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Study: Specific Gene Alterations May Increase Risk of Breast Cancer Relapse and Death

Researchers find new disease biomarker

Women whose early-stage breast cancers had reduced numbers of copies of the LRIG1 gene were more likely to have a relapse or to die of their disease, according to new data published in Cancer Research.

“Tumors with metastatic capability have cells within them that have stem cell-like properties, which resist chemotherapy, tend to sit quietly in the tumor, and are most likely the source of metastatic spread,” said lead investigator Patricia A. Thompson, PhD. “LRIG1 is a protein that is thought to control the growth of these cells and keep them quiet.”

Human cells have two copies of most genes. An increase or decrease in the copy number of certain genes is implicated in several diseases, including cancer.

Among women who were diagnosed with stage-1 or stage-2 breast cancers, those whose tumors had a loss of LRIG1 gene copy numbers were almost twofold more likely to have a relapse, 2.39-fold more likely to have a relapse 5 years after diagnosis or later, and 1.55-fold more likely to die of their disease compared with those whose tumors did not have a loss of LRIG1 copy numbers. Stage-1 and stage-2 breast cancers are generally considered to be at a lower risk for a relapse. These results could help clinicians identify patients at increased risk and monitor them more carefully, the authors say.

“First, we found that the loss of LRIG1 gene copy numbers in tumors of early-stage patients was associated with a higher risk of disease relapse, metastasis, and death,” said Thompson. “Second, we observed that the patients whose tumors had an increase in the copy numbers of LRIG1 had much better clinical and pathology characteristics, generally. This suggested that the gain of LRIG1 copy numbers may have contributed to the lower risk observed in these patients.”

Thompson and her colleagues analyzed breast-cancer tissue samples from 971 women who were treated at the MD Anderson Cancer Center for stage-1 or stage-2 breast cancers between 1985 and 2000.

Of the 971 samples, 3.7% had gains and 8.9% had losses in LRIG1 copy numbers. The researchers also found that the loss of LRIG1 copy numbers was more common in triple-negative (13.8%) and human epidermal growth factor receptor 2 (HER2)-positive (12.3%) breast cancers, which have a worse prognosis, compared with luminal A and luminal B subtypes (less than 10%).

The loss of LRIG1 copy numbers was also more prevalent in samples from black and Hispanic women (12.8% and 12.2%, respectively), who often have worse breast cancer outcomes, compared with samples from non-Hispanic white women (7.7%).

The researchers also found that the loss of LRIG1 copy numbers was significantly associated with disease relapse, distant metastasis, and death.

The investigators next used data from pooled, publicly available data sets yielding 1,576 samples to analyze alterations in LRIG1 and found that low expression of this gene was associated with increased distant metastasis and death compared with medium or high expression.

Outcomes from these two analyses did not change even after adjusting for known factors that influence relapse and metastasis, leading the researchers to conclude that alterations in LRIG1 copy numbers is an independent risk factor for breast cancer metastasis and death in otherwise low-risk patients.

“Efforts in developing LRIG1 [protein] as a tumor marker would help in developing new agents to kill or silence these cells as a means to prevent breast cancer relapse and metastasis,” Thompson said.

Source: AACR; May 30, 2014.

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