Background We previously investigated the association between five ‘first-generation’ measures of epigenetic aging and cancer risk in the Melbourne Collaborative Cohort Study. The present study assessed cancer risk associations for three recently developed methylation-based biomarkers of aging: PhenoAge, GrimAge, and predicted telomere length. Methods We estimated rate ratios (RRs) for the association between these three age-adjusted measures and risk of colorectal (N = 813), gastric (N = 165), kidney (N = 139), lung (N = 327), mature B-cell (N = 423), prostate (N = 846) and urothelial (N = 404) cancer, using conditional logistic regression models. We also assessed associations by time since blood draw and by cancer subtype, and investigated potential non-linearity. Results We observed relatively strong associations of age-adjusted PhenoAge with risk of colorectal, kidney, lung, mature B-cell, and urothelial cancers (RR per standard deviation [SD]was approximately 1.2–1.3). Similar findings were obtained for age-adjusted GrimAge, but the association with lung cancer risk was much larger after adjustment for smoking status, pack-years, starting age, time since quitting and other cancer risk factors (RR per SD = 1.82, 95%CI = 1.44–2.30). Most associations appeared linear, larger than for the first-generation measures, and were virtually unchanged after adjustment for a large set of sociodemographic, lifestyle and anthropometric variables. For cancer overall, the comprehensively-adjusted RR per SD was 1.13 (95%CI = 1.07–1.19) for PhenoAge and 1.12 (95%CI = 1.05–1.20) for GrimAge, and appeared larger within 5 years of blood draw (RR = 1.29, 95%CI = 1.15–1.44 and 1.19, 95%CI = 1.06–1.33, respectively). Conclusion The methylation-based measures PhenoAge and GrimAge may provide insights into the relationship between biological aging and cancer and be useful to predict cancer risk, particularly for lung cancer.

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1,384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n=749) or at the end (n=635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT; 5.7% vs 5.8%, p=0.98, 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n=1,253). In patients with high CNS international prognostic index (n=600), 3-year CNS relapse rate was 9.1% with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX versus EOT, with 308/1573 (19.6%) i-HD-MTX treatments resulting in delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk versus i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.