title: Prognostic significance of TIMP-2, MMP-2, and MMP-9 on high-grade serous ovarian carcinoma using digital image analysis.
abstract: The objective of this cohort study was to evaluate whether the immunohistochemical expression of tissue inhibitor of metalloprotease 2, matrix metalloproteinase (MMP) 2, and MMP-9 could predict the occurrence of death and progression in women with ovarian high-grade serous carcinoma (HGSC). A total of 100 women with primary HGSC who were treated by cytoreductive surgery and adjuvant chemotherapy at the Centre Hospitalier Universitaire de Québec (Canada) were included. Biomarker expression was evaluated by immunohistochemistry on tissue microarrays constructed from primary tumors. Immunostaining quantification was performed using digital image analysis, from algorithms created with Calopix software, and continuous H-score data were obtained. The cancer antigen-125 and/or the Response Evaluation Criteria In Solid Tumors criteria were used to define progression. Dates of death were obtained by record linkage with the Québec mortality files. Hazard ratios (HRs) of death and progression with their 95% confidence intervals (CIs) were estimated using the Cox proportional hazards regression model. Overall, a low variability of expression was observed for each marker. No association was found between the level of expression and standard prognostic factors. When assessed as a continuous variable, increased MMP-9 expression (10 units of H-score) was associated with death (HR, 1.08; 95% CI, 1.01-1.16; P = .02), but not with progression (HR, 1.03; 95% CI, 0.97-1.10; P = .29). There was no association between the expression of MMP-2 or tissue inhibitor of metalloprotease 2 and death or progression. In conclusion, in a homogeneous cohort of women with HGSC, increased MMP-9 tissue expression, as assessed by automated immunostaining quantification, was associated with a higher risk of death.
authors.affiliation: Laval University Cancer Research Center, Hôtel-Dieu-de-Québec, Centre Hospitalier Universitaire (CHU) de Québec, Québec, Québec, Canada, G1R 2 J6; Anatomic Pathology and Cytology Department, Hôpital du St-Sacrement, Centre Hospitalier Universitaire (CHU) de Québec, Laval University, Québec, Québec, Canada, G1S 4 L8.
authors.forename: Patrice
authors.initials: P
authors.lastname: Desmeules
authors.affiliation: Laval University Cancer Research Center, Hôtel-Dieu-de-Québec, Centre Hospitalier Universitaire (CHU) de Québec, Québec, Québec, Canada, G1R 2 J6; Department of Pathology, Centre Hospitalier Universitaire de Montréal, Montreal, Québec, Canada, H2X 3 J4; The Research Centre of the University of Montreal Teaching Hospital (CR-CHUM)/Montreal Cancer Institute, Montreal, Québec, Canada, H2X 0A9; Department of Pathology and Cellular Biology, University of Montreal, Montreal, Québec, Canada, H3T 1 J4. Electronic address: dominique.trudel.chum@ssss.gouv.qc.ca.
authors.forename: Dominique
authors.initials: D
authors.lastname: Trudel
authors.affiliation: Laval University Cancer Research Center, Hôtel-Dieu-de-Québec, Centre Hospitalier Universitaire (CHU) de Québec, Québec, Québec, Canada, G1R 2 J6.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Turcotte
authors.affiliation: Department of Pathology, Centre Hospitalier Universitaire de Montréal, Montreal, Québec, Canada, H2X 3 J4; Department of Pathology and Cellular Biology, University of Montreal, Montreal, Québec, Canada, H3T 1 J4.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sirois
authors.affiliation: Laval University Cancer Research Center, Hôtel-Dieu-de-Québec, Centre Hospitalier Universitaire (CHU) de Québec, Québec, Québec, Canada, G1R 2 J6; Gynecologic Oncology Division, Centre Hospitalier Universitaire (CHU) de Québec, L'Hôtel-Dieu-de-Québec, Québec, Québec, Canada, G1R 2 J6.
authors.forename: Marie
authors.initials: M
authors.lastname: Plante
authors.affiliation: Gynecologic Oncology Division, Centre Hospitalier Universitaire (CHU) de Québec, L'Hôtel-Dieu-de-Québec, Québec, Québec, Canada, G1R 2 J6.
authors.forename: Jean
authors.initials: J
authors.lastname: Grégoire
authors.affiliation: Gynecologic Oncology Division, Centre Hospitalier Universitaire (CHU) de Québec, L'Hôtel-Dieu-de-Québec, Québec, Québec, Canada, G1R 2 J6.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Renaud
authors.affiliation: Laval University Cancer Research Center, Hôtel-Dieu-de-Québec, Centre Hospitalier Universitaire (CHU) de Québec, Québec, Québec, Canada, G1R 2 J6.
authors.forename: Michèle
authors.initials: M
authors.lastname: Orain
authors.affiliation: Laval University Cancer Research Center, Hôtel-Dieu-de-Québec, Centre Hospitalier Universitaire (CHU) de Québec, Québec, Québec, Canada, G1R 2 J6; Anatomic Pathology and Cytology Department, Hôpital du St-Sacrement, Centre Hospitalier Universitaire (CHU) de Québec, Laval University, Québec, Québec, Canada, G1S 4 L8.
authors.forename: Bernard
authors.initials: B
authors.lastname: Têtu
authors.affiliation: Laval University Cancer Research Center, Hôtel-Dieu-de-Québec, Centre Hospitalier Universitaire (CHU) de Québec, Québec, Québec, Canada, G1R 2 J6.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bairati
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D015331:Cohort Studies; D003952:Diagnostic Imaging / Q000379:methods; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008875:Middle Aged; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D046888:Tissue Array Analysis / Q000379:methods; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C560823:TIMP2 protein, human; D019716:Tissue Inhibitor of Metalloproteinase-2; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: Digital image analysis; Immunohistochemistry; Matrix metalloproteinases; Ovarian serous carcinoma; Prognosis