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Abstract P3-05-15: TP53 mutation and nestin protein expression patterns affect the outcome of patients with triple negative breast cancer (TNBC)

Background-aim: Nestin has recently been proposed as an ideal positive biomarker for calling basal-like breast cancer (BL). BL and TNBC overlap in 70-80% of cases and, although very heterogeneous at the genomic and phenotypic levels, most of these carry TP53 mutations. Herein, we investigated the effect of TP53 mutations and Nestin expression on the outcome of early high-risk TNBC patients who had received adjuvant chemotherapy (anthracyclines and/or taxanes). Methods: TP53 mutations were assessed in 190 FFPE TNBC DNA samples with massive parallel sequencing (entire coding region) in Ion Torrent PI chips. Variant calling and annotation (Ion Reporter 1.6) was followed by stringent read quality filtering (p<0.001). Deleterious and hot-spot mutations (Ingenuity & Oncomine databases) in 183 informative tumors were accepted for analysis. Nestin protein expression was examined by immunohistochemistry (IHC) in 283 centrally assessed TNBC on tissue microarrays; positivity was set at 1% of cells regardless of staining intensity. Further BL and TNBC related IHC markers were also examined. Results: Nestin was expressed in 134/283 tumors (47.3%), more frequently in BL-TNBC (CK5+ and/or EGFR+, Fisher's exact p<0.001) and in highly proliferative tumors (p<0.001), while it was positively associated with high tumor grade (p = 0.017) and with P-cadherin IHC (p = 0.001). TP53 mutations were observed in 141/183 tumors (77%), out of which 30 carried truncating TP53 mutations (21.3%) and 59 double damaging mutations (41.8%) usually at similar coverage; among these, truncating mutations occurred in 16 cases. TP53 mutations were more common in BL-TNBC (p = 0.029). Double mutations were positively associated with E- and P-cadherin protein expression (p = 0.016 and p = 0.020, respectively) Although TP53 mutations in general and the presence of double mutations were not associated with p53 IHC, tumors with truncating mutations were almost exclusively p53 IHC negative (p<0.001) in line with the detection capacity of the employed antibody. As single markers, neither Nestin nor TP53 mutations (any pattern) had significant effects on patient outcome. When combined, a DFS-related interaction between Nestin and double TP53 mutations was observed (Wald's p = 0.016). Nestin positive tumors with double TP53 mutations (n = 22) conferred median DFS of 45 mo. This interval was significantly shorter as compared to that of patients with Nestin positive tumors without double TP53 mutations (n = 62; median DFS 56 mo; HR 2.2; 95%CI 1-4.5; p = 0.045) and Nestin negative tumors with double TP53 mutations (n = 25) that were associated with the most favorable DFS (median: 66 mo; HR 4; 95%CI 1.3-12.4; p = 0.016). Nestin negative tumors without double TP53 mutations performed similarly to both positive tumors, although not statistically significant. Conclusions: The presence of double TP53 mutations in TNBC may reflect the genetic instability and heterogeneity characterizing these tumors. This feature in combination with the putative cancer stem cell and BL marker Nestin seems to aggravate the outcome of TNBC patients treated with standard adjuvant chemotherapy regimens. These novel findings might be worthy pursuing for validation in larger patient series.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-05-15.