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Unique Gene Expression Profile Found in Young Women's Breast Cancer

NEW YORK (GenomeWeb News) – The biology of tumors found in women who are diagnosed with breast cancer before the age of 45 is distinct from that of older women, new research suggests.
An international team of researchers compared nearly 800 documented breast cancer cases from women in five countries and three continents to look at how age at diagnosis affected outcomes. The results, published online today in the Journal of Clinical Oncology, reveal a distinct gene expression signature in younger women, who also tend to have a worse prognosis. As such, researchers say, the work may eventually provide insights into treating these aggressive tumors.
“Clinicians have long noted that the breast cancers we see in women under the age of 45 tend to respond less well to treatment and have higher recurrence rates than the disease we see in older women, particularly over the age of 65,” Duke University oncologist Kimberly Blackwell, senior author on the paper, said in a statement. “Now we’re really understanding why this is the case, and by understanding this, we may be able to develop better and more targeted therapies to treat these younger women.”
Several studies have shown that breast cancers that are diagnosed in younger women are often harder to treat and more likely to return. As a result, younger women have worse breast cancer survival rates than women who are older at their time of diagnosis.
In an effort to understand why that might be the case, Blackwell and her colleagues assessed 784 clinically annotated, early-stage breast cancers from four publicly available datasets. Of these, 200 of the women were 45-years-old or younger and 211 were 65-years-old or older.
The team purposely selected samples for which gene expression had been measured using an Affymetrix Human Genome U133A or U95 array. They looked at expression profiles — in conjunction with prognoses, clinico-pathologic variables, oncogenic signaling activity, and other measures — and compared the younger and older groups.
Overall, the younger women had tumors with worse clinical features, including higher HER2 and epidermal growth factor receptor expression, larger tumors, and more cancers that involved the lymph node. The researchers found that these younger women also tended to have tumors that were less hormone sensitive.
Consequently, these women usually had a worse prognosis than their older counterparts. In general, the researchers reported that women who were 45-years-old or younger illustrated a “trend toward inferior disease-free survival.” And those who were less than 40-years-old when they were diagnosed with breast cancer tended to have even worse disease-free survival rates than those who were between 40 and 45-years-old.
Furthermore, using gene set enrichment analysis, the team identified 367 sets of genes that were active in tumors taken from women under 45-years-old but not in tumors from women over 65-years-old. These included genes involved in immune function, stem cell function, apoptosis, and several oncogenic signaling pathways. In contrast, they did not see a similar set of genes that were uniformly over-expressed in the tumors of older women.
Based on these results, the researchers concluded that the gene expression changes they observed in younger women represent a common biology in the tumors of younger women that is absent in those of older women — a discovery that Blackwell called “truly remarkable.”
“The genes that regulate things like immune function, oxygen supply, and mutations that we know are related to breast cancer, such as BRCA1, were preferentially expressed in tumors taken from younger women,” she said, “but when we compared younger women’s tumors to older women’s tumors, we found those same gene sets were not expressed in the ‘older’ tumors.”
The researchers conceded that there were certain limitations to the approach they used. For instance, the databases used in the study contained samples from women in several countries who may have received different treatments depending on where they live — something that could confound efforts to compare long-term outcomes.
To overcome such limitations, the researchers suggested that, in the future, additional, prospective clinical trials are necessary to look at clinical, pathologic, and genomic data in a more standardized group of patients.
Still, by recognizing the unique biology of breast cancer in younger women, the researchers argued, it may be possible to come up with novel treatments that specifically target the disease. “Identifying these distinguishing characteristics may be the first step in developing more effective treatments for these younger patients,” Blackwell said.

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