Gene Expression May Soon Guide Breast Cancer Treatment

A multinational group of researchers has developed and validated a new genomic microarray test that may replace current tests as the best way to determine whether a patient with newly diagnosed breast cancer would be likely to benefit from specific therapies.

“This is one important step toward diagnosing and planning treatment based on a genomic test of an individual tumor,” said W. Fraser Symmans, M.D., an associate professor in the Department of Pathology and the senior author of an article about the team’s findings, which was published in the March issue of Lancet Oncology.

The article reports the latest development in the team’s efforts to find a single test that would quickly and efficiently determine the characteristics and vulnerabilities of a patient’s cancer.

In their experiments, the expression of mRNA by two specific genes, ESR1 and ERBB2, correlated significantly with the status of the corresponding receptors: estrogen receptor and human epidermal growth factor receptor-2 (HER-2), respectively. The gene expression tests were 90% accurate for both receptors, which makes them comparable to, if not better than, the results obtained with immunohistochemistry assays and fluorescence in situ hybridization, the tests currently used to determine receptor status.

Of breast cancers, approximately 70% are estrogen-receptor-positive and can be treated with estrogensuppressing drugs. Another 15%–25% of breast cancers are HER-2-positive and are sensitive to antibody-based drugs, such as trastuzumab, that bind to HER-2 receptors and block them from coupling with growth factors that fuel tumor growth.

“We have moved a step closer to developing an integrated genomic test that could accomplish several important diagnostic needs at once,” said Lajos Pusztai, M.D., Ph.D., an associate professor in the Department of Breast Medical Oncology. Dr. Pusztai leads the research team with Dr. Symmans. “By combining these latest results with others, a genomic test could be designed to estimate the risk of cancer relapse after surgery, determine the estrogen-receptor and HER-2 receptor status, and gauge the sensitivity of the tumor to hormone therapy and chemotherapy.”

The efforts to refine the use of genomic microarray testing will continue with a prospective clinical trial at M. D. Anderson, in which these tests will be used to recommend treatment for patients with newly diagnosed stage I to III breast cancer.

Two-Gene Test Differentiates Similar Gastrointestinal Tumors

With near-perfect accuracy, a powerful two-gene test can distinguish between a pair of nearly identical gastrointestinal cancers that require radically different courses of treatment.

“This simple and accurate test has the potential to be relatively quickly implemented in the clinic to help doctors determine appropriate treatment,” said Wei Zhang, Ph.D., a professor in the Department of Pathology and the senior author of the article describing the study, published in the February issue of the Proceedings of the National Academy of Sciences.

One of the cancers, gastrointestinal stromal tumor (GIST), was once thought to be best grouped with spindle cell and other soft-tissue sarcomas, including leiomyosarcoma (LMS), because both originate in the smooth muscle cells of the gastrointestinal tract; but GIST has emerged as a distinct entity. In fact, GIST and LMS respond so differently to certain chemotherapies that the appropriate diagnosis can be a life-and-death decision, according to the researchers. Specifically, GIST tends to be very responsive to the tyrosine kinase inhibitors imatinib mesylate and sunitinib but resists cytotoxic therapy, while LMS responds to cytotoxic therapy but resists tyrosine kinase inhibitors.

Before the two-gene classifier, the best way to differentiate GIST from LMS was only about 87% accurate and could cause false-negative diagnoses, requiring intensive and time-consuming additional analyses.

“This new classifier may have been so successful because it used as simple an approach as possible to keep statistical pitfalls from lowering its accuracy,” Dr. Zhang said. “We expect that the use of simple marker pairs, like the one used in this test, will be clinically useful in many situations.”

Genomic approaches to diagnosing cancer, selecting treatment, and determining a cancer patient’s prospects of responding to care are beginning to work their way into the clinic, the researchers noted. These approaches can rely on dozens of genes as biomarkers. However, top-scoring pair analysis, the analytical technique employed to identify this classifier’s gene pair, allows the use of fewer genes to distinguish between similar cancers or between groups of patients who have one type of cancer but respond differently to treatment based on genetic indicators. For example, paired gene analysis may be used to determine which patients will benefit from different types of chemotherapy and which patients are at higher risk of relapse, the authors noted. As an analytical strategy, the method will have wider applications in the development of individualized treatments and diagnoses of other types of cancer, the researchers said.

For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

Other articles in OncoLog, April/May 2007 issue:

• Endocrine Center Unites Specialists
• Prescribing Hormone Replacement: What Now?
• House Call: Writing for Wellness: Keeping a Journal
• DiaLog: What Your Patients Aren’t Telling You

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