ELEVATED NM23 PROTEIN EXPRESSION IS CORRELATED WITH DIMINISHED PROGRESSION-FREE SURVIVAL IN PATIENTS WITH EPITHELIAL OVARIAN-CARCINOMA

Objectives: The role of the candidate metastasis-suppressor gene nm23- H1 first characterized in breast cancer remains controversial, with bo th metastasis suppression and disease progression being linked to elev ated nm23-H1 gene expression in different human tumor types. We sought to characterize (1) the pattern and intensity of nm23-H1/nucleoside d iphosphate (NDP) kinase expression in human epithelial ovarian carcino ma (EOC) and (2) the relationship between nm23-H1/NDP kinase expressio n and tumor extent at diagnosis (FIGO stage) and response to treatment as defined by progression-free survival and actuarial survival. Metho ds: Twenty-four patients with EOC aged 61.1 +/- 13.0 (mean +/- SD) yea rs were followed for 614.0 +/- 289.7 days after a debulking procedure, cisplatin-based chemotherapy (19 of 24), and second-look laparotomy ( 9 of 24). After the primary debulking procedure, 63% of patients had n o or microscopic residual disease. Overnight incubation of formalin-fi xed tumor sections at 4 degrees C with primary rabbit polyclonal IgG a ntibody to human nm23-H1/NDP kinase was followed by detection with sta ndard ABC method. Nonimmune rabbit serum and normal breast tissue serv ed as controls. Immunohistochemical staining was graded by a clinicall y blinded observer for intensity of staining (0, negative; 1, weak; 3, strong), pattern of staining (focal or diffuse), and histologic grade of tumor (1 through 4). Results: Of the EOCs, 54% were histologic gra de 3 or 4 and 58% were PICO stage III; 88% (21 of 24) stained positive ly, and 18 of 21 stained strongly and 14 of 21 stained diffusely. No c orrelation was found between either intensity or pattern of nm23-H1/ND P kinase immunostaining and histologic grade. No correlation was found between either staining pattern or intensity and FIGO stage. There wa s a trend toward decreased actuarial survival with both focal pattern (P = 0.12, log-rank test) and strong intensity (P = 0.15, log-rank tes t) of nm23-H1 staining. Decreased progression-free survival was likewi se correlated with focal nm23-H1/NDP kinase immunostaining pattern (P = 0.02, log-rank test) and strong intensity of nm23-H1/NDP kinase stai ning (P = 0.08, log-rank test). Conclusions: Expression of nm23-H1/NDP kinase is strongly upregulated in most EOCs. Redundant overexpression of nm23-H1/NDP kinase may contribute to deranged cell cycle progressi on and EOC proliferation. Pattern and intensity of nm23-H1/NDP kinase immunostaining of EOC tissue retrieved at primary operation may identi fy patients at risk for tumor progression and help guide treatment str ategies. These findings suggest that nm23-H1 gene expression may have distinct if not opposite biologic functions in EOC and breast carcinom a. (C) 1996 Academic Press, Inc.