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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 patient's 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

The MammaPrint service is a microarray based gene expression analysis of a tumor. The analysis is based on several processes: isolation of RNA from frozen turnor 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).

Here's a breakdown of the acceptance criteria and the study information for the MammaPrint® device, based on the provided text:

MammaPrint® Device Performance Study Analysis

1. Acceptance Criteria and Reported Device Performance

The provided document primarily focuses on demonstrating substantial equivalence to a predicate device (Agendia BV's MammaPrint (K070675)) rather than setting explicit, quantifiable clinical acceptance criteria for de novo approval. However, it does present analytical performance targets relative to the predicate and clinical outcomes from supporting studies.

Here's a table summarizing the implicit acceptance criteria (based on predicate performance) and the reported device performance from the analytical studies:

2. Sample Size and Data Provenance for Test Set (Analytical Performance)

• Precision Evaluation (Method Validation):
  • Sample Size: 3 samples with different outcome levels (high, low, borderline) were run repeatedly over 20 days. Two replicates per sample level per day. Also included High Risk Control (HRC) and Low Risk Control (LRC). Total 120 (3 samples x 2 replicates x 20 days), plus controls.
  • Data Provenance: Not explicitly stated, but likely internal laboratory data from Agendia BV. Retrospective, as these were established samples.
• LD and HD Microarray Comparison:
  • Sample Size: 98 historical MammaPrint service samples.
  • Data Provenance: Samples from the period 2004 through 2007. Origin country is not explicitly stated in this section, but the company is based in the Netherlands. This is retrospective data.
• Scanner Performance Comparison:
  • Sample Size: 26 newly hybridized slides (representing 104 samples). This included three samples with varying risk profiles, repeated, and LRC/HRC controls.
  • Data Provenance: Likely internal laboratory data from Agendia BV. Retrospective.

For Clinical Performance, the document refers to four published studies. These studies serve as the clinical evidence for the device's utility, rather than a single "test set" in the context of analytical validation. The details provided are for each study:

• Nature Paper (1): 78 patients
• NEJM Paper (2): 151 patients
• MammaPrint Paper (3): Not a clinical study for patient outcomes, focuses on reproducibility of (1) and (2).
• Transbig Paper (4): 302 patients

The provenance of these clinical studies would generally be international (e.g., European for Transbig). All are retrospective analyses of patient cohorts.

3. Number of Experts and Qualifications for Ground Truth (Test Set)

For the analytical performance studies, "ground truth" refers to the known characteristics of the samples (e.g., whether they were designed to be high, low, or borderline risk, or previously classified by the predicate device). No human experts are used to establish ground truth in these analytical comparisons; instead, it relies on the pre-determined characteristics of the control samples or the results from the predicate device.

For the extensive clinical studies referenced (Nature, NEJM, Transbig), the ground truth for patient outcomes (e.g., metastasis-free survival) would have been established through long-term clinical follow-up by medical professionals, including oncologists and pathologists. The number and specific qualifications of these experts are not detailed in this 510(k) summary, as it refers to published peer-reviewed literature. Typically, these studies involve panels of clinicians (e.g., pathologists, oncologists) determining initial diagnosis and patient outcomes.

4. Adjudication Method for the Test Set

• Analytical Performance: No adjudication method as human interpretation is not involved in comparing array results or scanner outputs. The comparisons are quantitative.
• Clinical Performance (Referenced Studies): The 510(k) summary does not detail the specific adjudication methods used in the referenced clinical studies (e.g., for outcome endpoints like metastasis). Such details would typically be found within the full publications.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No MRMC study is mentioned or implied. MammaPrint is a gene expression profiling test, which is an automated, quantitative assay. Human readers do not directly interpret the "cases" (gene expression profiles) in the same way they would an image. The device provides a quantitative risk score (Low Risk, High Risk) that physicians use to make decisions, but the device itself does not involve human interpretation for its output. Therefore, a study demonstrating how human readers improve with AI vs. without AI assistance is not applicable here.

6. Standalone Performance Study

Yes, the entire submission describes the standalone performance of the MammaPrint device (the algorithm/system itself) in classifying tissue samples as High Risk or Low Risk based on gene expression profiles. The analytical performance metrics (precision, reproducibility, classification accuracy) are all measures of the algorithm's performance in isolation from human interpretation.

7. Type of Ground Truth Used

• Analytical Performance:
  • Known outcome levels for control samples (high, low, borderline).
  • Results from the predicate device (FDA cleared Low Density microarray).
• Clinical Performance (Referenced Studies):
  • Long-term clinical follow-up data: Metastasis-free survival.
  • Clinicopathological factors (e.g., tumor size, lymph node status, age).

8. Sample Size for the Training Set

The document mentions: "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 "template" of 44 tumors appears to be a core component of the algorithm's development.

The broader clinical studies referenced (e.g., Nature Paper (1) with 78 patients) were likely instrumental in the initial development and refinement (training) of the 70-gene profile itself. The MammaPrint Paper (3) describes the "Development of MammaPrint" and "Converting a breast cancer microarray signature into a high-throughput diagnostic test," implying further training and optimization steps using data from earlier studies.

Therefore, the initial "training set" for defining the gene profile involved patient cohorts (e.g., the 78 patients in the Nature paper, or the 44 specific "good clinical outcome" tumors).

9. How the Ground Truth for the Training Set Was Established

For the "44 tumors with a known good clinical outcome" that form the template, the "known good clinical outcome" would have been established through:

• Long-term clinical follow-up: Patients whose tumors formed this template would have had a prolonged period without recurrence or distant metastasis.
• Clinicopathological data: Standard clinical assessments (e.g., pathology reports, surgical findings) would have confirmed the characteristics of these tumors and the patients' disease stage.

For the broader training of the 70-gene profile, as implied by the referenced papers, the ground truth was established by:

• Clinical outcome data: Patients were followed for several years (e.g., 5-10 years) to determine their metastasis-free survival or overall survival.
• Pathology: Original biopsy/surgical pathology diagnoses, including tumor type, grade, and lymph node status, were used.
• Expert Consensus: While not explicitly stated for individual training cases in this summary, the clinical outcomes and pathological assessments that defined "good clinical outcome" and "poor clinical outcome" would have been made by qualified medical professionals (pathologists, oncologists).

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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

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.

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MammaPrint® is a qualitative in vitro diagnostic test service, performed in a single laboratory, using the gene expression profile of fresh frozen 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 who are lymph node negative. The MammaPrint® result is indicated for use by physicians as a prognostic marker only. along with other clinicopathological factors.

The MammaPrint® test is performed and provided as a service by Agendia Laboratory. The test is a microarray based gene expression analysis of RNA extracted from breast tumor tissue. The test is a custom-designed array chip manufactured by Agilent Technologies using the Agilent oligonucleotide microarray platform which assesses the mRNA expression of the 70 genes in triplicate. The MammaPrint® microarray features eight 1900-feature subarrays per glass slide which can each be individually hybridized. Per subarray 232 reporter genes are printed in triplicate, including the 70 genes which make up the MammaPrint® prognostic profile. Each subarray additionally includes 915 normalization genes and 289 spots for hybridization and printing quality control.

The analysis is based on several processes: isolation of RNA from frozen tumor tissue sections, DNAse treatment of isolated RNA, linear amplification and labeling of DNAse treated RNA, cRNA purification, hybridization of the cRNA to the MammaPrint® microaray, 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, Low Risk Borderline, High Risk Borderline).

Here's a detailed breakdown of the acceptance criteria and the study that proves the MammaPrint® device meets them, based on the provided text:

Acceptance Criteria and Reported Device Performance

Study Details for Clinical Performance (TRANSBIG Study)

2. Sample Size Used for the Test Set and Data Provenance:

• Sample Size: 302 patients
• Data Provenance: Retrospective, from five European centers (Villejuif, France; Stockholm, Sweden; Saint-Cloud, France; London, U.K.; Oxford, U.K.). No US patients were included.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Their Qualifications:
The document does not explicitly state the number or specific qualifications of experts used to establish the "ground truth" (i.e., metastasis events or metastasis-free survival) for the TRANSBIG test set. However, it mentions:

• "Paraffin embedded tumor samples from this validation series were independently evaluated." This implies a pathologist, but no specific number or qualifications are given.
• Clinical outcome (metastatic disease within 5 or 10 years) is an objective outcome and generally requires clinical follow-up data, not primary expert interpretation of the initial diagnostic material in the way an imaging study would.

4. Adjudication Method for the Test Set:
The document does not explicitly describe an adjudication method (like 2+1 or 3+1 consensus) for establishing the ground truth outcomes (metastasis events) in the TRANSBIG study. The outcome data appears to be based on observed clinical events over time.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, and the Effect Size:

• No, an MRMC comparative effectiveness study was not done in the context of comparing human readers with and without AI assistance.
• The MammaPrint® is a standalone gene expression profiling test, not a tool for human readers to interpret clinical images or data with AI assistance.
• The study did report an unadjusted hazard ratio for time to distant metastases of 2.32 (95% CI: 1.35 to 4.00), which reflects the standalone performance of the gene signature in predicting outcomes, not its assistive effect on human readers. When adjusted for clinical factors (Adjuvant online), the hazard ratio was 2.13 (95% CI: 1.19 to 3.82). This indicates the gene signature provides additional prognostic information beyond standard clinical factors.

6. If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done:

• Yes, a standalone performance study was done. The entire clinical validation (TRANSBIG study) describes the performance of the MammaPrint® algorithm (the 70-gene signature) without human interpretation in the loop. The device directly outputs a "Low Risk" or "High Risk" classification. The hazard ratios and NPV/PPV values directly reflect this standalone performance.

7. The Type of Ground Truth Used:

• The primary ground truth for the clinical studies (especially TRANSBIG) was outcomes data and pathology. Specifically, the ground truth was the occurrence or non-occurrence of distant metastasis within specific timeframes (5 and 10 years) and the pathology confirmation of breast cancer.

8. The Sample Size for the Training Set:

• Nature Paper (1): 78 patients
• This paper describes the "Development of breast cancer prognosis 70-gene profile."

9. How the Ground Truth for the Training Set Was Established:

• The Nature paper (1) description states it was for "Development of breast cancer prognosis 70-gene profile." While the specific methodology for establishing ground truth isn't detailed in this summary, typically for such studies, it would involve adjudicated clinical outcomes (e.g., metastasis-free survival status) confirmed through patient follow-up and medical records, often correlating with pathology reports for initial diagnosis and tumor characteristics. The mention of "metastasis risk" directly implies reliance on long-term clinical outcome data.

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