up-regulation of the expression of
downstream genes such as carbonic anhydrase IX (CA 9).
Methods. We
examined the expression of HIF-1α and CA 9 by
immunohistochemistry in glioblastoma multiform (GBM)
biopsies, and investigated their relationship with response
to radiation therapy.
The response to irradiation was assessed by comparing
contrast-enhanced magnetic resonance images obtained before
and six weeks after the completion of radiotherapy.
Assessment of odds ratio were based on the logistic
regression model with stepwise adjustment.
The multivariate model included HIF-1α and CA 9 coded
on a semi quantitative scale according to the positive
tumor cell percentage (0 = no expression; + = 1–10%; ++ =
11–50%; +++ = 51–100%), and age.
Results. Fifty six
consecutive patients with inoperable glioblastoma treated
with radiotherapy (59.4 Gy in 1.8 Gy/fraction) at the
Pitie-Salpetriere hospital between 1995 and 2002, were included
in this study (median age: 56 years, range, 30 to 67 years).
HIF-1α was expressed in 33 of 56 (59%), and CA 9 in 38 of
52 (73%) of glioblastomas.
Tumor HIF-1α expression correlated significantly with
that of CA 9 (Kappa = 0.23, p = 0.003).
The response rate to radiotherapy for the entire population
was 29%.
The expressions of HIF-1α and CA 9 were correlated inversely
with the rate of response to radiotherapy (univariate analysis:
HIF-1α +: odds ratio 0.21, 95% CI [0.06, 0.71], p = 0.012;
CA 9 +: odds ratio 0.15, 95% CI [0.04, 0.59], p =
0.0063).
The multivariate analysis showed that HIF-1α + (odds
ratio 0.13, 95% CI [0.03, 0.65], p = 0.013), CA 9 +++ (odds
ratio 0.21, 95% CI [0.04, 0.98], p = 0.047) and age (odds
ratio 0.91, 95% CI [0.82, 0.99], p = 0.046) were
independent predictors of response to radiotherapy.
Conclusions.
Glioblastomas with a hypoxic profile (expression of HIF-1α
and/or CA 9) were associated with a significantly worse
response to radiotherapy, independently of known prognostic factors.
Grant from Regional PHRC: AOR 03059,
Assistance Publique - Hopitaux de Paris
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