IGF-IR gene expression as a predictive marker of ionizing radiation response for patients with locally advanced cervical cancer

In Colombia the cancer of uterine cervix is diagnosed in advanced stages and its treatment is based on the application of the radiotherapy or radiotherapy more chemotherapy. Most of studies show that the IGF-IR expression leads to the cellular increase of resistance to radiation, that the tumor like hypoxia induces the IGF-IR expression and selects cells that overexpressing IGF-IR. The aim of this study was to evaluate the effect of expression of IGF-IR, IGF-I, IGF-II, GAPDH, and hemoglobin concentration on tumoral response to ionizing radiation in patients with locally advanced cervical cancer. A series of 37 consecutive patients were recruited from 2002 to 2004. For each patient, a representative tumoral sample in fresh was taken at the time of diagnosis before the beginning of the treatment. In order to have a group control for the analysis of gene expression, 30 samples of normal tissue of uterine cervix from patients treated by exclusive hysterectomy were also analyzed. The mean age of the remaining 37 patients was 46 years (ranging from 33 to 70 years). All patients received exclusive pelvic external beam radiotherapy (EBRT). Treatment consisted of teletherapy using 6 to 18 MV photons with standard four field technique delivering a total dose of 45— 50,4 Gy in 28 fractions (1.8 Gy per fraction, 5 consecutive days per week, overall EBRT treatment time 5 weeks). Follow-up was scheduled at 6 weeks after completion of intracavitary brachytherapy, then every three months during the next 2 years. Complete remission was defined as no evidence of residual disease on clinical examination and radiological imaging, six weeks to three months after completion of the therapeutic sequence. Gene expression of IGF-IR, IGF-I, IGF-II and GAPDH was determined by Real Time PCR and IGF-IR protein was detected using Western Blot. Hemoglobin levels were also evaluated as a parameter of oxygenation before the beginning of ionizing radiation (Hgb≤11g/dl). Gene expression levels were compared between complete responders and non responders using Anova or Kruskal-allis Anova. A major increase was observed in gene expression IGF-IR (34%), followed by the expression of IGF-II (24%) in the cases of cancer in comparison with the control group (expression not detected). Gene expression of IGF-IR (p=0.04) and incomplete treatment (p=0.019) were associated with the lack of treatment response. Patients expressing IGF-IR had 4.6 times more risk of non treatment response; GAPDH expression was directly correlated with the IGF-IR expression, IGF-IR and IGF-II co-expression under anemic hypoxia conditions (Hgb≤11g/dl), demonstrated a possible activation of a glicolytic pathway as an answer to the high metabolic rate of tumoral cells. This is the first report in the clinical setting that relates the expression of IGF-IR as a strong marker of responsiveness. Therefore, the IGF-IR can be considered as a molecular target for optimizing the treatment of cervical cancer with radiotherapy.