(102 days)
MammaPrint® is a qualitative in vitro diagnostic test service, performed in a single laboratory, using the gene expression profile of fresh breast cancer tissue samples to assess a patients' risk for distant metastasis.
The test is performed for breast cancer patients who are less than 61 years old, with Stage I or Stage II disease, with tumor size ≤ 5.0 cm and lymph node negative. The MammaPrint® result is indicated for use by physicians as a prognostic marker only, along with other clinicopathological factors.
The MammaPrint service is a microarray based gene expression analysis of a tumor. The analysis is based on several processes: using fresh tissue stored in RNAlater, isolation of RNA from frozen tumor tissue sections, DNA'se treatment of isolated RNA, linear amplification and labeling of DNA'se treated RNA, cRNA purification, hybridization of the cRNA to the MammaPrint microarray, scanning the MammaPrint microarray and data acquisition (feature extraction), calculation and determination of the risk of recurrence in breast cancer patients.
The MammaPrint analysis is designed to determine the gene activity of specific genes in a tissue sample compared to a reference standard. The result is an expression profile, or fingerprint, of the sample.
The correlation of the sample expression profile to a template (the mean expression profile of 44 tumors with a known good clinical outcome) is calculated and the molecular profile of the sample is determined (Low Risk, High Risk).
This document describes the MammaPrint® device, a gene expression profiling test system for breast cancer prognosis.
Acceptance Criteria and Device Performance
| Criteria | Reported Device Performance |
|---|---|
| Analytical Accuracy | 98.5% (based on 190+ independent analyses of control samples) |
| Classification Accuracy | 97.7% for High Risk/Low Risk classification |
| Borderline Samples | Less than 5% of analyzed samples |
| Repeatability | Considered Precise, Reproducible, Sensitive, Specific, Accurate, and Robust |
Study Details
2. Sample Size and Data Provenance
- Training Set Sample Size:
- Nature Paper (1): 78 patients
- NEJM Paper (2): 151 patients
- Validation Set Sample Size:
- NEJM Paper (2): 151 patients (used for both training and validation)
- Transbig Paper (4): 302 patients
- Data Provenance: Not explicitly stated, but the studies mention "independent European validation" for the Transbig Paper, implying data from Europe. The "comprehensive three-way inter-laboratory comparison study between three independent laboratories in three different countries (Dutch, French and U.S.)" indicates data from these countries for analytical performance, but not specifically for clinical studies. Retrospective or prospective nature is not specified, but the "time frame" for clinical studies (e.g., 2002, 2006) and the reporting of 5-year and 10-year metastasis-free survival strongly suggest retrospective analysis of existing patient cohorts.
3. Number of Experts and Qualifications for Ground Truth
- Not explicitly stated for the clinical studies. The clinical performance is based on outcomes data (metastasis-free survival) rather than expert consensus on individual cases.
4. Adjudication Method for Test Set
- Not applicable as the ground truth is based on clinical outcomes (metastasis-free survival) rather than expert consensus requiring adjudication.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
- No, a multi-reader multi-case (MRMC) comparative effectiveness study was not performed or mentioned in the provided text. The device is a diagnostic test, not an AI-assisted interpretation tool for human readers.
6. Standalone Performance Study
- Yes, the performance reported is a standalone (algorithm only) performance. The MammaPrint is a gene expression analysis that directly provides a risk classification (High Risk or Low Risk) based on the gene activity profile. The "Classification performance" states "the accuracy of classifying a sample as High Risk or Low Risk, is 97.7% (i.e., 1.1% false negative classification)," which refers to the algorithm's performance.
7. Type of Ground Truth Used for Clinical Studies
- Outcomes Data: The clinical studies (Nature Paper, NEJM Paper, Transbig Paper) used clinical outcomes data, specifically metastasis-free survival at 5 and 10 years, as the ground truth for validating the prognostic ability of the MammaPrint profile. This is indicated by phrases like "Metastasis-free survival by profile at 10 yrs."
8. Sample Size for the Training Set
- As detailed in Section 2, the training set sizes were:
- Nature Paper (1): 78 patients
- NEJM Paper (2): 151 patients (also used for validation)
9. How the Ground Truth for the Training Set Was Established
- The ground truth for the training set (and validation set) was established using clinical outcomes data, specifically the occurrence of distant metastasis over time. The studies measured "metastasis-free survival" in patient cohorts. This implies that the initial patient samples were analyzed by MammaPrint, and then patients were followed over several years to observe their clinical outcome regarding metastasis.
§ 866.6040 Gene expression profiling test system for breast cancer prognosis.
(a)
Identification. A gene expression profiling test system for breast cancer prognosis is a device that measures the ribonucleic acid (RNA) expression level of multiple genes and combines this information to yield a signature (pattern or classifier or index) to aid in prognosis of previously diagnosed breast cancer.(b)
Classification. Class II (special controls). The special control is FDA's guidance document entitled “Class II Special Controls Guidance Document: Gene Expression Profiling Test System for Breast Cancer Prognosis.” See § 866.1(e) for the availability of this guidance document.