Radiotherapy responsive markers in sequential biopsy samples from cervical cancer patients during fractionated radiotherapy

We previously reported radiotherapy-responsive genes, which were revealed by comprehensive transcriptome analysis using the microarray technology for sequential biopsies for cervical cancer patients with radiotherapy (RT). We found several tens of RT-responsive genes, including well-known radiation-responsive apoptosis/cell cycle-related genes, such as cdkn1a/p21, CAD, and Bax, and several tens of genes categorized into extracellular matrix (ECM), such as HPSE and CD44. In addition, several cytokines were also included. In this study, we investigated the possibility that some of those molecules, which were changed their expressions by RT, might be new biomarkers for the effectiveness of RT. Sequential biopsy samples were immunohistochemically analyzed before and during RT in cervical cancer patients, and the prognostic value of such changes of 15 candidate molecules for disease failure after RT were evaluated. \nPatients and Methods: Biopsy specimens were obtained from 91 patients with cervical cancers before (pretreatment) and 1 week after initiation (midtreatment) of radiotherapy. which were in RT-responsive genes or related with those genes, were performed to detect protein expression using an automated streptavidin-biotin immunoperoxidase staining system. Positive area/numbers of cells proportion (%) of immunostaining were analyzed using an image analysis system or the positive staining appearance was scored by grading system. Patients were defined as good or poor responders based on their two-year disease-free survival. Aberrant genomic change, human papillomavirus infection, and p53 status in tumor were also evaluated. \nResults: Protein expression of cdkn1a/p21, Bax, p53 and FGF2 in midtreatment samples (mid) was significantly higher than in pretreatment samples (pre). Protein expression of P-cadherin, ICAD, S100, p73 and VEGF in mid was significantly lower than in pre. Discontinuity of laminin staining pattern in mid was significantly higher than in pre. The ratio change (mid versus pre) of FGF2 expression in poor responders was significantly lower than that in good responders (P < 0.05). The number of cases with discontinuity of laminin staining pattern at pre was significantly higher in the poor responders (P < 0.05). \nConclusions: Using biopsy specimens from pretreatment and midtreatment cervical cancers, we revealed significant changes in expression of several proteins during fractionated radiotherapy. We also found that some of these ratio changes were significantly associated with prognosis. These molecular features in sequential biopsy samples might help us to identify patients at high risk of disease failure after radiotherapy and to provide tool for personalized radiotherapy.
European Society for Therapeutic Radiology and Oncology Annual Congress(ESTRO27)