RESUMO
High hypoxic, glycolytic and acidosis metabolisms characterize cervical cancer tumors and have been described to be involved in chemoradioresistance mechanisms. Based on these observations, the present study assessed four selected novel biomarkers on the prognosis of locally advanced cervical carcinoma. A total of 66 patients with stage IIB/IIIB cervical cancer were retrospectively included. The protein expression levels of glucose transporter 1 (GLUT1), carbonic anhydrase 9 (CAIX) and hexokinase 1 (HKII) were investigated by immunohistochemistry on tumor biopsies, hemoglobin was measured and the disease outcome was monitored. A total of 53 patients (80.3%) presented a complete response. For these patients, the protein expression levels of GLUT1, CAIX and HKII were overexpressed. A significant difference was observed (P=0.0127) for hemoglobin levels (≤11 g/dl) in responsive compared with non-responsive patients. The expression of GLUT1 is associated with a lower rate of both overall and disease-free survival, with a trend of decreased risk of 1.1x and 1.5x, respectively. Co-expression of GLUT1 and HKII is associated with a decreased trend risk of 1.6x for overall survival. Patients with hemoglobin levels ≤11 g/dl had a 4.3-fold risk (P=0.02) in decreasing both to the rate of overall and disease-free survival. The presence of anemic hypoxia (hemoglobin ≤11 g/dl) and the expression of GLUT1 and/or HKII influence treatment response and are associated with a lower overall and disease-free survival. The present results demonstrated that these biomarkers may be used as predictive markers and suggested that these metabolic pathways can be used as potential novel therapeutic targets.
RESUMO
AIM: The aim of this study was to evaluate the predictive utility of Insulin-like growth factor-1 receptor (IGF1R), IGF1, IGF2, Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and of hemoglobin levels for tumor response to exclusive radiotherapy, in patients with locally advanced Human papillomavirus (HPV) 16-positive cervical cancer. PATIENTS AND METHODS: From 102 patients treated at our institutes, 38 patients with histologically-proven HPV16-positive cervical cancer were included in this prospective case-controlled study. All patients underwent exclusive radiotherapy-only. Complete response was defined as an absence of residual disease at clinical examination and radiological imaging, three months after the completion of treatment. Gene expression levels, assessed before radiotherapy, were compared between responders and non-responders. Controls consisted of normal cervical tissue samples from 30 patients with non-oncological indications. RESULTS: Twenty patients (52.6%) showed a complete response. Gene expressions of IGF1R (34%), IGF2 (24%), and GAPDH (median=3.26 versus 2.12) were increased in cancer patients, in comparison with the control group. Higher levels of expression of GAPDH were observed in patients co-expressing IGF2 and IGF1R, who had a hemoglobin level ≤ 11 g/dl (p=0.05). Clinical characteristics in the responder and in the non-responder groups were similar. In bi-variate and multi-variate analyses, IGF1R expression was the only factor predictive of response to radiotherapy (p=0.018). Accordingly, patients with IGF1R expression had a 28.6-fold greater risk of treatment failure. CONCLUSION: In our study, IGF1R was a strong predictive marker of lack of response to radiotherapy. Larger prospective trials are needed to validate IGF1R as a biomarker of radiation response for patients with HPV16-positive cervical cancer.