On the interplay between dosiomics and genomics in radiation-induced lymphopenia of lung cancer patients

Purpose: To investigate the interplay between spatial dose patterns and single nucleotide polymorphisms in the development of radiation-induced lymphopenia (RIL) in 186 non-small-cell lung cancer (NSCLC) patients undergoing chemo-radiotherapy (RT). Methods: This study included NSCLC patients enrolled in a randomized trial of protons vs. photons with available absolute lymphocyte counts at baseline and during RT and XRCC1-rs25487 genotyping data. After masking the GTV, planning CT scans and dose maps were spatially normalized to a common anatomical reference. A Voxel-Based Analysis (VBA) was performed to assess voxel-wise relationships of dosiomic and genomic explanatory variables with RIL. The underlying generalized linear model was designed to include both the explanatory variables (3D dose distributions and the XRCC1-rs25487 genotypes) and possible nuisance variables significantly correlated with RIL. The maps of model coefficients as well as their significance maps were generated. Results: Measures for RIL definition during RT were characterized, including kinetic parameters for lymphocyte loss. The VBA generated three-dimensional maps of correlation between RIL and dose in lymphoid organs as well as organs with abundant blood pools. The identified voxel-wise relationships account for XRCC1-rs25487 polymorphism and demonstrate the variant AA genotype being detrimental to lymphocyte depletion (p = 0.03). Conclusion: The performed analyses blindly highlighted relevant anatomical regions that contributed most to lymphocyte depletion during RT and the interplay of the variant XRCC1-rs25487 AA genotype with the dose delivered to the primary lymphoid organs. These findings may help to guide the development of dosimetric RIL mitigation strategies for the application of effective individualized RT.