Gene Signature Identifies Early Versus Late Versus No Recurrence in Hormone Receptor-Positive Breast Cancer

Minetta C. Liu, MD

It may be possible to predict which women with hormone receptor-positive (HR+) invasive breast cancer will experience recurrence despite treatment with tamoxifen by using a series of gene expression profiles; these profiles appear to distinguish between women who will experience early recurrence (within less than 3 years) versus later recurrence (more than 10 years), according to results of a preliminary study presented at the CTRC-AACR San Antonio Breast Cancer Symposium.

“There are clear biological differences within the supposedly unified group of hormone receptor-positive [HR+] breast cancers, and these differences distinguish subtypes relative to the time at which they recur. Our study confirms what many have suspected — that there are biological drivers present at the time of tumor development that define whether or not breast cancer will recur early, late, or not at all. Now we need to validate these findings and move to the next step,” said lead researcher Minetta C. Liu, MD, associate professor of medicine and oncology and director of translational research at Georgetown Lombardi Comprehensive Cancer Center, Washington, DC. Research is ongoing to validate selected genes as biological drivers of metastasis, she explained.

Specifically, the study showed that increased expression of ESR1, ESR2, EGFR, BCL2, and AR was associated with late recurrence, while increased expression of CALM1, CALM2, CALM3, SRC, CDK1, and MAPK1 was associated with early recurrence.

“Some of the genes that were identified were expected and reassuring, while others were unexpected and novel,” Liu said.

The study was a collaboration with researchers from Georgetown, the University of Edinburgh in Scotland, and Virginia Polytechnic Institute. High-quality, frozen tumor samples were obtained at time of diagnosis from women with Stage I-III HR+ breast cancer before being treated with tamoxifen (but not chemotherapy) at the University of Edinburgh, Scotland. All women were followed for more than 10 years for recurrence and metastatic disease. The tissue samples were linked to data on treatment and clinical outcomes.

RNA was extracted from the tumor samples and arrayed on gene chips, and scientists at Virginia Polytechnic Institute examined the gene expression patterns using a novel computational procedure; these researchers created a statistical model of the signaling patterns. A sophisticated sampling method identified estrogen receptor network topology represented by the genes and their predicted interconnections. The results were validated using an established dataset from a study by Loi et al. Liu and colleagues were able to identify gene expression patterns among the tumor samples that correlated strongly with the development of distant metastatic disease.

She said that the study focused on the development of distant recurrences and that they are still analyzing the data to identify gene expression patterns for women who did not have a recurrence.

Women with HR+ breast cancer are often treated with tamoxifen, which can prevent or delay recurrence. However, some tamoxifen-treated women will recur more than 10 years after their original diagnosis. Until this study, the molecular basis for early versus late recurrence was unknown, she explained. Her group plans to study gene expression patterns for recurrence in patients treated with aromatase inhibitors.

“The ability to predict patterns of recurrence will lead to more appropriate recommendations for adjuvant therapy. It might also identify those women who would benefit most from studies using investigational agents that enhance the effects of hormonal therapy, such as tamoxifen or aromatase inhibitors,” Liu suggested.

The next step is to validate the predictive model for the timing of recurrence on treatment with tamoxifen so that physicians and patients can make more informed decisions about treatments and whether or not patients should participate in clinical trials. “We will also investigate combinations of molecular targets with the ultimate goal of delaying or preventing the development of metastatic breast cancer,” Liu said.

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