Association between epigenetic clocks and chemotoxicity in older adults with early breast cancer.

Abstract

12135 Background: Epigenetic clocks are blood-based biomarkers developed to predict biological age and mortality risk from DNA methylation data. Here, we investigated the association between epigenetic clocks and grade 2+ chemotoxicities, given that low grade toxicity has significant clinical impact in older adults with breast cancer. Methods: This was a secondary analysis of a prospective cohort of 394 adults age ≥65 with stage I-III breast cancer who completed treatment with neo/adjuvant chemo. We analyzed peripheral blood DNA methylation to estimate epigenetic age acceleration (EAA) prior to chemo. We estimated EAA using three generations of epigenetic clocks (1st gen: Horvath and Hannum; 2nd gen: PhenoAge and GrimAge; 3rd gen: DunedinPACE). Our outcomes of interest were the five most frequently reported grade 2+ chemotoxicities. Using multivariable logistic regression, we examined the association between EAA (as continuous variables) and the chemotoxicities of interest, adjusting for age, stage, race/ethnicity, education, regimen, organ function, cell composition, and geriatric assessment variables. Results: The median (range) chronological age of the participants was 70 (65-85). Most (65%) had stage II/III disease, 38% received anthracycline, and 75% received G-CSF prophylaxis. A total of 334 (84.8%) participants experienced a grade 2+ toxicity. The five most common grade 2+ toxicities were fatigue (34%), anemia (31%), infection (30%), neuropathy (20%), and diarrhea (13%). On multivariable analysis, we observed an association between pretreatment GrimAge and infection (OR=1.35, 95% CI 1.03-1.77, p=0.03) as well as DunedinPACE and diarrhea (OR=1.43, 95% CI 1.01-2.03, p=0.04). Conclusions: In this study of older adults with early breast cancer, we saw an association between some measures of EAA and select grade 2+ toxicities. Further research is needed to examine how measures of biological age can guide the care of older adults with early breast cancer. Clinical trial information: NCT01472094 . Grade 2+ chemotoxicity in older adults with early breast cancer, odds ratio (95% CI). Measures of EAA* Fatigue(n=134) Anemia(n=121) Infection(n=120) Neuropathy(n=77) Diarrhea(n=53) First gen Horvath 0.86 (0.67-1.10) 0.97 (0.75-1.26) 0.95 (0.75-1.22) 1.22 (0.91-1.65) 1.02 (0.74 -1.41) Hannum 0.90 (0.69-1.16) 1.14 (0.86-1.50) 1.03 (0.79-1.33) 1.15 (0.84-1.56) 0.81 (0.56-1.17) Second gen PhenoAge 1.13 (0.86-1.48) 1.10 (0.81-1.48) 1.02 (0.77-1.35) 1.22 (0.88-1.69) 1.10 (0.76-1.60) GrimAge 1.11 (0.86-1.44) 1.17 (0.88-1.56) 1.35 (1.03-1.77) 1.04 (0.76-1.43) 1.39 (0.98-1.96) Third gen DunedinPACE 1.24 (0.96-1.61) 1.09 (0.82-1.44) 1.06 (0.81-1.38) 1.14 (0.83-1.56) 1.43 (1.01-2.03) *The first and second gen clocks are in chronologic years and DunedinPACE is in biological year per chronologic year. OR adjusted for age, stage, race/ethnicity, education, regimen, organ function, cell composition, and geriatric assessment variables.