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Tumor subtype and menopausal status are strong predictors of breast cancer (BC) prognosis. We aimed to find and validate subtype- or menopausal-status-specific changes in tumor DNA methylation (DNAm) associated with all-cause mortality or BC progression. Associations between site-specific tumor DNAm and BC prognosis were estimated among The Cancer Genome Atlas participants (n = 692) with Illumina Infinium HumanMethylation450 BeadChip array data. All-cause mortality and BC progression were modeled using Cox proportional hazards models stratified by tumor subtypes, adjusting for age, race, stage, menopausal status, tumor purity, and cell type proportion. Effect measure modification by subtype and menopausal status were evaluated by incorporating a product term with DNAm. Site-specific inference was used to identify subtype- or menopausal-status-specific differentially methylated regions (DMRs) and functional pathways. The validation of the results was carried out on an independent dataset (GSE72308; n = 180). We identified a total of fifteen unique CpG probes that were significantly associated ( P≤1×10-7 with survival outcomes in subtype- or menopausal-status-specific manner. Seven probes were associated with overall survival (OS) or progression-free interval (PFI) for women with luminal A subtype, and four probes were associated with PFI for women with luminal B subtype. Five probes were associated with PFI for post-menopausal women. A majority of significant probes showed a lower risk of OS or BC progression with higher DNAm. We identified subtype- or menopausal-status-specific DMRs and functional pathways of which top associated pathways differed across subtypes or menopausal status. None of significant probes from site-specific analyses met genome-wide significant level in validation analyses while directions and magnitudes of coefficients showed consistent pattern. We have identified subtype- or menopausal-status-specific DNAm biomarkers, DMRs and functional path

Patients with breast cancer metastases have very poor survival. Delays in the initiation of breast cancer treatment may adversely affect survival. Comorbid illness is more common in older women. Comorbid illness may explain effects of age on metastatic breast cancer survival outcomes. Comorbid illness may affect treatment delay.The purpose of the present study was to 1) identify factors related to survival following metastatic breast cancer diagnosis, 2) assess the impact of delay in treatment on survival while controlling for immortal time bias, and 3) evaluate the role of comorbidity as a mediator of survival disparity between younger (≤ 51 years) and older (> 51 years) patients.A total of 557 patients with the initial breast cancer metastasis diagnosis have been followed up between January 1, 1999 and June 30, 2008. Prognostic factors and outcomes of these patients were analyzed using log-rank test and Cox regression model, demonstrating that hypertension, ER/PR, HER2 status, number of metastatic sites, and BMI at metastatic breast cancer diagnosis were the most relevant prognostic factors for survival. Backward stepwise selection of covariates was conducted among 553 patients and showed that treatment delays of > 12 weeks had a marginal impact on poor survival (HR 1.76, 95% CI 0.99-3.13). Moreover, the interval of 12-24 weeks, compared to the interval of 4-12 week was a prognostic factor for survival from first treatment (HR 2.39, 95% CI 1.19-4.77). To assess comorbidity variable as a mediator of age-survival relationship among 553 patients, we applied two approaches: 1) Baron Kenny approach, and 2) alternative assessment to compute the percentage change in the HRs. Hypertension was related to survival (HR 1.45, 95% CI 1.12-1.89) and hypertension augmented Charlson comorbidity score (hCCS) explained survival disparity between young and old patients by 44% compared to 40 % of hypertension and 14% of the Charlson comorbidity score (CCS). Looking for opportunities