Exploring Host Germline Genetics to Help Identify Patients with Early Stage Lymphoma Who Might Benefit From the Addition of Radiation Therapy

Abstract

Radiation therapy (RT) improves event-free survival (EFS) for a subset of patients after systemic therapy for early stage classical Hodgkin (HL) and diffuse large B-cell lymphoma (DLBCL); however it is poorly understood which patients are most likely to benefit from the addition of RT. Host genetic background in immune function or chemotherapy metabolism genes may interact with treatment to impact outcome. In an exploratory study, we assessed whether single nucleotide polymorphisms (SNPs) from 27 candidate immune function and 20 chemotherapy metabolism genes predicted EFS in patients treated with chemotherapy (CT) alone , and for those SNPs associated with inferior EFS, whether this association was observed in patients treated with CT + RT. We used a prospective cohort study of patients with Stage I/II HL or DLBCL. Event-free survival (EFS) was defined as time from diagnosis to disease progression, retreatment, or death. 265 SNPs from our candidate genes were selected from HapMap using a standard tagging approach (r2 ≥0.80 and minor allele frequency ≥0.05) and included SNPs 5kb upstream and downstream from the gene. Genotyping was conducted using a custom panel. The most prevalent homozygous genotype was used as the reference, and each SNP was modeled as having a log-additive effect in a Cox regression model adjusted for age and lymphoma subtype. In Stage 1, we identified SNPs that were associated with inferior EFS (p<0.05) in patients treated with CT alone. In stage 2, SNPs found to be associated with inferior EFS in Stage 1 were analyzed for an association with EFS in patients treated with CT+RT. A total of 348 patients (138 HL; 210 DLBCL) were included in the analysis. The mean age was 54.5 years (range, 18-92) and 54% were male. Patients treated with CT only (n = 190) compared to CT+RT (n = 158) were more likely to have DLBCL (72 vs. 46%) and thus older (56 vs 45 years), but were similar on sex, performance status, and IPI/IPS risk grouping. In the CT only cohort, there were 80 events, while in the CT+RT cohort there were 29 events. In stage 1, 10 SNPs within the 7 candidate immune function genes and no chemotherapy metabolism genes were associated with inferior EFS in patients treated with CT only. In Stage 2, 7 of 10 SNPs associated with inferior EFS in Stage 1 were not associated with inferior EFS for patients treated with CT+RT, as displayed in the Table. In this preliminary analysis, germline variation in 5 immune function genes was associated with differing EFS for patients treated with CT alone vs those treated with CT+RT. Further exploration is needed to determine if the addition of radiation could mitigate inferior outcomes associated with these genes.Abstract 253; TableStage 1CT onlyStage 2CT+RTGeneSNPHRp-valueHRp-valueBCL2rs99551901.680.0050.980.946TBX21rs169470581.550.0081.000.995rs20741901.450.0400.880.663PTPN6rs107447242.270.0080.240.143C4BPArs48445731.560.0100.860.587rs45719691.450.0550.690.285PRF1rs109994232.440.0360.930.906 Open table in a new tab