The prognostic potential of HER2, TP53 mutations, PAI-1 protein levels, angiogenesis and proliferation were investigated in tumours from 408 patients with early breast cancer followed >10 years. One hundred and sixty seven patients (41%) died from breast cancer.
Tumour sections were stained for HER2, CD34, and MIB-1. HER2 scores were based on staining intensity, 3+ being considered HER2+. Angiogenesis was scored by the Chalkley method. MIB-1 was evaluated using systematic random sampling. PAI-1 was measured by ELISA. TP53 mutations were evaluated by DGGE analysis and DNA sequencing.
Ninety one patients (22%) were HER2 positive. TP53 was mutated in 101 cases (25%). Median PAI-1, Chalkley and MIB-1 was 0.72 ng/mg protein (range, 0-90 ng/mg protein), 5.00 (range, 2.67-12.00) and 15% (range, 1-83%). MIB-1 was correlated with HER2+, Chalkley counts, TP53 mutations (all p <0.0001), and PAI-1 (p =0.002). In univariate analyses with DSS as endpoint, HER2+ (p <0.0001), mutated TP53 (p <0.0001), high Chalkley (p =0.008), MIB-1 (p =0.002), tumour size (p =0.008), grade (p <0.0001), negative estrogen receptor (p =0.0001), and lymph node status (p <0.0001) were prognostic markers. Among node-negative patients, HER2+ (p =0.0002), mutated TP53 (p =0.001), high PAI-1 levels (p =0.02), and grade (p =0.03) indicated poor DSS. In node-positive patients, HER2+ (p =0.0002), mutated TP53 (p <0.0001), MIB-1 (p =0.01), Chalkley scores (p =0.007), negative estrogen receptor (p <0.0001) and grade (p =0.001) indicated poor prognosis. In multivariate analysis, metastatic nodes (1-3 positive: RR 1.56 95% CI 1.02-2.38; >3 positive: RR 3.70 95% CI 2.54-5.38), HER2+ (RR 1.91, 95% CI 1.35-2.70), mutated TP53 (RR 1.70, 95% CI 1.21-2.38), PAI-1 (RR 1.04, 95% CI 1.01-1.07) and grade 3 (RR 1.96, 95% CI 1.83-3.22) were independent markers of poor outcome.
Compared to PAI-1 protein levels, Chalkley counts and MIB-1, HER2+ and mutations of TP53 were the strongest independent markers of poor prognosis irrespective of nodal status.
"HER2 overexpression/amplification is an established marker of poor prognosis in both early  and late  stage breast cancer. HER2 overexpression is also associated with an increased risk of metastasis [22,23] and a poor response to chemotherapy in the metastatic setting [24,25]. "
[Show abstract][Hide abstract] ABSTRACT: Inducible cyclooxgenase-2 (COX-2) is commonly overexpressed in breast tumors and is a target for cancer therapy. Here, we studied the association of COX-2 with breast cancer survival and how this association is influenced by tumor estrogen and HER2 receptor status and Akt pathway activation.
Tumor COX-2, HER2 and estrogen receptor α (ER) expression and phosphorylation of Akt, BAD, and caspase-9 were analyzed immunohistochemically in 248 cases of breast cancer. Spearman's correlation and multivariable logistic regression analyses were used to examine the relationship between COX-2 and tumor characteristics. Kaplan-Meier survival and multivariable Cox proportional hazards regression analyses were used to examine the relationship between COX-2 and disease-specific survival.
COX-2 was significantly associated with breast cancer outcome in ER-negative [Hazard ratio (HR) = 2.72; 95% confidence interval (CI), 1.36-5.41; comparing high versus low COX-2] and HER2 overexpressing breast cancer (HR = 2.84; 95% CI, 1.07-7.52). However, the hazard of poor survival associated with increased COX-2 was highest among patients who were both ER-negative and HER2-positive (HR = 5.95; 95% CI, 1.01-34.9). Notably, COX-2 expression in the ER-negative and HER2-positive tumors correlated significantly with increased phosphorylation of Akt and of the two Akt targets, BAD at Ser136 and caspase-9 at Ser196.
Up-regulation of COX-2 in ER-negative and HER2-positive breast tumors is associated with Akt pathway activation and is a marker of poor outcome. The findings suggest that COX-2-specific inhibitors and inhibitors of the Akt pathway may act synergistically as anticancer drugs in the ER-negative and HER2-positive breast cancer subtype.
BMC Cancer 11/2010; 10(1):626. DOI:10.1186/1471-2407-10-626 · 3.36 Impact Factor
"Tumour material was collected from two series. The first cohort consisted of 401 consecutive patients with early breast cancer diagnosed from January 1990 to 1994 and fulfilled the following criteria: having primary unilateral breast carcinoma with no clinical evidence of metastasis; availability of complete clinical, histopathological and biological information ; having no other malignancies; having received radical surgical therapy according to the DBCG89 criteria (for details, see Offersen et al.  ). "
[Show abstract][Hide abstract] ABSTRACT: p53 accumulation and TP53 mutations are known prognostic markers for breast cancer. To clarify their interrelationship and the importance of different TP53 mutation types, these markers were investigated in tumours from 630 patients with breast cancer.
Tumour sections were stained for p53 and scored based on staining intensity and percentages of invasive tumour cells with nuclear staining. TP53 mutations were identified by sequencing. Patient cohorts were from the DBCG (Danish Breast Cancer Cooperative Group) protocols DBCG82 and DBCG89.
TP53 was mutated in 29% of the patients. The disease-specific survival (DSS) at 15 years of follow-up for patients with missense mutations directly involved in DNA or zinc binding was 21+/-8%. Patients with the remaining missense mutations within the structural/conserved domains and patients with null mutations had a DSS of 36+/-6% and 31+/-17%, respectively. For patients without TP53 mutations and patients with mutations affecting amino acids outside these domains, the 15 year DSS was 51+/-3% and 71+/-10%, respectively. p53 accumulation was successfully scored in 567 patients and categorized into three groups. Tumours with no p53 expression had a high frequency of null mutations (37% compared to 10% in the whole cohort), and tumours with high p53 expression contained 82% of the missense mutations inside structural/conserved domains including those directly involved in DNA or zinc binding.
The clinical outcome for breast cancer patients is significantly different for different TP53 mutation types, but further functional studies are required to clarify the exact role of these mutation types. Most of the mutations that lead to mutant p53 protein accumulation can be detected by immunohistochemistry but the specificity is low. Samples showing lack of detectable p53 protein should be considered as an indication of a possible null mutation.
[Show abstract][Hide abstract] ABSTRACT: In advanced ovarian cancers (OCs), p53 mutations are frequently observed. The objective of this study was to explore the value of the p53 mutational status, using four different techniques, in advanced OC patients as a predictive marker for responsiveness to platinum-based chemotherapy.
One hundred and four, mostly serous papillary OC specimens were analyzed, of which all received a platinum containing chemotherapy after optimal cyto-reductive surgery. To verify the p53 mutational status, immunohistochemical staining with monoclonal antibodies, functional yeast assay (FASAY), single-strand conformation polymorphism analysis (SSCP) and genomic sequencing was performed in parallel.
Out of ten OC patients [2 low malignant potential (LMP)/8 G1] only two had a mutant p53, whereas eight showed a wild-type p53. 40 out of 63 (G2/3) patients with G2/3 OC showed mutant p53 and 23 patients showed a wild-type pattern. p53 status was significantly different between these two groups (LMP/G1 vs. G2/3) (P = 0.015). A progressive disease after chemotherapy completion was noted in 35.6% of the patients (26 out of 73); in 69.2%, a mutated p53 and in 30.8%, a wild-type p53 was found. Nine (12.3%) patients showed a complete response at the end of the first-line chemotherapy. Out of these nine patients five had a mutated and four a wild-type p53. A partial response was observed in nine (12.3%) patients of whom four had a mutated p53. With respect to response to first-line chemotherapy (six cycles of platinum containing regimen), the p53 status was not predictive; no statistical significance regarding the p53 mutational status was observed when the two extreme groups PD versus PR/CR were compared (P > 0.05).
In this study, the p53 mutational status was not predictive for responsiveness to platinum-based chemotherapy; but p53 was significantly more frequently mutated in poorly differentiated OCs.
Journal of Cancer Research and Clinical Oncology 07/2009; 136(1):79-88. DOI:10.1007/s00432-009-0639-8 · 3.08 Impact Factor
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