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Prior studies have suggested that women who take aspirin before being diagnosed with breast cancer (BC) may live longer than women who haven’t historically used aspirin, but study data is limited and inconsistent. Research headed by scientists at the University of North Carolina (UNC) at Chapel Hill has now found that DNA methylation may represent the missing link in this relationship. Their population-based study in more than 1,000 women with breast cancer found that global DNA methylation, and methylation of the promoters for two specific cancer-related genes, may impact on whether prediagnosis aspirin use can influence breast cancer-specific mortality, and death from all causes.

“Consideration of DNA methylation profiles as potential modifiers of the aspirin-mortality association may provide new insights on the underlying biological mechanisms on aspirin use in relation to mortality after breast cancer diagnosis,” said Tengteng Wang, PhD, MSPH, who is first and corresponding author of the team’s published paper in Cancer. “Our findings, if confirmed, may also impact clinical decision-making by identifying a subgroup of patients, using epigenetic markers, for whom prediagnosis aspirin use impacts subsequent mortality, and may help refine risk reduction strategies to improve survival among women with breast cancer,” added research lead Marilie Gammon, PhD, professor of epidemiology at UNC, Chapel Hill. The team’s paper is titled “Prediagnosis Aspirin Use, DNA Methylation, and Mortality After Breast Cancer: A Population-Based Study.”

Breast cancer is the second leading cause of cancer death among women in the United States, and is expected to cause 41,760 deaths in 2019, the researchers wrote. Aspirin is an anti-inflammatory pain relief drug that both lab and epidemiological studies have suggested reduces the risk of breast cancer development because it can inhibit cyclooxygenase-2 (COX-2)-mediated prostaglandin synthesis, which plays an important role in both inflammation and estrogen synthesis. However, the authors also pointed out, prediagnosis aspirin use among women with BC has been linked with improved survival in some epidemiologic studies but not others, and, as they stated, “the underlying biological mechanisms and epidemiological findings on aspirin use in relation to prognosis and mortality after BC are limited and inconsistent.” The authors’ recent report of no association between aspirin use and mortality after BC is also consistent with “a recent meta-analysis that failed to find an inverse association between prediagnostic aspirin use and either all-cause or BC-specific mortality.”

Given that breast cancer progression will likely involve complex interactions among genetic/epigenetic, hormonal, and inflammatory factors, the researchers hypothesized that inconsistent results from studies on breast cancer mortality and aspirin use may relate to differences in DNA methylation, a mechanism for gene regulation that impacts on gene function without causing changes to gene sequence. Prior studies, including those by Gammon’s team, had already linked global and tumor gene-specific changes in DNA methylation with breast cancer prognosis. “Aberrant DNA methylation may lead to whole-genomic instability and altered gene transcription, which may further induce increased mutation rates of key genes (including COX-2) upon which that aspirin acts,” they suggested. “Thus, it is biologically plausible that aspirin works in conjunction with DNA methylation state to influence mortality after BC diagnosis,” they wrote.

To investigate their hypothesis the team designed a study to evaluate whether prediagnosis aspirin use might interact with two global methylation markers in peripheral blood DNA, and the methylation of 13 breast cancer-related gene promoters—including BRCA1 and PR—in tumors, to influence mortality. “To our knowledge, no study has systematically addressed the interplay between aspirin use and DNA methylation in the context of BC progression,” they wrote.

The study involved 1,266 women who had been diagnosed with breast cancer between 1996 and 1997, 476 of whom had died from any cause, and 202 had died specifically from breast cancer by the end of 2014. The results of analysis on patient data and samples showed that “all-cause mortality after BC was elevated among aspirin ever users with methylated tumor promotor of BRCA1, but not those with unmethylated tumors.” Conversely, BC-specific mortality was lower among aspirin users with unmethylated tumor promoters of BRCA1 and PR, and with hypermethylation of long interspersed elements-1 (LINE-1), which serves as a surrogate for overall cellular DNA methylation status and genomic instability.

BRCA1 is a tumor suppressor gene involved in the DNA repair complex, which plays an important role in maintaining genomics stability, while PR is a member of the nuclear receptor family that involved in normal breast development and tumorigenesis, the team explained. “Collectively, it is plausible that a tumor environment characterized with BRCA1 and PR promoter methylation may contribute to low sensitivity to aspirin exposure for the host, which would result in little benefit from prediagnosis aspirin use on BC prognosis and overall survival,” the investigators suggested. “Thus it is plausible that tumor promoter methylation can be linked to a worse BC prognosis, which prediagnosis use of aspirin is not able to reverse.”

The team also suggested that their results could be interpreted to indicate that in the case of LINE-1 hypermethylation (and so improved genomic stability), aspirin may be able to function normally, or even better, with respect to lowering BC-related mortality. Conversely, in the case of LINE-1 hypomethylation (and increased genomic instability), the risk reduction benefit from aspirin wouldn’t be evident. “In conclusion, in a population-based cohort of women diagnosed with a first primary BC, we are first to report significant heterogeneity of the aspirin-mortality association by BRCA1 and PR promoter methylation and LINE-1 global methylation profiles,” Gammon and colleagues concluded.

The authors acknowledge that their study did have certain limitations, and suggest the need for additional research that would include larger patient cohorts and a more extensive panel of genes. Nevertheless, they say, “Our study may help to identify women who may benefit from aspirin use to improve survival after a BC diagnosis because of their DNA methylation profile … These findings, if confirmed, may provide new biological insights into the association between aspirin use and BC prognosis, may affect clinical decision making by identifying a subgroup of patients with BC using epigenetic markers for whom prediagnosis aspirin use affects subsequent mortality, and may help refine risk-reduction strategies to improve survival among women with BC.”

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