Metastasis-Associated Gene Identified and May Prove Useful as Marker for Relapse

HOUSTON—A gene that has been labeled metastasis-associated gene appears to be related to poor disease-free survival. Investigators at Baylor College of Medicine in Houston have produced a polyclonal antibody to metastasis-associated tumor antigen (MTA1)-specific isotopes that may prove useful as a prognostic marker for recurrence.

"We previously reported that markers D14S62 and D14S521 detect loss of heterozygosity (LOH) at significantly higher rates in node-negative relative to node-positive primary cancers (68% vs 24%; P = .001). "We have since determined that, in addition to a presumptive tumor suppressor gene, these LOH events encompass a metastasis-related gene (MTA1)," explained Peter O’Connell, MD, formerly of Baylor University and now at the Medical College of Virginia in Richmond.

MTA1 has homology to the nuclear receptor co-repressor 1 gene and is a subunit of the nuclear remodeling and histone deacetylation complex. MTA1 is mapped to the same gene locus, specifically the 14qter LOH metastatic locus.

An immunohistochemical assay was developed for the MTA1-specific antibody to test formalin-fixed, paraffin-embedded archival tissue from 1,000 primary breast tumors and control tissues with long-term follow-up in the Baylor tissue bank.

MTA1 expression, according to immunohistochemistry staining, was positively correlated with progesterone and estrogen receptor positivity, but was not correlated with traditional risk factors of relapse, including lymph node positivity, tumor size, and S phase, Dr. O’Connell reported.

"Our question then became, since MTA1 is unrelated to traditional risk factors, is MTA1 measuring something new?" he said.

The investigators conducted a multivariate analysis of disease-free and overall survival in 997 patients, but since strong treatment effects were seen for chemotherapy and endocrine therapy, the current analysis was restricted to patients who were node-negative and therefore received no treatment after surgery.

In univariate analysis, high MTA1 correlated strongly with estrogen receptor and progesterone receptor status. In multivariate analysis, high MTA1 was a significant predictor of disease recurrence.

"We found that MTA1 was the strongest predictor of early relapse in untreated node-negative patients," he reported. "MTA1 was a better indicator of relapse potential than tumor size or S phase fraction in untreated patients. Estrogen and progesterone receptor status was not predictive."

Overall Survival Not Assessed

Since patients were treated upon disease recurrence, and since treatment eliminates the effect of MTA1 on relapse risk, the analysis could not determine the impact of MTA1 on overall survival, he explained. "In terms of disease-free survival, we are seeing an effect of MTA1, but because of the positive impact of treatment, we could not assess overall survival," he said.

In Kaplan-Meier analysis, medium and high levels of MTA1 were present in a significant fraction of the recurrences in untreated node-negative patients. There was a strong correlation between high MTA1 level and decreased relapse-free survival, and this correlation was eliminated by treatment. MTA1 was not correlated with traditional factors of relapse risk, and may be a marker of something different, such as micrometastasis, he said.

"MTA1 is a marker for relapse in node-negative breast cancer. It identifies a high-risk subset that may be more likely to respond to therapy," he said.