Molecular alterations in key-regulator genes among patients with T4 breast carcinoma

Abstract

Background: Prognostic factors in patients who are diagnosed with T4 breast carcinomas are widely awaited. We here evaluated the clinical role of some molecular alterations involved in tumorigenesis in a well-characterized cohort of T4 breast cancer patients with a long follow-up period.

Methods: A consecutive series of 53 patients with T4 breast carcinoma was enrolled between 1992 and 2001 in Sardinia, and observed up for a median of 125 months. Archival paraffin-embedded tissue sections were used for immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analyses, in order to assess alterations in expression levels of survivin, p53, and pERK1-2 proteins as well as in amplification of CyclinD1 and h-prune genes. The Kaplan-Meier and Cox regression methods were used for survival assessment and statistical analysis.

Results: Overall, patients carrying increased expression of pERK1-2 (p = 0.027) and survivin (p = 0.008) proteins as well as amplification of h-prune gene (p = 0.045) presented a statistically-significant poorer overall survival in comparison with cases found negative for such alterations. After multivariate analysis, the pathological response to primary chemotherapy and the survivin overexpression in primary carcinoma represented the main parameters with a role as independent prognostic factors in our series.

Conclusions: Although retrospective, our study identified some molecular parameters with a significant impact on prediction of the response to therapy or prognosis among T4 breast cancer patients. Further large prospective studies are needed in order to validate the use of such markers for the management of these patients.

Figure 1

Immunohistochemistry and FISH analysis. (Up-middle) Typical examples of T4 breast carcinoma tissue sections positive (left) or negative (right) for p53, pERK_1-2, and survivin protein expression. (Bottom) Typical examples of double-colour FISH results. Nuclei extracted from paraffin-embedded tissues after hybridization with probes specific for cyclinD1 or h-prune loci (red signals) and control chromosome centromeres (green signals).

Figure 2

Comparison between molecular markers and survivals among T4 breast cancer patients. (A) Overall survival curves based on the Kaplan-Meier method. Statistical comparison between observed and predicted survival data for each subset of patients [with (+) or without (-) alterations in expression of p53, pERK_1-2 and survivin proteins or in copy number of h-prune and cyclinD1 genes) is reported. (B) Median disease-free and overall survivals (DFS and OS, respectively), expressed in months, for each subset of patients.