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Prediagnosis aspirin use, DNA methylation, and mortality after breast cancer: A population-based study.

ABSTRACT: BACKGROUND:The authors hypothesized that epigenetic changes may help to clarify the underlying biologic mechanism linking aspirin use to breast cancer prognosis. To the authors' knowledge, this is the first epidemiologic study to examine whether global methylation and/or tumor promoter methylation of breast cancer-related genes interact with aspirin use to impact mortality after breast cancer. METHODS:Prediagnosis aspirin use was assessed through in-person interviews within a population-based cohort of 1508 women diagnosed with a first primary breast cancer in 1996 and 1997. Global methylation in peripheral blood was assessed by long interspersed elements-1 (LINE-1) and the luminometric methylation assay. Promoter methylation of 13 breast cancer-related genes was measured in tumor by methylation-specific polymerase chain reaction and the MethyLight assay. Vital status was determined by the National Death Index through December 31, 2014 (N = 202/476 breast cancer-specific/all-cause deaths identified among 1266 women with any methylation assessment and complete aspirin data). Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs, and the likelihood ratio test was used to evaluate multiplicative interactions. RESULTS:All-cause mortality was elevated among aspirin users who had methylated promotor of BRCA1 (HR, 1.67; 95% CI, 1.26-2.22), but not among those with unmethylated promoter of BRCA1 (HR, 0.99; 95% CI, 0.67-1.45; P for interaction ?.05). Decreased breast cancer-specific mortality was observed among aspirin users who had unmethylated promotor of BRCA1 and PR and global hypermethylation of LINE-1 (HR, 0.60, 0.78, and 0.63, respectively; P for interaction ?.05), although the 95% CIs included the null. CONCLUSIONS:The current study suggests that the LINE-1 global methylation and promoter methylation of BRCA1 and PR in tumor may interact with aspirin use to influence mortality after breast cancer.

SUBMITTER: Wang T

PROVIDER: S-EPMC7147530 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Prediagnosis aspirin use, DNA methylation, and mortality after breast cancer: A population-based study.

Wang Tengteng T McCullough Lauren E LE White Alexandra J AJ Bradshaw Patrick T PT Xu Xinran X Cho Yoon Hee YH Terry Mary Beth MB Teitelbaum Susan L SL Neugut Alfred I AI Santella Regina M RM Chen Jia J Gammon Marilie D MD

Cancer 20190812 21

<h4>Background</h4>The authors hypothesized that epigenetic changes may help to clarify the underlying biologic mechanism linking aspirin use to breast cancer prognosis. To the authors' knowledge, this is the first epidemiologic study to examine whether global methylation and/or tumor promoter methylation of breast cancer-related genes interact with aspirin use to impact mortality after breast cancer.<h4>Methods</h4>Prediagnosis aspirin use was assessed through in-person interviews within a popu ...[more]

PMID: 31402456

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Project description:BackgroundResults from previous studies indicate that use of low-dose aspirin may improve breast cancer prognosis. We evaluated aspirin use and breast cancer outcomes in relation to clinical characteristics as well as dose and duration of aspirin use.MethodsWe used information from the Regional Breast Cancer Quality-of-Care Registries in three Swedish regions to identify 21,414 women diagnosed with a first stage I-III breast cancer between 1 April 2006 and 31 December 2012. The cohort was further linked to nationwide registers to retrieve information about dispensing low-dose aspirin before and after breast cancer diagnosis, comorbidity and causes of death. In a separate analysis, we investigated time to breast cancer death among 621 women with stage IV disease at diagnosis. Associations were evaluated using a multivariable Cox proportional hazards model.ResultsAmong women with stage I-III breast cancer, 2660 (12.4%) used low-dose aspirin shortly before breast cancer diagnosis and 4091 (19.1%) were users during follow-up. Women were followed for a median of 3.8 years after diagnosis. There was no association between aspirin use and breast cancer-specific death in multivariable analyses (use before diagnosis: hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.77-1.12; use after diagnosis: HR 1.00, 95% CI 0.74-1.37). Similarly, aspirin use was not associated with risk of first recurrence/metastases in a subgroup of stage I-III breast cancer patients (HR 0.97, 95% CI 0.86-1.10). However, in analyses stratified by stage, an inverse association between low-dose aspirin use after diagnosis and breast cancer death was found for women with stage I tumors (HR 0.53, 95% CI 0.29-0.96). Among women with stage IV disease at diagnosis, aspirin use was not associated with time to breast cancer death (HR 0.91, 95% CI 0.67-1.23).ConclusionIn this large population-based cohort study there was no evidence that low-dose aspirin use before or after breast cancer diagnosis is associated with a reduced risk of adverse outcomes overall in breast cancer. However, a potential benefit was noted among women with stage I tumors, warranting further investigation.

Project description:Lymph node-positive breast tumors are more likely to express COX2 than node-negative tumors. In preclinical studies, COX2 inhibition prevents breast tumor spread to lymph nodes. Therefore, we examined the association between recent (1 year) prediagnostic use of aspirin (COX1/COX2 inhibitor), lymph node involvement at breast cancer diagnosis, and breast cancer-specific mortality. Women with stage I-III breast cancer diagnosed from 2001 to 2006 (N = 2,796) were identified from Ireland's National Cancer Registry. These data were linked to prescription refill and mammographic screening databases. Relative risks (RR) were estimated for associations between prediagnostic aspirin use and lymph node-positive status at diagnosis. HRs were estimated for associations between pre- and postdiagnostic aspirin use and 5-year mortality, stratified by lymph node status. Women with prediagnostic aspirin use were statistically significantly less likely to present with a lymph node-positive tumor than nonusers [RR = 0.89; 95% confidence interval (CI), 0.81-0.97], particularly those with larger (Pinteraction = 0.036), progesterone receptor (PR)-negative (Pinteraction < 0.001) or estrogen receptor (ER)-negative (Pinteraction = 0.056) tumors. The magnitude of this association increased with dose (Ptrend < 0.01) and dosing intensity (Ptrend < 0.001) and was similar in women with or without screen-detected tumors (Pinteraction = 0.70). Prediagnostic aspirin use was associated with lower 5-year breast cancer-specific mortality among women with lymph node-negative tumors (HR, 0.55; 95% CI, 0.33-0.92) but not node-positive tumors (HR, 0.91; 95% CI, 0.37-1.22). Tests for effect-modification were, however, not statistically significant (Pinteraction = 0.087). Postdiagnostic aspirin use was not associated with breast cancer-specific mortality (HR, 0.99; 95% CI, 0.68-1.45). Our findings indicate that recent prediagnostic aspirin use is protective against lymph node-positive breast cancer. This is a plausible explanation for reductions in breast cancer mortality reported in observational studies of aspirin use.

Project description:BackgroundLong-term daily use of aspirin has been associated with reduced cancer mortality. To explore this association, we compared tumour TNM characteristics among aspirin users with those among non-users.MethodsFrom the Swedish Cancer Register, we identified patients diagnosed with colorectal, lung, prostate and breast cancers between 2006 and 2009 and matched them to the Swedish Prescribed Drug Register to obtain information on low-dose aspirin use prior to diagnosis. Contingency table and logistic regression analyses were used to test for association and obtain odds ratios (ORs).ResultsWe identified 17,041 colorectal, 9766 lung, 29,770 prostate and 20,299 breast cancer patients. The proportion of low-dose aspirin users was ~26% among colorectal, lung and prostate cancer patients and ~14% among breast cancer patients. Adjusted for age, gender, education level and place of residence, low-dose aspirin use was associated with lower tumour extent (T) for colorectal and lung cancers (P<0.0001) but not for prostate and breast cancers. The adjusted OR of aspirin use for the T4 vs T1 categories was ~0.7 (95% confidence interval (CI) 0.6-0.8). For all cancers, we found no evidence of association of aspirin use with nodal involvement (N). Except for a borderline result in prostate cancer (OR ~0.9; 95% CI 0.8-1.0), aspirin use was associated with a lower rate of metastatic disease (ORs ~0.6-0.8). Among the histological subgroups of lung cancer, significant differences in tumour extent were observed most clearly within the adenocarcinoma subgroup (OR ~0.6, 95% CI 0.5-0.8), although numbers of other subtypes were more limited; and there was a significant reduction of ~20-30% in the odds of metastasis among the aspirin users across the subgroups.ConclusionUse of low-dose aspirin in the year prior to diagnosis was found to be associated with lower tumour extent and fewer metastatic disease for colorectal and lung cancers. For these cancers, the benefit of aspirin use appears to be during both early and late cancer progression.

Project description:ImportanceThe potential relationship between obesity and colorectal cancer (CRC) outcome is poorly understood in patients with late-stage disease. Increased body mass index may negate aspirin use for cancer prevention, but its role as a factor on the effectiveness of postdiagnosis aspirin use is unclear.ObjectiveTo evaluate how prediagnosis obesity and postdiagnosis aspirin use may be associated with overall survival in patients with late-stage colorectal cancer.Design, setting, and participantsThis cross-sectional study used self-reported data from patients with metastatic or treatment-refractory disease who consented to a clinical protocol at MD Anderson Cancer Center, a large US cancer treatment center. Patients were enrolled between 2010 and 2018 and followed up for mortality through July 2020. Analyses were conducted through March 2022.ExposuresBody mass index in the decade prior to initial diagnosis and regular aspirin use at survey completion.Main outcomes and measuresOverall survival was measured from stage IV diagnosis until death or last follow-up. Cox proportional hazards models were constructed to estimate associations of prediagnosis obesity and postdiagnosis aspirin use with overall survival.ResultsOf 656 patients included in this analysis, 280 (42.7%) were women, 135 (20.6%) were diagnosed with CRC before age 45 years, 414 (63.1%) were diagnosed between ages 45 and 65 years, and 107 (16.3%) were diagnosed at 65 years or older; 105 patients (16.0%) were Black or Hispanic, and 501 (76.4%) were non-Hispanic White. Controlling for age, sex, race, stage at initial diagnosis, and weight change between prediagnosis and survey date, patients with obesity in the decade prior to CRC diagnosis had significantly higher likelihood of death (hazard ratio, 1.45; 95% CI, 1.11-1.91) compared with those with normal prediagnosis body mass index. Furthermore, only patients with normal prediagnosis body mass index experienced significant survival benefit with postdiagnosis aspirin use (hazard ratio, 0.59; 95% CI, 0.39-0.90).Conclusions and relevanceIn this cross-sectional study, our findings suggest potentially differential tumor development in the long-term physiologic host environment of obesity. Confirmation and further evaluation are needed to determine whether prediagnosis body mass index may be used to estimate the benefit from postdiagnosis aspirin use.

Project description:BackgroundAbnormal DNA methylation is well established for breast cancer and contributes to its progression by silencing tumor suppressor genes. DNA methylation profiling platforms might provide an alternative approach to expression microarrays for accurate breast tumor subtyping. We sought to determine whether the distinction of the inflammatory breast cancer (IBC) phenotype from the non-IBC phenotype by transcriptomics could be sustained by methylomics.Methodology/principal findingsWe performed methylation profiling on a cohort of IBC (N?=?19) and non-IBC (N?=?43) samples using the Illumina Infinium Methylation Assay. These results were correlated with gene expression profiles. Methylation values allowed separation of breast tumor samples into high and low methylation groups. This separation was significantly related to DNMT3B mRNA levels. The high methylation group was enriched for breast tumor samples from patients with distant metastasis and poor prognosis, as predicted by the 70-gene prognostic signature. Furthermore, this tumor group tended to be enriched for IBC samples (54% vs. 24%) and samples with a high genomic grade index (67% vs. 38%). A set of 16 CpG loci (14 genes) correctly classified 97% of samples into the low or high methylation group. Differentially methylated genes appeared to be mainly related to focal adhesion, cytokine-cytokine receptor interactions, Wnt signaling pathway, chemokine signaling pathways and metabolic processes. Comparison of IBC with non-IBC led to the identification of only four differentially methylated genes (TJP3, MOGAT2, NTSR2 and AGT). A significant correlation between methylation values and gene expression was shown for 4,981 of 6,605 (75%) genes.Conclusions/significanceA subset of clinical samples of breast cancer was characterized by high methylation levels, which coincided with increased DNMT3B expression. Furthermore, an association was observed with molecular signatures indicative of poor patient prognosis. The results of the current study also suggest that aberrant DNA methylation is not the main force driving the molecular biology of IBC.

Dataset Information

Prediagnosis aspirin use, DNA methylation, and mortality after breast cancer: A population-based study.

Publications

Prediagnosis aspirin use, DNA methylation, and mortality after breast cancer: A population-based study.

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