c-MET Overexpression Is Associated with Breast Cancer Distant Metastasis and Loco-Regional Recurrence
Joseph P Bergeron, Hope T Richard, Jorge A Almenara, Michael O Idowu. Virginia Commonwealth University, Richmond, VA
Background: Dysregulation of the c-Met receptor tyrosine kinase has been shown to confer resistance to DNA-damaging chemotherapeutic agents and is also associated with overall poor prognosis in a variety of tumors. Several clinical trials are currently investigating the use of novel c-Met inhibitors as a potential target for future therapeutic modalities. In particular, the agent ARQ 197 (Ds-5178) is currently being tested in a clinical trial for lung carcinoma. Currently, limited information is available on the association of c-Met overexpression with distant metastatic or recurrent disease in breast carcinomas. This study evaluated the relationship between c-Met expression and distant metastases along with a variety of other clinico-pathologic parameters including Ki-67 expression, local recurrence, triple negative hormone receptor status, and lymph node status.
Design: The clinical outcome and pathologic characteristics of breast carcinoma cases from 1992 to 2008 with adequate follow up information were reviewed. A minimum of 60 months of follow-up was required for inclusion of cases without recurrence or metastases. For each case, tissue microarrays (TMA) were created by obtaining 1 mm cores in triplicate from different areas of the tumor using an automated TMA system (Beecher ATA-27). The specimens were stained with a rabbit polyclonal antibody to c-MET (Abcam, Ma USA). Cases with moderate to intense membranous staining were considered positive. Statistical significance was determined using a Chi-squared test.
Results: Of 281 cases, 84 had distant metastases and 33 had loco-regional recurrence. The median follow-up period for all cases was 72 months, and ranged from 12 to 228 months. A greater proportion of cases with distant metastases and cases with local recurrence were associated with c-MET positivity (67 vs 17, p <0.05) and (26 vs 7, p <0.05), respectively. Additionally, c-MET positivity was associated with high Ki-67 (>30%), triple negative hormone receptor status, axillary lymph node positivity, and high histologic grade.
|c-MET pos||c-MET neg|
|% dist mets (n=84)||80% (67)||20% (17)||1.1 x 10 e-5|
|% local recur (n=33)||79% (26)||21% (7)||1.93 x 10e-5|
|% grade III (n=109)||72%(79)||28% (30)||1.98 x 10e-5|
|% high Ki67 (n=95)||75% (71)||25% (24)||3.22 x 10e-5|
|% triple neg (n=74)||66% (49)||34% (25)||7.26 x 10e-6|
|% LN pos||85% (97)||15% (17)||3.16 x 10e-7|