Favorable prognostic value of tissue human kallikrein 11 (hk11) in patients with ovarian carcinoma

Human kallikrein II (hKII/trypsin-like serine protease/ TLSP, encoded by the KLKII gene) is a member of the kallikrein family of secreted serine proteases. Recently, we developed a highly sensitive and specific immunoassay for hKII and found that this protease is expressed in the prostate, stomach and trachea as well as in amniotic fluid and milk of lactating women. Elevated serum hKII levels were found in 60% of men with prostate cancer and 70% of women with ovarian cancer. Also, hKII expression was found to be under the regulation of steroid hormones, particularly estrogens, at the level of KLKII transcription. We hypothesized that hKII may be implicated in endocrine-related malignancies and serve as a novel prostate and ovarian cancer serological marker. The aim of our study was to examine if hKII expression in ovarian tumors bears any prognostic significance. The concentration of hKII (ng per mg of total protein) in 104 ovarian tumor cytosolic extracts was quantified and correlated with clinicopathologic variables and outcome over a median follow-up period of 67 months. Outcome was defined as progression-free survival (PFS) and overall survival (OS). hKII concentration in ovarian tumor cytosols ranged from 0-21 ng/mg of total protein, with a median of 0.54 ng/mg. An optimal cutoff value of 0.54 ng/mg was selected to categorize tumors as hKII-positive or -negative. hKII-positive tumors were more frequently associated with early stage (Stage I/II) disease, pre-/peri-menopausal status and patients who exhibited complete or partial response to chemotherapy (p < 0.05). Univariate analysis revealed that patients with hKII-positive tumors had a significantly decreased risk of relapse with a hazard ratio (HR) of 0.45 (p = 0.007) and death (HR of 0.34, p = 0.005). Cox multivariate analysis indicated that hKII was an independent prognostic indicator of OS (HR of 0.41, p = 0.025). Kaplan-Meier survival curves further confirmed that women with hKll-positive tumors have longer PFS and OS (p = 0.005 and p = 0.003, respectively). Similarly, in the subgroup of patients with grade I-2 tumors, hKII-positivity was associated with higher OS in both univariate and multivariate analysis (HR of 0.23 and 0.17, p < 0.05). Finally, in women with optimal debulking after surgery (< 1 cm residual tumor), hKII positivity was associated with a slower disease progression. These results indicate that hKII is a novel, independent marker of favorable prognosis in patients with ovarian cancer. (C) 2003 Wiley-Liss, Inc.