MammaPrint

Description
MammaPrint is commercial microarray¹ based prognostic breast cancer gene-expresion² profiling test of 70 genes.
The MammaPrint test measures the level of activity of each of these genes in a sample of a woman's surgically removed breast cancer tumor, then uses a specific algorithm, to produce a score that determines whether the patient is deemed "low risk"³ or "high risk"⁴ for spread of the cancer to another site and is prognostic for development of distant metastasis in lymph node negative (LNO) patients. The result may help a doctor in planning appropriate follow-up for a patient when used with other clinical information and laboratory tests (e.g. to select patients for adjuvant systemic chemotherapy and/or hormonal therapy).

Selection criteria

• Stage I invasive breast cancer with estrogen receptors positive ir negative (ER+ or ER-)
• Stage II invasive breast cancer with ER+ or ER- and lymph node negative

Analysed genes
70 genes involved in cell cycle, invasion, metastasis and angiogenesis of breast cancer cells.

Sample preparation
Fresh unfixed tumor tissue. MammaPrint® analysis cannot be performed on formalin-fixed paraffin embedded (FFPE) tumor tissue as this fixation procedure causes the RNA to degrade.

• Wear gloves when handling tumor
• Immediately take unfixed tumor tissue to the pathology department after surgery
• Representative biopsy must be taken within an hour after the surgery
• Use the biopsy punch provided in kit to obtain tumor sample with a minimum thickness of 3 mm and a maximum thickness of 5 mm from the periphery of the tumor.
• Avoid necrotic (middle of the tumor) and stromal tissue (boarders of the tumor) to be take in a sample
• Place the biopsy directly in the preservative solution of the sample tube provided
• Label sample tube with ID-sticker
• Seal and place the small sample tube into a large tube and put it into the envelope.

• The sample is stable for a week in the preservation solution at room temperature, but should preferably be send to Agendia immediately after the biopsy has been taken [11].

Workflow

Test technology
Customized DNA microarrays, manufactured by Agilent. For each patient, triple measurements of 70 genes sets are obtained from two microarrays.

Clinical validation

Mammaprint is based on study published by van 't Veer et al in Nature 2002 [1].

• In February, 2007 the Food and Drug Administration (FDA) cleared the MammaPrint test for marketing in the U.S. under the In Vitro Diagnostic Multivariate Index Assay (IVDMIA) Guidelines for use breast cancer prognosis in node negative women under 61 years of age with tumors of less than 5cm [2, 3].
• In June 2007, Agendia received a second clearance from the FDA for its MammaPrint®sampling and room temperature shipping procedure, using a RNA preserving solution (RNARetain®), what could allow shipping of tumor biopsies at ambient temperature [12]. RNARetain® is a trademark of Asuragen Inc., RNA-based therapeutic and diagnostics company.

Clinical test performance is based on several studies:

• van 't Veer et al. Nature 2002 [1] - development of breast cancer prognosis 70-gene profile multivariate profile in 78 patients (LNO, <55yrs), 6.4% receiving adjuvant treatment (gene signature⁵ development phase)
• van de Vijver MJ et al. N. Engl. J. Med. 2002 [4] - validation of the 70-gene profile in consecutive series of breast cancer 151 patients, 5.2% receiving adjuvant treatment. Metastasis-free survival by profile at 10 years: low-risk 87%, high risk 44% (gene signature validation phase)
• Glas AM et al. BMC Genomics 2006 [5] - development of MammaPrint, reproducibility of previous studies (assay development phase)
• Buyse M et al. J. Natl. Cancer Inst. 2006 [6] - independent European validation of 70-gene signature in 302 patients (LNO, <61yrs); metastasis-free survival by profile at 10 years: low-risk 88%, high risk 71% (at 5 yrs: 96% and 83% respectively) (assay validation phase)
• Ach RA et al. BMC Genomics 2007 [7] - examined the reproducibility of a 70-gene breast cancer signature in a series of experiments performed in three laboratories (Amsterdam, California, Paris).

Summarry by Marchionni L et al. Ann Intern Med (2008) [9].

Awards

• The 2007 Frost & Sullivan European Product Innovation Award in the field of biomarker-based breast cancer diagnostics [13]
• Time Magazine: one of five best innovations of the year 2007 in the health category

Sensitivity, specificity, positive-predictive value
N/A

Video
From Oncologypodcasting.com

Limitations

1. It is not yet clear which are the optimal patient populations for the use of this test, exactly what its performance is in those populations, and how many of its predictions would result in different therapeutic decisions. Larger independent validation studies in therapeutically homogeneous groups would be very valuable [8].
2. no evidence for the degree to which this test predicts the benefit of adjuvant chemotherapy [8].
3. no clinical trials assessing the utility of adjuvant therapy in high risk versus low-risk individuals [[10]

Price
The cost in the US is $3,200; UK - £ 1650.

Turnaround time
10 working days

Ordering
By physicians only.

Producer
Agendia BV
Slotervaart Hospital 9D
Louwesweg 6
1066 EC AMSTERDAM
the Netherlands
T: 0031 20 512 9161
F: 0031 20 512 9162
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Bibliography

1. van 't Veer LJ, Dai H, van de Vijver MJ, et al (2002). "Gene expression profiling predicts clinical outcome of breast cancer". Nature 415 (6871): 530–6.

2. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01555.html

3. FDA Mammaprint document (.pdf)

4. van de Vijver MJ, He YD, van't Veer LJ, et al (2002). "A gene-expression signature as a predictor of survival in breast cancer". N. Engl. J. Med. 347 (25): 1999–2009

5. Glas AM, Floore A, Delahaye LJ, et al (2006). "Converting a breast cancer microarray signature into a high-throughput diagnostic test". BMC Genomics 7: 278

6. Buyse M, Loi S, van't Veer L, et al (2006). "Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer". J. Natl. Cancer Inst. 98 (17): 1183–92

7. Ach RA, Floore A, Curry B et. al (2007) Robust interlaboratory reproducibility of a gene expression signature measurement consistent with the needs of a new generation of diagnostic tools. BMC Genomics. 8:148

8. Impact of Gene Expression Profiling Tests on Breast Cancer Outcomes (Agency for Healthcare Research and Quality), January 2008

9. Marchionni L, Wilson RF, Wolff AC et al. Systematic Review: Gene Expression Profiling Assays in Early-Stage BreastCancer. . Ann Intern Med. 2008 Feb 4; (Epub ahead of print)

10. Wikipedia: MammaPrint

11. Sampling instructions for MammaPrint (Agendia)

12. MedicalNewsToday article

13. Frost & Sullivan Award press release

Definitions

1. DNA microarray (also called gene chip or DNA chip): A collection of microscopic DNA spots, representing single genes or transcripts, arrayed on a solid surface by covalent attachment to chemically suitable matrices, or directly synthesized on them. DNA microarrays use DNA as part of their detection system. Qualitative or quantitative measurements with DNA microarrays use the selective nature of DNA–DNA or DNA–RNA hybridization under high-stringency conditions and fluorophore-based detection. DNA arrays are commonly used for gene expression profiling, i.e., monitoring expression levels of thousands of genes simultaneously, or for comparative genomic hybridization.

2. Gene expression: The translation of the information encoded in a gene into an RNA transcript. Expressed transcripts include messenger RNAs translated into proteins, as well as other types of RNA, such as transfer RNA, ribosomal RNA, micro RNA, and non-coding RNA, which are not translated into protein. Gene expression is a highly specific process by which cells switch genes on and off in a timely manner, according to their state. The study of messenger RNAs expression in a cell is an indirect way to study the proteins counterpart.

3. 'Low risk' means chance of developing metastasis within 10 years is 10-15% (10-year survival rate is 97%).

4. 'High risk' indicates a chance of 50% or more that cancer will metastasize within 10 years (10-year survival rate is 50%).

5. The gene signature is the collection of genes whose expression levels are measured in a given test, together with the algorithm that combines those levels into a prognostic index.

Comments

ramunas 1203413244|%e %b %Y, %H:%M %Z|agohover

medice, curate ipsum

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