P4-09-21: A Novel Prognostic Marker for Triple-Negative Breast Cancers

Autor: Robin M Ciocca, Vlasta Zemba-Palko, George C. Prendergast, Jennifer L Sabol, UM Wallon, Ned Z. Carp, BS Wojciechowski
Rok vydání: 2011
Předmět:
Zdroj: Cancer Research. 71:P4-09
ISSN: 1538-7445
0008-5472
DOI: 10.1158/0008-5472.sabcs11-p4-09-21
Popis: BACKGROUND: Triple-negative breast cancers (TNBC) represent a highly aggressive form of this disease with few treatment options available. Currently, even the smallest node negative cancers are considered by many to warrant treatment with chemotherapy (CTX). While many recur early (within 2–3 years), there is a subset of long-term survivors illustrating the heterogeneity within this group. Here we report our ongoing effort to establish tissue inhibitor of metalloproteinase-4 (TIMP-4) as a prognostic marker in all early breast cancers a. While the canonical function of TIMPs is to inhibit tissue degradation, numerous reports have established that TIMPs exert tumor promoting activity. In our prospective study, we evaluated TIMP-4 as prognostic marker for TNBC and its role in disease progression. METHODS: Specimens from our retrospective and prospective cohorts were assessed by immunohistochemical staining using standard techniques and a monoclonal antibody for TIMP-4b in accordance with the IRB approved protocol. Staining intensity was documented on a scale of 0–3. No data was released to the treating physicians at the time of collection. Outcome data from a total of 240 pts was obtained through tumor registry and clinician practices. Staining intensity was then correlated with outcome to calculate sensitivity and specificity of the marker. To determine the role of TIMP-4 in TNBC cell behavior we have performed microarray analyses. The effects of TIMP-4-induced signaling were tested using invasion and clonogenic survival assays under normal growth conditions and after exposure to gamma radiation. RESULTS: Elevated TIMP-4 expression identified a high risk of relapse and short survival time with 75% sensitivity and 80% specificity. No discernable differences were noted between retrospective and prospective cohorts. Array analyses revealed activation of the PI3K/AKT pathway in the presence of TIMP-4. Furthermore, elevated TIMP-4 increased the invasive behavior of breast cancer cells in Matrigel™-coated invasion chambers and reduced sensitivity to gamma irradiation. These effects were reversible by addition of either a PI3K inhibitor or an anti-TIMP-4 antibody, suggesting their use as potential therapeutic strategies. CONCLUSIONS: On the basis of these clinical data we suggest that TIMP-4 may offer a simple prognostic marker for TNBC patients at highest risk. The presence of TIMP-4 identifies a patient population likely to recur quickly despite standard CTX treatment. Our research suggests that targeted therapy of the PI3K/AKT pathway and/or a biological therapeutic approach directed against TIMP-4 may be of benefit in this subset of pts and should be explored. Therefore, TIMP-4 testing of TNBC patients could aid in the selection of a treatment regimen to improve survival outcome. a Liss, M et.al. Am. J. Pathol. 2009 b Donover, P et.al. J. Cell. Biochem. 2010 Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-21.
Databáze: OpenAIRE
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