Epigenetic signatures differentiate triple negative breast cancers

When the breast cancer DNA methylome was compared with that of healthy persons, distinct methylation patterns were revealed in the primary biopsy breast cancer cells. These patterns indicated a better or worse prognosis, according to a new study published in Nature Communications (2015; doi:10.1038/ncomms6899).

The methylome provides a new picture of the genome and shows how it is epigenetically decorated with methyl groups, a process known as DNA methylation.

Triple negative breast cancers, which make up 15% to 20% of all breast cancers, lack any of the three receptors (estrogen, progesterone, or HER2) that would make them responsive to targeted drugs. Overall, patients have a higher risk of disease recurrence and shorter survival than those with other breast cancers.

Patients with triple negative breast cancer tend to fall into two categories: those that succumb to their disease within 3 to 5 years, regardless of treatment; and those that remain disease-free for longer than the average patient whose breast cancer is not triple-negative type (at least 8 years postdiagnosis).

At present, there is no reliable way to stratify triple negative cancers into these two subgroups. Clinicians use tumor size, degree of spread, and infiltration of lymph nodes to determine whether a patient falls into a high-risk or low-risk category. Ironically, the outcome of triple negative breast cancers is far less associated with cancer stage than other breast cancers.

The research was led by Professor Susan Clark, PhD, Sydney's Garvan Institute of Medical Research, in Australia. Her team performed whole genome methylation capture sequencing on archival tissue samples from patients with triple negative breast cancer and matched normal samples, followed by next generation sequencing to determine cancer-specific changes in DNA methylation.

"This is the first study to investigate the methylome of triple negative breast cancer and its association with disease outcome," said Clark.

"There is a clear need for better informed disease management. In the absence of robust prognostic tools, too many women are being overtreated.”

"The information we have at the moment is based on statistics and probability, and we are forced to treat triple negative breast cancer patients as a group, even though we know that they are not a uniform population," said Professor Glenn Francis, MD, also of Garvan, who analyzed the tissue samples for the study.

"By stratifying tumors epigenetically, this study should enable us to track selected groups of patients over time, monitoring how they respond to different treatments. From a purely practical standpoint, it's useful that reliable results were obtained from formalin-fixed, paraffin embedded tissue—as this is the material routinely used for diagnosis."

The research team developed the methodology to sequence the methylome using DNA extracted from the archived tissue blocks.

Clark acknowledged that the findings now warrant further investigation in much larger breast cancer cohorts.

"We are very encouraged to have found that epigenetics provides a promising new prognostic tool, and we look forward to the results from the next phase of validation," she said.

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