Clinical validation of GAGE family protein as a biomarker for radiotherapy resistance in cervical cancer.

42 Background: Cervical cancer is the 4th most common cancer in females. Treatment recommendation for locally advanced cervical cancer includes concurrent chemo-radiotherapy (RT) followed by brachytherapy. However, primary treatment failure is not uncommon and is attributed to RT resistance. In view of RT-associated complications, identification of RT-resistant groups at diagnosis will help to minimize exposure to unnecessary toxicities. Methods: Our initial studies analyzing the genetic profile of RT-sensitive and RT-resistant tumours from xenograft models have identified the GAGE-family protein as a genetic marker that is selectively upregulated in RT-resistant xenograft tumours in vitro & in animal studies and is associated with more aggressive phenotypes of these tumors. To clinically validate these findings, we carried out a pilot study on 8 patients and also analyzed GAGE-family protein levels in retrospective study samples obtained from initial biopsy samples from from patients who have completed chemoRT and brachytherapy for cervical cancer to correlate their initial GAGE-family protein levels with treatment response. Results: Immuno-histological staining of pathology samples from 8 patients in our pilot study have shown that those with a higher expression of GAGE-family protein at mRNA and protein levels are more resistant to standard RT. Our retrospective analysis of 43 cervical cancer biopsy samples showed significantly elevated levels of GAGE-family protein mRNA ( P= 0.0028) and GAGE-family protein intensity score ( P= 0.026) in the 20 patients who were found to be resistant to standard definitive RT on subsequent follow-up compared to 23 patients who responded well. Median follow-up was 42 months. Conclusions: GAGE-family protein mRNA and protein expressions are elevated in patients resistant to standard definitive RT. We aim to develop a classification system to stratify patients into responders versus poor responders based on their GAGE-family protein levels at initial diagnosis in order to personalize treatment regimen whereby good responders can be treated with reduced RT dose and poor responders can receive escalated RT dose and further therapies in order to improve outcome.