Genomic Health recently announced that its breast cancer assay, Oncotype DX is now available for clinical use in most states. Oncotype DX is a clinically validated assay that evaluates a tumors expression of 21 genes and quantifies the likelihood of a distant recurrence in women with node negative, ER positive breast cancer.
The optimal strategy for treatment of women with localized breast cancer who do not have axillary lymph node spread has not been identified and continues to be a topic of research. However, it is clear that without adjuvant therapy a significant number of women with node-negative breast cancer will relapse. For patients who are hormone receptor positive, anti-estrogen therapy is usually administered. For women who are hormone receptor negative, chemotherapy is usually given. Age or menopausal status may determine the type of adjuvant therapy administered. Identifying the molecular basis of each node-negative cancer may provide an even more precise way to individualize treatment. Oncotype DX may be a valuable tool for identifying gene expression in breast cancer.
Oncotype DX measures expression of 21 genes. The gene panel contains 16 breast cancer-related genes and 5 reference genes. Oncotype DX utilizes formalin-fixed, paraffin-embedded tumor tissue, which is an advantage over other molecular diagnostic methods because this form is usually readily available because it is routinely generated following tissue biopsy and is easily stored. The Recurrence Score is calculated using an algorithm developed from three independent clinical trials involving a total of 447 patients.
Assay method: The method used for evaluating the gene expression is reverse transcription polymerase chain reaction (RT-PCR). Polymerase chain reaction (PCR) is an in vitro laboratory method that amplifies a segment of DNA from a small sample, making it detectable. With PCR, relatively small sequences of known DNA can be replicated into millions of copies over a short period of time. In RT-PCR, traditional PCR is combined with reverse transcription, which is the translation of RNA back into a strand of complimentary DNA. This allows the amplification of mRNA, and therefore the DNA sequences that are expressed.
PCR procedure: PCR requires four principle components: 1) the sample DNA, 2) an ample supply of nucleotides, 3) a heat-stable polymerase enzyme which is responsible for copying DNA, and 4) primers, short sequence of nucleotides which lie on either side of the DNA fragment of interest and signal the polymerase to begin replication of the specific DNA segment.
PCR is a three step process, with each step occurring at a different temperature. The sample DNA is first heated to approximately 90ºC in order to separate the 2 paired DNA strands. Once separated, it is cooled to a temp that allows the primers to hybridize to their complementary sequence on the target DNA, approximately 40ºC. Lastly, DNA replication occurs at approximately 70ºC, the temperature at which DNA polymerase is most active. This process is repeated 20 to 30 times, resulting in approximately 1 million-fold amplification of the DNA fragment of interest.
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Clinical validation: Oncotype DX was prospectively validated by the National Surgical Adjuvant Breast and Bowel Project (NSABP) that involved 668 women with node negative, ER-positive breast cancer treated with tamoxifen. The Recurrence Score is calculated from the tumors expression of 21 genes which include those measuring proliferation, HER-2, estrogen, and invasion. The scale of the score is 1-100. Patients with a score of <18 have a low risk of recurrence, those with a score of 18-31 have an intermediate risk, and those with a score of 31 or more have a high risk of relapse.
Data from the NSABP trial (see table 1) demonstrated that the Recurrence Score is a strong predictor of distant recurrence-free survival (p<0.00001), and it was also found to be predictive of relapse-free survival (includes local recurrences and new primary tumors) and overall survival (p<0.0001).
Table 1 Oncotype DX clinical validation data with distant recurrence and survival as endpoints
| Risk group | % of patients | 10 year distant recurrence | 10 year survival |
|---|
| Low (score <18) | 51% | 6.8% | 90% |
| Intermediate (score 18-31) | 22% | 14.3% | 78% |
| High (score >31) | 27% | 30.5% | 68% |
Recurrence Score performance exceeded standard measures such as patient age, tumor size, and tumor grade in predictive power.
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References
1. Tefferi A, Wieben ED, Dewald GW, et al. Primer on Medical Genomics Part II: Background Principles and Methods in Molecular Genetics.
Mayo Clinic Proceedings 2002;77:785-808.
2. Paik S, Shak S, Tang G, et al. Multi-gene PT-PCR assay for predicting recurrence in node negative breast cancer patientsNSABP studies B-20 and B-14. Proc of the 26th Annual San Antonio Breast Cancer Symposium. December 3-8k, 2003; San Antonio, TX, Abstract #16.
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