Abstract
Most cancer deaths are due to metastases. Markers of epithelial-mesenchymal transition (EMT) measured in primary tumor cancer cells could be helpful to assess patient risk of metastatic disease, even among those otherwise diagnosed with local disease. Previous studies of EMT markers and patient outcomes used inconsistent methods and did not compare the clinical impact of different expression cut points for the same marker. Using digital image analysis, we measured the EMT markers Snail and E-cadherin in primary tumor specimens from 190 subjects in tissue microarrays from a population-based prospective cohort of colorectal cancer patients and estimated their associations with time-to-death. After measuring continuous marker expression data, we performed a systematic search for the cut point for each marker with the best model fit between dichotomous marker expression and time-to-death. We also assessed the potential clinical impact of different cut points for the same marker. After dichotomizing expression status at the statistically-optimal cut point, we found that Snail expression was not associated with time-to-death. When measured as a weighted average of tumor cores, low E-cadherin expression was associated with a greater risk of dying within 5 years of surgery than high expression (risk difference = 33 %, 95 % confidence interval 3–62 %). Identifying a clinically-optimal cut point for an EMT marker requires trade-offs between strength and precision of the association with patient outcomes, as well as consideration of the number of patients whose treatments might change based on using the marker at a given cut point.
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Acknowledgments
This research was funded in part by Grants from the National Institutes of Health (P30 DK034987, U01 CA93326). The Translational Pathology Laboratory is supported in part by grants from the National Cancer Institute (3P30CA016086) and the University of North Carolina at Chapel Hill University Cancer Research Fund. ELB was supported in part by a Grant from the National Cancer Institute (5T32CA009001).
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
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Busch, E.L., Keku, T.O., Richardson, D.B. et al. Evaluating markers of epithelial-mesenchymal transition to identify cancer patients at risk for metastatic disease. Clin Exp Metastasis 33, 53–62 (2016). https://doi.org/10.1007/s10585-015-9757-7
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DOI: https://doi.org/10.1007/s10585-015-9757-7