Search Results

The CellSearch® Circulating Tumor Cell Kit is intended for the enumeration of circulating tumor cells (CTC) of epithelial origin (CD45-, EpCAM+, and cytokeratins 8, 18+, and/or 19+) in whole blood. The presence of CTC in the peripheral blood, as detected by the CellSearch® Circulating Tumor Cell Kit, is associated with decreased progression free survival and decreased overall survival in patients treated for metastatic breast, colorectal or prostate* cancer. The test is to be used as an aid in the monitoring of patients with metastatic breast, colorectal or prostate cancer. Serial testing for CTC should be used in conjunction with other clinical methods for monitoring metastatic breast, colorectal and prostate cancer. Evaluation of CTC at any time during the course of disease allows assessment of patient prognosis and is predictive of progression free survival and overall survival.

*Metastatic prostate cancer patients in this study were defined as having two consecutive increases in the serum marker PSA above a reference level, despite standard hormonal management. These patients are commonly described as having androgen-independent, hormone-resistant, or castration-resistant prostate cancer.

The CellSearch® Circulating Tumor Cell Kit contains a ferrofluid-based capture reagent and immunofluorescent reagents. The ferrofluid reagent consists of small particles with a magnetic core surrounded by a polymeric layer coated with antibodies targeting the EpCAM antigen for capturing CTC. After immunomagnetic capture and enrichment, fluorescent reagents are added for identification and enumeration of CTC. The fluorescent reagents include the following: anti-CK-Phycoerythrin (PE) specific for the intracellular protein cytokeratin (characteristic of epithelial cells), DAPI, which stains the cell nucleus, and anti-CD45-Allophycocyanin (APC) specific for leukocytes.

The reagent/sample mixture is dispensed by the CellTracks® AutoPrep® System into a cartridge that is inserted into a MagNest® cell presentation device. The strong magnetic field of the MagNest® device attracts the magnetically labeled epithelial cells to the surface of the cartridge. The CellTracks Analyzer II® or CellSpotter® Analyzer automatically scans the entire surface of the cartridge, acquires images and displays any event to the user where CK-PE and DAPI fluorescence are co-located. Images are presented to the user in a gallery format for final classification. An event is classified as a tumor cell when its morphological features are consistent with that of a tumor cell and it exhibits the phenotype EpCAM+, CK+, DAPI+ and CD45-.

The provided document (K103502) describes a 510(k) submission for a modified CellSearch® Circulating Tumor Cell Kit. However, it does not contain a study with acceptance criteria and a detailed report of device performance against those criteria in the way typically expected for a new or significantly modified device efficacy trial.

Instead, this 510(k) is a Special 510(k), which is submitted when there are minor changes to a legally marketed device that do not affect the intended use, fundamental scientific technology, mode of operation, or specimen type. In this particular case, the changes were labeling changes to assist the operator.

Therefore, the submission demonstrates equivalence to the predicate device (K073338) through verification of labeling specifications for the modified device and labeling process validation, rather than through a new clinical study with performance metrics against acceptance criteria.

Due to the nature of this particular 510(k) submission, many of the requested details about a clinical study, such as sample size, ground truth establishment for test and training sets, expert adjudication, and MRMC studies, are not present in the provided text.

Here's a breakdown of the available information:

1. A table of acceptance criteria and the reported device performance:

2. Sample size used for the test set and the data provenance:

• Not applicable / Not provided. The submission focused on equivalence based on labeling and process validation, not a new clinical performance study.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

• Not applicable / Not provided. No new clinical test set requiring expert ground truth was described.

4. Adjudication method for the test set:

• Not applicable / Not provided.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

• No. This device is for circulating tumor cell enumeration, not an imaging device requiring human reader interpretation in the context of an MRMC study comparing AI assistance. The CellTracks Analyzer II® or CellSpotter® Analyzer presents images to the user for final classification, but the 510(k) does not detail MRMC studies for this specific change.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:

• Not explicitly stated as a new study for this 510(k). The device involves an automated process for capture, enrichment, and initial scanning, with a user performing final classification. The submission focuses on the impact of labeling changes, not on a standalone algorithm performance study.

7. The type of ground truth used:

• Not applicable / Not provided for this specific 510(k). For the original predicate device, the "ground truth" for CTC identification would likely be based on the biological markers detected (EpCAM+, CK+, DAPI+, CD45-) and morphological features recognized by trained operators. However, this 510(k) does not present new performance data.

8. The sample size for the training set:

• Not applicable / Not provided. No new algorithm training was described for this submission.

9. How the ground truth for the training set was established:

• Not applicable / Not provided.

In summary: K103502 is a Special 510(k) for minor labeling changes to an already cleared device. It establishes substantial equivalence by demonstrating that these changes do not affect the device's fundamental performance, rather than by presenting new clinical performance data from a dedicated study with specific acceptance criteria and detailed methodologies for establishing ground truth, sample sizes, or reader studies. The "study" proving the device meets acceptance criteria in this context is the verification of labeling specifications and validation of the labeling process, demonstrating that the modified device remains functionally identical to the predicate.

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The CellSearch™ Circulating Tumor Cell Kit is intended for the enumeration of circulating tumor cells (CTC) of epithelial origin (CD45-, EpCAM+, and cytokeratins 8, 18+, and/or 19+) in whole blood.

The presence of CTC in the peripheral blood, as detected by the CellSearch™ Circulating Tumor Cell Kit, is associated with decreased progression free survival and decreased overall survival in patients treated for metastatic breast, colorectal or prostate* cancer. The test is to be used as an aid in the monitoring of patients with metastatic breast, colorectal or prostate cancer. Serial testing for CTC should be used in conjunction with other clinical methods for monitoring metastatic breast, colorectal and prostate cancer. Evaluation of CTC at any time during the course of disease allows assessment of patient prognosis and is predictive of progression free survival and overall survival.

*Metastatic prostate cancer patients in this study were defined as having two consecutive increases in the serum marker PSA above a reference level, despite standard hormonal management. These patients are commonly described as having androgen-independent, hormone-resistant, or castration-resistant prostate cancer.

The CellSearch" Circulating Tumor Cell Kit contains a ferrofluid-based capture reagent and immunofluorescent reagents. The ferrofluid reagent consists of nanoparticles with a magnetic core surrounded by a polymeric layer coated with antibodies targeting the EpCAM antigen for capturing CTC. After immunomagnetic capture and enrichment, fluorescent reagents are added for identification and enumeration of CTC. The fluorescent reagents include the following: anti-CK-Phycoerythrin (PE) specific for the intracellular protein cytokeratin (characteristic of epithelial cells), DAPI which stains the cell nucleus, and anti-CD45-Allophycocyanin (APC) specific for leukocytes.

The reagent/sample mixture is dispensed by the CellTracks® AutoPrep® System into a cartridge that is inserted into a MagNest® cell presentation device. The strong magnetic field of the MagNest® device attracts the magnetically labeled epithelial cells to the surface of the cartridge. The CellTracks Analyzer II or CellSpotter® Analyzer automatically scans the entire surface of the cartridge, acquires images and displays any event to the user where CK-PE and DAPI fluorescence are co-located. Images are presented to the user in a gallery format for final classification. An event is classified as a tumor cell when its morphological features are consistent with that of a tumor cell and it exhibits the phenotype EpCAM+, CK+, DAPI+ and CD45 -.

Here's an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided text:

Device: CellSearch™ Circulating Tumor Cell Kit (expanded indications for use in Metastatic Prostate Cancer)

1. Table of Acceptance Criteria and Reported Device Performance:

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The CellSearch™ Circulating Tumor Cell Kit is intended for the enumeration of circulating tumor cells (CTC) of epithelial origin (CD45-, EpCAM+, and cytokeratins 8, 18+, and/or 19+) in whole blood.

The presence of CTC in the peripheral blood, as detected by the CellSearch™ Circulating Tumor Cell Kit, is associated with decreased progression free survival and decreased overall survival in patients treated for metastatic breast or metastatic colorectal cancer. The test is to be used as an aid in the monitoring of patients with metastatic breast or metastatic colorectal cancer. Serial testing for CTC should be used in conjunction with other clinical methods for monitoring breast and colorectal cancer. Evaluation of CTC at any time during the course of disease allows assessment of patient prognosis and is predictive of progression free survival and overall survival.

The CellSearch" Circulating Tumor Cell Kit contains a ferrofluid-based capture reagent and immunofluorescent reagents. The ferrofluid reagent consists of nanoparticles with a magnetic core surrounded by a polymeric layer coated with antibodies targeting the EpCAM antigen for capturing CTC. After immunomagnetic capture and enrichment, fluorescent reagents are added for identification and enumeration of CTC. The fluorescent reagents include the following: anti-CK-Phycoerythrin (PE) specific for the intracellular protein cytokeratin (characteristic of epithelial cells), DAPI which stains the cell nucleus, and anti-CD45-Allophycocyanin (APC) specific for leukocytes.

The reagent/sample mixture is dispensed by the CellTracks® AutoPrep® System into a cartridge that is inserted into a MagNest® cell presentation device. The strong magnetic field of the MagNest® device attracts the magnetically labeled epithelial cells to the surface of the cartridge. The CellTracks® Analyzer II or CellSpotter® Analyzer automatically scans the entire surface of the cartridge, acquires images and displays any event to the user where CK-PE and DAPI fluorescence are co-located. Images are presented to the user in a gallery format for final classification. An event is classified as a tumor cell when its morphological features are consistent with that of a tumor cell and it exhibits the phenotype EpCAM+, CK+, DAPI+ and CD45 -.

Here's a breakdown of the acceptance criteria and the study details for the CellSearch™ Circulating Tumor Cell Kit, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance

The document describes several performance characteristics without explicitly stating "acceptance criteria" for each. However, the study results clearly demonstrate the device's performance in these areas.

• 1300 expected: 1215 mean observed (91-95% range)
• 325 expected: 308 mean observed (82-101% range)
• 81 expected: 85 mean observed (80-136% range)
• 20 expected: 22 mean observed (95-140% range)
• 5 expected: 7 mean observed (120-200% range)
  Linear regression: Y=0.93x + 3.87, R=0.999. |
  | Linearity/Reportable Range | Detection of CTCs should be linear over the reportable range. | Linear detection over the reportable range of 0 to 1238 tumor cells. After factoring out percent recovery, regression of observed vs. expected tumor cells yielded a slope of 1.007, an intercept of 3.0, and an R² = 0.990 (R = 0.995). |
  | Limit of Detection (LoD) | Ability to detect a low number of CTCs. | 1 CTC per 7.5 mL can be detected by the CellTracks® Analyzer II. The 7% loss in recovery does not reduce this LoD. |
  | System Reproducibility (Control) | Consistent results for control samples. | Low Control (N=99): Mean cell count 48, Total Precision Standard Deviation (% CV) 18%.
  High Control (N=99): Mean cell count 969, Total Precision Standard Deviation (% CV) 5%. |
  | System Reproducibility (Patient Samples - MBC) | Consistent results for duplicate patient samples for MBC. | MBC (N=163 duplicate samples): Regression equation Y=0.98x + 0.67, R=0.99. |
  | System Reproducibility (Patient Samples - MCRC) | Consistent results for duplicate patient samples for MCRC. | MCRC (N=1627 duplicate samples): Regression equation Y=0.98x + 0.18, R²=0.96. |
  | PFS Prediction (MCRC) | Ability to differentiate patient groups with significantly different Progression Free Survival based on CTC levels. | Baseline CTC: Median PFS significantly longer in

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The CellSearch™ Circulating Tumor Cell Kit is intended for the enumeration of circulating tumor cells (CTC) of epithelial origin (CD45-, EpCAM+, and cytokeratins 8, 18+, and/or 19+) in whole blood.

The presence of CTC in the peripheral blood, as detected by the CellSearch™ Circulating Tumor Cell Kit, is associated with decreased progression free survival and decreased overall survival in patients treated for metastatic breast cancer. The test is to be used as an aid in the monitoring of patients with metastatic breast cancer. Serial testing for CTC should be used in conjunction with other clinical methods for monitoring breast cancer. A CTC count of 5 or more per 7.5 mL of blood at any time during the course of the disease is predictive of shorter progression free survival and overall survival.

The CellSearch™ Circulating Tumor Cell Kit contains a ferrofluid-based capture reagent and immunofluorescent reagents. The ferrofluid reagent consists of nanoparticles with a magnetic core surrounded by a polymeric layer coated with antibodies targeting the EpCAM antigen for capturing CTC. After immunomagnetic capture and enrichment, fluorescent reagents are added for identification and cnumeration of CTC. The fluorescent reagents include the following: anti-CK-Phycoerythrin (PE) specific for the intracellular protein cytokeratin (characteristic of epithelial cells), DAPI which stains the cell nucleus, and anti-CD45-Allophycocyanin (APC) specific for leukocytes.

The reagent/sample mixture is dispensed by the CellTracks AutoPrep® System into a cartridge that is inserted into a MagNest® cell presentation device. The strong magnetic field of the MagNest® device attracts the magnetically labeled epithelial cells to the surface of the cartridge. The CellTracks® Analyzer II or CellSpotter® Analyzer automatically scans the entire surface of the cartridge, acquires images and displays any event to the user where CK-PE and DAPI fluorescence are co-located. Images are presented to the user in a gallery format for final classification. An event is classified as a tumor cell when its morphological features are consistent with that of a tumor cell and it exhibits the phenotype EpCAM+, CK+, DAPI+ and CD45-.

The CellSearch™_Circulating Tumor Cell Kit is intended for the enumeration of circulating tumor cells (CTC) of epithelial origin (CD45-, EpCAM+, and cytokeratins 8, 18+, and/or 19+) in whole blood. The presence of CTC in the peripheral blood, as detected by the CellSearch™_Circulating Tumor Cell Kit, is associated with decreased progression free survival and decreased overall survival in patients treated for metastatic breast cancer. The test is to be used as an aid in the monitoring of patients with metastatic breast cancer. Serial testing for CTC should be used in conjunction with other clinical methods for monitoring breast cancer. A CTC count of 5 or more per 7.5 mL of blood at any time during the course of the disease is predictive of shorter progression free survival and overall survival.

ACCECPTANCE CRITERIA

STUDY DETAILS

1. Sample size used for the test set and the data provenance:

   • Recovery and Linearity: 30 samples from 5 healthy donors. Spiked with cultured breast cancer cells (SK-BR-3).
   • Reproducibility (Patient Samples): 163 duplicate samples from 47 patients.
   • Expected Values (Control Subjects): 345 total samples (145 healthy volunteers, 101 women with non-malignant breast disease, 99 women with other non-malignant diseases).
   • Clinical Study (Metastatic Breast Cancer): 177 patients with metastatic breast cancer. Follow-up analyses had varying sample sizes at different time points (e.g., 126 at 3-5 weeks, 138 for imaging comparison).
   • Data Provenance: Retrospective for recovery, linearity, and reproducibility. Prospective, multi-center clinical trial for metastatic breast cancer patients. Country of origin not specified, but the applicant is Veridex, LLC, located in Warren, NJ, USA.

2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

   • Clinical Study (Imaging Ground Truth): Two expert radiologists initially, blinded to clinical information. A third independent radiologist adjudicated disagreements. Qualifications are not specified beyond "expert radiologists."

3. Adjudication method for the test set:

   • Imaging Ground Truth:
     • If one radiologist categorized as Indeterminate (I) and the other as Stable Disease (S), Partial Response (PR), or Progressive Disease (PD), the latter radiologist's classification was used (n=11).
     • If both radiologists categorized as Indeterminate (I), the data was not used (n=3).
     • A third independent radiologist adjudicated disagreements between the two primary readers regarding PD and NPD (n=27). If the third radiologist rendered "Indeterminate (I)", the data was not used (n=2).

4. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

   • The study did not describe an MRMC comparative effectiveness study involving AI or human readers being assisted by AI. The comparison was betweenCTC measurements and radiological assessments, primarily on their prognostic value and variability. The device is not an AI-assisted diagnostic tool for human readers but rather an automated system for CTC enumeration.

5. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:

   • Yes, the performance of the CellSearch™ system, which includes automated scanning and image acquisition (CellTracks® Analyzer II or CellSpotter® Analyzer) with user classification of events, was evaluated. The "user classification" aspect suggests a human-in-the-loop for final interpretation of events presented by the system, but the core processing and initial identification are automated. The recovery, linearity, limits of detection, and reproducibility studies assess the standalone performance of the system for enumerating CTCs.

6. The type of ground truth used:

   • Recovery & Linearity: Expected cell counts from spiked cultured breast cancer cells.
   • Reproducibility: Comparison of duplicate samples processed by the system.
   • Clinical Study:
     • Prognosis (PFS/OS): Clinical outcomes data (progression-free survival and overall survival) based on CT scans, clinical signs and symptoms, and time to death.
     • Imaging Comparison: Expert consensus of radiologists based on World Health Organization (WHO) bi-dimensional criteria for disease assessment (NPD vs. PD).

7. The sample size for the training set:

   • The document does not explicitly describe a separate "training set" for the device's development or a machine learning algorithm. The studies detailed are primarily validation studies of the device's technical performance and clinical utility.

8. How the ground truth for the training set was established:

   • Not applicable as no specific training set for a machine learning algorithm is described. The device operates based on immunomagnetic capture and fluorescent labeling with rule-based classification principles, followed by user classification, rather than being a trained AI model in the modern sense.

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The CellSearch™ Circulating Tumor Cell Kit is intended for the enumeration of circulating tumor cells (CTC) of epithelial origin (CD45-, EpCAM+ and cytokeratin 8 & 18+, and/or cytokeratin 19+) in whole blood in conjunction with the CellTracks® AutoPrep System, the CellSpotter® Analyzer or CellTracks® Analyzer II, and the CellSearch™ Circulating Tumor Cell Control Kit.

The presence of CTC in the peripheral blood, as detected by the CellSearch™ Circulating Tumor Cell Kit, is associated with decreased progression free survival and decreased overall survival in patients treated for metastatic breast cancer. A CTC count of 5 or more per 7.5 mL of blood generally is predictive of shorter progression free survival and shorter overall survival.

Not Found

This document is a 510(k) clearance letter for the CellSearch™ Circulating Tumor Cell Kit, not a study report. Therefore, it does not contain the detailed acceptance criteria and study results in the format requested. The letter confirms that the FDA has found the device to be substantially equivalent to legally marketed predicate devices.

However, I can extract what is present related to device function and some context of a study that would have been submitted to the FDA for this clearance.

Missing Information: Most of the requested information regarding detailed acceptance criteria, sample sizes, ground truth establishment, expert qualifications, adjudication methods, and MRMC study details are not available within this document. This information would typically be found in the 510(k) submission itself, which is a much larger technical dossier.

Here's what can be gathered, with the understanding that key details are absent:

1. A table of acceptance criteria and the reported device performance

• Acceptance Criteria: Not explicitly stated in the document. The clearance letter only states that the device is "substantially equivalent" to predicate devices for its intended use. This implies the device met certain performance criteria compared to the predicate, but these criteria are not itemized here.
• Reported Device Performance: The document provides the intended use and clinical significance of the device's measurements, rather than raw performance metrics.

2. Sample size used for the test set and the data provenance (e.g., country of origin of the data, retrospective or prospective)

• Sample Size: Not available in this document.
• Data Provenance: Not available in this document.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience)

• Not available in this document. Since this is an assay for enumerating circulating tumor cells using technology like immunomagnetic separation and image analysis, the "ground truth" would likely involve methods beyond just human expert review, potentially including independent staining and manual counting by trained laboratory personnel.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set

• Not available in this document.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

• This device is for automated enumeration of circulating tumor cells using an analyzer (CellSpotter® Analyzer or CellTracks® Analyzer II). While there's a human element in initiating the test and interpreting the clinical significance, it's primarily an automated system. An "MRMC study" in the traditional sense (improving human reader performance with AI) is unlikely to be directly applicable as the primary claim is the enumeration by the device. The "AI" would be embedded in the CellSpotter® Analyzer's image analysis algorithms. The document does not provide details on such a study or effect sizes.

6. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done

• Yes, the core claim is for the "CellSearch™ Circulating Tumor Cell Kit" used in conjunction with the "CellTracks® AutoPrep System, the CellSpotter® Analyzer or CellTracks® Analyzer II". This implies a standalone performance component of the automated system in enumerating CTCs. However, the exact performance metrics of this standalone component are not provided in this clearance letter. The indications for use describe the kit's function with the automated analyzers.

7. The type of ground truth used (expert concensus, pathology, outcomes data, etc)

• The "Indications for Use" mentions the device "is associated with decreased progression free survival and decreased overall survival in patients treated for metastatic breast cancer." This suggests that clinical outcomes data (progression-free survival and overall survival) were used to establish the clinical utility and significance of the CTC counts provided by the device. The "ground truth" for enumerating CTCs would typically involve orthogonal methods like manual microscopy counts by trained cytotechnologists or other validated cell counting methods, though this is not explicitly stated.

8. The sample size for the training set

• Not available in this document.

9. How the ground truth for the training set was established

• Not available in this document.

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The CellSearch™ Circulating Tumor Cell Kit is intended for the enumeration of circulating tumor cells (CTC) of epithelial origin (CD45-, EpCAM+ and cytokeratin 8 & 18+, and/or cytokeratin 19+) in whole blood in conjunction with the CellTracks® AutoPrep System, the CellSpotter® Analyzer or CellTracks® Analyzer II, and the CellSearch™ Circulating Tumor Cell Control Kit.

The presence of CTC in the peripheral blood, as detected by the CellSearch™ Circulating Turnor Cell Kit, is associated with decreased progression free survival and decreased overall survival in patients treated for metastatic breast cancer. A CTC count of 5 or more per 7.5 mL of blood generally is predictive of shorter progression free survival and shorter overall survival.

Epithelial cells are immunomagnetically labeled by targeting the Epithelial Cell Adhesion Molecule (EpCAM) antigen. Anti-EpCAM monoclonal antibodies conjugated to ferrofluid particles are colloidal and, when mixed with a sample containing the target epithelial cells, bind to the EpCAM antigen associated with the epithelial cells. After immunomagnetic selection of epithelial cells from 7.5 mL of blood. Fluorescent reagents are added at this time to discriminate between the immunomagnetically selected cells. Anti-Cytokeratin - Phycoerythrin (CK-PE) stains the intracellular cytoskeleton cytokeratin proteins expressed in cells of epithelial origin, anti-CD45-Allophycocyan (CD45-APC) stains leukocytes and DAPI stains DNA present in the cell nucleus. A strong magnetic field is applied to the processed reagent/sample mixture that causes the labeled target cells to move to the cartridge surface. The cartridge is then placed on the CellTracks® Analyzer II for data acquisition and analysis. The CellTracks® Analyzer II acquires images of PE, APC and DAPI fluorescence staining of the entire viewing surface.

After data acquisition is completed, the images are analyzed for any event where cytokeratin-PE and DAPI are within a specified space in the cartridge, i.e. indicating the possible presence of a cell with a nucleus that expresses cytokeratin. Images from each fluorescent color as well as a composite image of the cytokeratin staining (green) and the nuclear staining (purple) are presented to the user in a gallery for final cell classification. A cell is classified as a tumor cell when it its EpCAM+ (i.e., it is captured), CK+, DAPI+ and CD45-. A check mark placed by the operator next to the composite images classifies the event as a Circulating Tumor Cell (CTC) and the software tallies all the checked boxes to obtain the CTC count.

Our data demonstrate that metastatic breast cancer patients with 5 or more CTC/per 7.5 mL of blood have a significantly greater probability for shorter progression free and overall survival than patients who have fewer than 5 CTC per 7.5 mL of blood.

Response:

1. Table of Acceptance Criteria and Reported Device Performance

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