Gene Expression Profiling for Breast Cancer: What is it and how is it used?

Each woman's breast cancer is different with unique molecular signatures or patterns.  The current scientific research seeks to understand what these patterns mean, how they relate to whether a woman's cancer will return, and which treatment would be most beneficial to the patient.  Gene expression profiling looks for patterns among many genes in a tumor cell to understand the heterogeneous nature and behavior of breast cancers.

Gene expression profiling measures the activity of thousands of genes to create a global picture of cellular function.  Some gene expression profiling tests use fresh tissue while others use tissue preserved in paraffin.  Using tumor samples from a biopsy or other surgical procedure, gene expression profiling measures the specific messenger RNA that the genes code.  The messenger RNA in a tumor is measured to approximate which genes in a cell are active.  Knowing which genes are active can reveal a tumor's characteristics that will determine clinical outcome in breast cancer patients.  

Using computers to analyze the results, researchers have assessed relationships between the gene expression patterns and information from the women's medical records (i.e., cancer recurrence and whether the woman benefited from treatment such as chemotherapy). Researchers then developed numbering scales or scores that predict how likely cancer will come back or how likely a woman would benefit from treatment.

MammaPrint® and Oncotype DX® are two known gene expression profiling tests for breast cancer (Marchionni, 2008; Weigelt, 2010).  These tests measure gene expression levels within the tumor to produce number scores associated with the risk of distant disease recurrence.  The tests can be used together with information such as a woman's age, whether her cancer has spread, and whether the tumor tests positive for hormone receptors to guide treatment decisions. 

MammaPrint® is a 70-gene signature assay derived from the analysis of 78 frozen samples from lymph node-negative breast cancers smaller than 5 cm from patients younger than 55 years treated at the Netherlands Cancer Institute (Weigelt, 2010).  By comparing the expression profiles of tumors from patients who developed distant metastasis within 5 years with those who did not, a prognostic signature was identified comprising 70 genes.

Oncotype DX® is a 21-gene RT-PCR assay for estrogen receptor (ER)-positive breast cancer.  This assay was based upon prospective selection of 250 genes associated with cancer pathology and prognosis from the published literature and genomic databases.

MammaPrint® uses fresh-frozen tumor tissue which is more frequently available from procedures done in Europe while Oncotype DX® uses tissues preserved in paraffin, a typical procedure in the United States.  Because the two tests have not been directly compared to each other in the most rigorous way, the issue remains unresolved on which test is better than the other at predicting what the best treatment will be or whether a breast cancer will return.

In a prospective, randomized phase III clinical trial called the MINDACT, the 70-gene signature assay is currently being assessed (Weigelt, 2010; MINDACT trial EORTC 10041/BIG 3-04).  This phase III trial will enroll 6,000 patients and will compared MammaPrint® to Adjuvant Online!, a common clinical-pathological prognostic tool, to select patients for adjuvant chemotherapy in node-negative breast cancer.  The Oncotype DX® test is being evaluated in another prospective, randomized phase III trial called TAILORx (Weigelt 2010; TAILORx).  This phase III trial will enroll over 10,000 women at 900 sites in the United States and Canada to examine whether genes frequently associated with recurrence can be used to assign early breast cancer patients to the most appropriate and effective treatment.

Both Oncotype DX® and MammaPrint® are meant for women who have hormone receptor-positive early breast cancer.  These two tests have only one gene in common.  The lack of overlap in genes may have to do with how the tumor tissues are prepared for the tests and other differences in methods that the laboratories use.  Also, the heterogeneous nature of breast cancer means that many genes are involved in the cancer molecular pathway. 

MammaPrint® has been approved by the US Food and Drug Administration (FDA) for its prognostic value (i.e., predicting the likelihood that breast cancer will return).  MammaPrint® is not approved for predicting the response to treatment. That question is still being studied.  Oncotype DX has yet to be approved by the FDA, although the safety and performance standards of the test conducting labs are regulated under the Clinical Laboratory Improvements Amendments (CLIA).  While the two tests are widely available for use by physicians, more evidence is needed to understand how clinically useful the tests are. 

References

Marchionni L, Wilson RF, Wolff AC et al. Systematic review: gene expression profiling assays in early-stage breast cancer. Annals of Internal Medicine 2008; 148:358-369.

MINDACT trial. http://www.eortc.be/services/unit/mindact/MINDACT_websiteii.asp

Weigelt B, baehner FL, and Reis-Filho JS. The contribution of gene expression profiling to breast cancer classification, prognostication, and prediction: A retrospective of the last decade. J Pathol 2010; 220:263-280. Access the content on Wiley InterScience.

TAILORx trial. http://www.cancer.gov/clinicaltrials/digestpage/TAILORx