Association of radiation-induced normal tissue toxicity with a high genetic risk for rheumatoid arthritis.

Purpose: Overlapping genes are involved with rheumatoid arthritis (RA) and DNA repair pathways. Therefore, we hypothesised that patients with a high polygenic risk score (PRS) for RA will have an increased risk of radiotherapy (RT) toxicity given the involvement of DNA repair.

Methods: Primary analysis was performed on 1494 prostate cancer, 483 lung cancer and 1820 breast cancer patients assessed for development of RT toxicity in the REQUITE study. Validation cohorts were available from the Radiogenomics Consortium. All patients had undergone curative-intent radiotherapy and were assessed prospectively for toxicity. Germline genomic data was available for all patients, allowing a PRS to be calculated using 101 RA risk variants. PRS was analysed as a continuous variable and with >90th percentile cut-off. Associations with acute and late standardised total average toxicity (STAT) scores and individual toxicity end-points were analysed in multivariable models with preselected adjustment variables.

Results: Increasing PRS for RA did not increase the risk of acute or late STAT in any cohort. There was an increased risk of late oesophagitis in the lung cancer cohort (coefficient 0.018, p = .01), however this was not validated (p = .79). No individual acute or late toxicity endpoints were significantly associated with PRS for the prostate or breast cohorts. No significant results were found in the validation cohorts in multivariable models.

Conclusions: Patients with a high genetic risk for RA do not show increased levels of toxicity after radiotherapy suggesting treatment planning does not need to be modified for such patients.