PURPOSE: To evaluate the predictive value of the disintegrin and metalloproteinases, ADAM-9, ADAM-10, ADAM-11, and ADAM-12, and of the matrix metalloproteinases, MMP-2 and MMP-9, in patients with recurrent breast cancer treated with tamoxifen. EXPERIMENTAL DESIGN: A retrospective study was done on 259 frozen specimens of estrogen receptor-positive primary breast carcinomas from patients who developed recurrent disease and were treated with tamoxifen as the first line of therapy. The expression levels of the biological factors were assessed by real-time quantitative reverse transcriptase PCR. RESULTS: Using log-transformed continuous variables, increasing levels of ADAM-9 [odds ratio (OR) = 1.41; P = 0.015] and decreasing levels of MMP-9 (OR, 0.81; P = 0.035) predicted favorable disease control independent from the traditional predictive factors. Furthermore, when tumors were dichotomized at the median level of 70% tumor cell nuclei, our univariate analysis showed particularly strong results for the group of 153 patients with primary tumors containing 30% or more stromal cells. Although estrogen receptor levels lost their predictive power for this group of patients, high levels of ADAM-9 (OR, 1.59; P = 0.007) and ADAM-11 (OR, 1.65; P = 0.001) were significantly associated with a higher efficacy of tamoxifen therapy. CONCLUSIONS: Our results show that especially for primary tumors containing stromal elements, the assessment of mRNA expression levels of ADAM-9 and ADAM-11 could be useful to identify patients with recurrent breast cancer who are likely to benefit or fail from tamoxifen therapy.

ADAM Proteins/*genetics/metabolism, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Hormonal/therapeutic use, Breast Neoplasms/*drug therapy/genetics/metabolism, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Matrix Metalloproteinase 2/genetics/metabolism, Matrix Metalloproteinase 9/genetics/metabolism, Middle Aged, Multivariate Analysis, Neoplasm Recurrence, Local, Predictive Value of Tests, Prognosis, RNA, Messenger/genetics/metabolism, Receptors, Estrogen/*genetics/metabolism, Receptors, Progesterone/genetics/metabolism, Retrospective Studies, Reverse Transcriptase Polymerase Chain Reaction, Survival Analysis, Tamoxifen/*therapeutic use
dx.doi.org/10.1158/1078-0432.CCR-05-0560, hdl.handle.net/1765/13955
Clinical Cancer Research
Erasmus MC: University Medical Center Rotterdam

Sieuwerts, A.M, Meijer van Gelder, M.E, Timmermans, M.A, Trapman, A.M, Garcia, R.R, Arnold, M, … Foekens, J.A. (2005). How ADAM-9 and ADAM-11 differentially from estrogen receptor predict response to tamoxifen treatment in patients with recurrent breast cancer: a retrospective study. Clinical Cancer Research, 11(20), 7311–7321. doi:10.1158/1078-0432.CCR-05-0560