Abstract 680: A DNA repair biomarker signature to predict radiotherapy side-effects in breast and prostate cancers

Abstract

Abstract Introduction: About 50% of patients with solid tumors receive radiotherapy (RT) which induces cancer cells death through radiation-induced DNA damage. Five to 10% of these patients experience severe toxicity that can heavily impact their quality of life. The identification of predictive biomarkers to discriminate patients at high risk of developing radiotoxicity is needed to move towards a personalized treatment and to improve the management of these patients. Purpose: The aim of this clinical proof-of-concept was to identify blood radiotoxicity biomarkers based on a comprehensive analysis of several DNA repair activities. We relied on the hypothesis that DNA damage, DNA repair and inflammation are functionally associated and mutually supportive, and related to the appearance of side effects. Methods: 200 patients with either prostate or breast cancer who underwent RT were enrolled at the Lucien Neuwirth Cancer institute. Late radio-induced adverse events were recorded 6 months after the beginning of the treatment. Three blood samples per patient were collected before and early during the treatment course to monitor the ability of enzymes contained in lymphocytes to repair series of DNA lesions immobilized on biochip (Glyco-SPOT assay). We analyzed the association between the Base Excision Repair (BER), the primary pathway responsible for DNA repair during inflammation, and the appearance of severe late radiation-induced effects (3 in the female and 4 in the male cohort). Results: Late severe (Grade ≥3) and late moderate (Grade ≥2) radiation-induced events were recorded. Cutaneous, and gastro-intestinal and genitourinary adverse events, were considered respectively in breast cancer and prostate cancer patients. We observed some significantly lower BER activities in breast cancer patients who developed severe late events compared to those who did not. By contrast, it was the opposite in prostate cancer patients. In both cohort we defined a combination of biomarkers that predicted the appearance of severe late adverse events with 100% sensitivity and 100% negative predictive value using the blood sample taken after the first dose of RT. Conclusion: The risk of late radiotoxicity could be accurately predicted on the basis of combination of BER-related biomarkers. Interestingly, the biomarkers differed in breast and prostate cancer patients suggesting that beyond inflammation, hormone pathway regulation impacted the BER response to ionizing radiation, and the relationship with long-term severe side effects. These results require confirmation on a larger cohort. Citation Format: Giovanna Muggiolu, Libert Libert, Elisabeth Daguenet, Thierry Maillet, Claire Rodriguez-Lafrasse, Sylvie Sauvaigo, Nicolas Magné. A DNA repair biomarker signature to predict radiotherapy side-effects in breast and prostate cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 680.