Lack of relationship between TIMP-1 tumour cell immunoreactivity, treatment efficacy and prognosis in patients with advanced epithelial ovarian cancer

Abstract

Background: Tissue inhibitor of metalloproteinase 1 (TIMP-1) is a natural inhibitor of the matrix metalloproteinases (MMPs) which are proteolytic enzymes involved in degradation of extracellular matrix thereby favoring tumour cell invasion and metastasis. TIMP-1 activity in tumour tissue may therefore play an essential role in the progression of a malignant tumour.The primary aim of the present study was to evaluate TIMP-1 protein immunoreactivity in tissue from primary ovarian cancer patients and associate these findings with the course of the disease including response to treatment in the individual patient.

Methods: TIMP-1 was assessed by immunohistochemistry (in tissue micro arrays) in a total of 163 ovarian cancer specimens obtained from primary debulking surgery during 1991-1994 as part of a randomized clinical protocol.

Results: Positive TIMP-1 immunoreactivity was found in 12.3% of the tumours. The median survival time for the 143 patients with TIMP-1 negative tumours was 23.7 months [19.0-29.4] 95% CI, while the median survival time for the 20 patients with TIMP-1 positive tumours was 15.9 months [12.3-27.4] 95% CI. Although a difference of 7.8 months in median overall survival in favor of the TIMP-1 tumour negative patients was found, this difference did not reach statistical significance (p = 0.28, Kaplan-Meier, log-rank test). Moreover, TIMP-1 immunoreactivity was not associated with CA125 response (p = 0.53) or response at second look surgery (p = 0.72).

Conclusion: TIMP-1 immunoreactivity in tumour tissue from patients with primary epithelial ovarian cancer did not correlate with patient survival or response to combination platinum/cyclophosphamide therapy.

Figure 1

TMA used for TIMP-1 immunohistochemistry

Figure 2

TIMP-1 immunohistochemical staining. A. Negative TIMP-1 staining (X200): Serous adenocarcinoma with staining intensity=0 (absent) and percentage positive cells =0 (no tumor cells with staining). B. Negative TIMP-1 staining (X200): Serous adenocarcinoma with staining intensity=1 (weak) and percentage positive cells =2 (between >10% and 25% tumor cells with staining). C. Negative TIMP-1 staining (X200): Serous adenocarcinoma with staining intensity=2 (moderate) and percentage positive cells =1 (between >0% and 10% tumor cells with staining). D. Positive TIMP-1 staining (X200): Serous adenocarcinoma with staining intensity=2 (moderate) and percentage positive cells =4 (>50% tumor cells with staining). E. Positive TIMP-1 staining (X200): Serous adenocarcinoma with staining intensity=3 (strong) and percentage positive cells =3 (between >25% and 50% tumor cells with staining).

Figure 3

Kaplan Meier Overall Survival (OS) curves and TIMP-1. Median OS for patients with TIMP-1 negative tumours (N = 139): 23.7 months [19.0-29.4] 95% CI. Median OS for patients with TIMP-1 positive tumours (N = 21): 15.9 months [12.3-27.4] 95% CI.