Evaluating markers of epithelial-mesenchymal transition to identify cancer patients at risk for metastatic disease.
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.
Department of Epidemiology, University of North Carolina at Chapel Hill, McGavran-Greenberg Hall, CB #7435, Chapel Hill, NC, 27599, USA.|Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.|Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
Evan L
EL
Busch
Department of Medicine, University of North Carolina at Chapel Hill, 4157 Bioinformatics Building, CB #7555, Chapel Hill, NC, 27599, USA.
Temitope O
TO
Keku
Department of Epidemiology, University of North Carolina at Chapel Hill, McGavran-Greenberg Hall, CB #7435, Chapel Hill, NC, 27599, USA.
David B
DB
Richardson
Translational Pathology Laboratory, University of North Carolina at Chapel Hill, 919 Brinkhous-Bullitt, CB #7525, Chapel Hill, NC, 27599, USA.
Stephanie M
SM
Cohen
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 450 West Drive, CB #7295, Chapel Hill, NC, 27599, USA.
David A
DA
Eberhard
Department of Epidemiology, University of North Carolina at Chapel Hill, McGavran-Greenberg Hall, CB #7435, Chapel Hill, NC, 27599, USA.
Christy L
CL
Avery
Department of Epidemiology, University of North Carolina at Chapel Hill, McGavran-Greenberg Hall, CB #7435, Chapel Hill, NC, 27599, USA. rsandler@med.unc.edu.|Department of Medicine, University of North Carolina at Chapel Hill, 4157 Bioinformatics Building, CB #7555, Chapel Hill, NC, 27599, USA. rsandler@med.unc.edu.
Robert S
RS
Sandler
D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D015820:Cadherins / Q000032:analysis; D015179:Colorectal Neoplasms / Q000401:mortality / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000473:pathology*; D016016:Proportional Hazards Models; D012307:Risk Factors; D000071250:Snail Family Transcription Factors; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000032:analysis
D014408:Biomarkers, Tumor; D015820:Cadherins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors
Diagnosis; Epithelial-mesenchymal transition; Metastasis; Outcomes; Risk; Stratification