Three-dimensional pathological size assessment in primary breast carcinoma.

Maximal tumor diameter (MD) is traditionally an important prognostic factor in breast cancer. It must be questioned, however, how well a one-dimensional parameter alone can represent the actual morphologic condition of a three-dimensional body. Along with the pathologically assessed MD and two perpendicular diameters (PDs) of a lesion, eccentricity (EF) and the three-dimensional parameters tumor volume (TV) and surface area (TSA) of 395 ductal invasive breast carcinomas of limited size (10-40 mm) were calculated. The dependent prognostic variable was axillary lymph node involvement (ALNI). MD, TV and TSA area were highly significant predictors of ALNI; these variables had similar levels of prediction accuracy (univariate analyses: MD: P = 0.0003, TV: P = 0.0009, TSA: P < 0.0001; multivariate analyses: MD: P = 0.0018, TV: P = 0.0109, TSA: P = 0.0009; pseudo R-squared values: MD: 0.42, TV: 0.39, TSA: 0.39). Despite certain variations in tumor shape, TV and TSA with similar MD, there is no evidence that three-dimensional pathologic measurements (TV/TSA) are more precise prognostic predictors of ALNI compared to the one-dimensional measurement alone.

Low E2F1 transcript levels are a strong determinant of favorable breast cancer outcome.

INTRODUCTION: We investigated whether mRNA levels of E2F1, a key transcription factor involved in proliferation, differentiation and apoptosis, could be used as a surrogate marker for the determination of breast cancer outcome. METHODS: E2F1 and other proliferation markers were measured by quantitative RT-PCR in 317 primary breast cancer patients from the Stiftung Tumorbank Basel. Correlations to one another as well as to the estrogen receptor and ERBB2 status and clinical outcome were investigated. Results were validated and further compared with expression-based prognostic profiles using The Netherlands Cancer Institute microarray data set reported by Fan and colleagues. RESULTS: E2F1 mRNA expression levels correlated strongly with the expression of other proliferation markers, and low values were mainly found in estrogen receptor-positive and ERBB2-negative phenotypes. Patients with low E2F1-expressing tumors were associated with favorable outcome (hazard ratio = 4.3 (95% confidence interval = 1.8-9.9), P = 0.001). These results were consistent in univariate and multivariate Cox analyses, and were successfully validated in The Netherlands Cancer Institute data set. Furthermore, E2F1 expression levels correlated well with the 70-gene signature displaying the ability of selecting a common subset of patients at good prognosis. Breast cancer patients' outcome was comparably predictable by E2F1 levels, by the 70-gene signature, by the intrinsic subtype gene classification, by the wound response signature and by the recurrence score. CONCLUSION: Assessment of E2F1 at the mRNA level in primary breast cancer is a strong determinant of breast cancer patient outcome. E2F1 expression identified patients at low risk of metastasis irrespective of the estrogen receptor and ERBB2 status, and demonstrated similar prognostic performance to different gene expression-based predictors.

Correlation and significance of histopathological and clinical features in breast cancer with skin involvement (T4b).

A retrospective review was performed to investigate the prognostic significance and validity of the pathological and clinical TNM staging of noninflammatory skin involvement in breast cancer. In 128 tumors with histologically proven skin involvement and a size up to 5 cm (64% of the entire group), we distinguished clearly between group A) cases showing the classical clinical signs (cT4b) and those that do not, and between group B) carcinomas infiltrating the epidermis (pT4b) and those infiltrating only the dermis. We found only moderate concordance (kappa = 0.44) between the pathological and clinical TNM staging system. In the analysis of 80 patients with a tumor size from 2.1 to 5.0 cm, neither the appearance of classical clinical signs nor the histological diagnosis of infiltration of the epidermis was shown to be a relevant factor. In comparison to the control groups, similar clinicopathologic entities without significant differences in long-term outcome were observed. After regrouping of the patients having tumor infiltration of the papillary dermis from the control group into the study group (pT4), the study group showed a significant higher number of involved axillary lymph nodes (P = .014) and a more extensive lymph node involvement (pN3; P = .025). The combination epidermis-papillary dermis seems to be more a functional unit than the epidermis alone that is defined as the crucial and delineating factor in the TNM Classification. Our results challenge the validity of the TNM rules and recommendations concerning T4b breast cancer because it leads, in the majority of cases, to tumors of comparable extent and prognosis being placed in different categories.

Prognostic relevance of gene amplifications and coamplifications in breast cancer.

Multiple different oncogenes have been described previously to be amplified in breast cancer including HER2, EGFR, MYC, CCND1, and MDM2. Gene amplification results in oncogene overexpression but may also serve as an indicator of genomic instability. As such, presence of one or several gene amplifications may have prognostic significance. To assess the prognostic importance of amplifications and coamplifications of HER2, EGFR, MYC, CCND1, and MDM2 in breast cancer, we analyzed a breast cancer tissue microarray containing samples from 2197 cancers with follow-up information. Fluorescence in situ hybridizations revealed amplifications of CCND1 in 20.1%, HER2 in 17.3%, MDM2 in 5.7%, MYC in 5.3%, and EGFR in 0.8% of the tumors. All gene amplifications were significantly associated with high grade. HER2 (P < 0.001) and MYC amplification (P < 0.001) were also linked to shortened survival. In case of HER2, this was independent of grade, pT, and pN categories. MYC amplification was almost 3 times more frequent in medullary cancer (15.9%), than in the histologic subtype with the second highest frequency (ductal; 5.6%; P = 0.0046). HER2 and MYC amplification were associated with estrogen receptor/progesterone receptor negativity (P < 0.001) whereas CCND1 amplification was linked to estrogen receptor/progesterone receptor positivity (P < 0.001). Coamplifications were more prevalent than expected based on the individual frequencies. Coamplifications of one or several other oncogenes occurred in 29.6% of CCND1, 43% of HER2, 55.7% of MDM2, 65% of MYC, and 72.8% of EGFR-amplified cancers. HER2/MYC-coamplified cancers had a worse prognosis than tumors with only one of these amplifications. Furthermore, a gradual decrease of survival was observed with increasing number of amplifications. In conclusion, these data support a major prognostic impact of genomic instability as determined by a broad gene amplification survey in breast cancer.

Implant-based breast reconstruction using a titanium-coated polypropylene mesh (TiLOOP Bra): a multicenter study of 231 cases.

BACKGROUND: An alternative to implant-based breast reconstruction using acellular dermal matrix is the use of a titanium-coated polypropylene mesh. The mesh was approved for implant-based breast reconstruction in Europe in 2008, but only limited clinical data are available. METHODS: Two hundred seven patients (231 breasts) with skin-sparing/nipple-sparing or modified radical mastectomy and immediate or delayed implant-based breast reconstruction using titanium-coated polypropylene mesh were evaluated retrospectively. The primary endpoints were identification of patient-related and surgical factors that were predictive for an adverse outcome and the development of recommendations for patients eligible for implant-based breast reconstruction using the mesh. Complications were divided into major (need for additional surgery), minor (conservative treatment), and implant loss. Univariate and multivariate logistic regression analyses were performed to determine the influence of the patient- and procedure-related characteristics on postoperative complications and implant loss. RESULTS: No risk factors were observed for patient-associated complications. Major complications occurred in 13.4 percent, minor complications in 15.6 percent, and implant loss in 8.7 percent of patients. Univariate analysis revealed procedure-related risk factors for postoperative complications with a bilateral procedure (p = 0.013) or skin expansion before implant surgery (p = 0.043). Multivariate analysis confirmed these risk factors and revealed an increased risk for implant loss in patients with skin necrosis (p < 0.001) and capsule fibrosis (p < 0.001). CONCLUSIONS: This titanium-coated polypropylene mesh shows acceptable complication rates and can be a helpful device in implant-based breast reconstruction. The mesh should only be used in primary cases and, when adhering to the proposed indications, is a safe and convenient option in implant-based breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Non-inflammatory skin involvement in breast cancer, histologically proven but without the clinical and histological T4 category features.

BACKGROUND: The study evaluates characteristics and prognostic significance of breast cancer with histologically proven non-inflammatory skin involvement but without the clinical and histological features that are mandatory for inclusion in the T4 category. METHODS: We compared retrospectively the clinical course of 55 patients with this clinico-pathologic entity to the outcome of a control group of 309 consecutive patients with tumors of the same size but without skin involvement. The median follow-up time was 6.6 years in the study and 8.4 years in the control group. Two subsets were analyzed: (A) 1.1-2.0 cm (T1c); (B) 2.1-5.0 cm (T2). RESULTS: The distribution of TNM stages within Study Group A was: Stage I: 28.6%, Stage II: 61.9%, Stage III: 9.5%. The distribution within Study Group B was: Stage II: 67.7%, Stage III: 23.5%, and Stage IV: 8.8%. Differences in disease-specific survival (DSS) between study and control groups were not significant. In multivariate analysis, skin involvement was not a significant variable, while lymph node involvement was found to be significant for worse outcome (Group A: HR=3.99 [1.33-12.05], P=0.014; Group B: HR=2.37 [1.37-4.08], P=0.002). CONCLUSION: Breast carcinomas with histologically proven skin involvement without the clinical and histological correlate are a heterogeneous group of cases, but the majority of the patients have Stage I/II disease. While lymph node involvement had a most significant effect on DSS, skin involvement was not a significant prognostic factor. Physicians must be aware of this clinico-pathologic entity in order not to misclassify these cases as T4 and consider them falsely as being locally advanced breast cancer.

A new approach in breast cancer with non-inflammatory skin involvement.

The widely accepted image of breast cancer with non-inflammatory skin involvement (T4b) is determined by the tenet that all these tumors are locally advanced (Stage IIIB). The study addresses the question whether this view is justified. Data from 453 non-metastatic breast cancer patients were collected retrospectively. Eighty-one patients had T4b disease. To assess the malignant potential of tumors independent of the feature skin involvement, a reclassification only considering tumor size was undertaken. We compared the clinical course of three study groups (A: Stage II; B: Stage IIIA; C: Stage IIIC) with control groups of 372 patients without skin involvement. In the study groups, we found a broad distribution among the stages (A:36.2%; B:33.7%; and C:27.7%) with significant differences in disease-specific survival (DSS) (A/B: p = 0.032; B/C: p = 0.048). There were no significant differences in DSS between the study and the corresponding control group. In multivariate analysis, skin involvement was not a significant predictor of DSS. Heterogeneity of the T4b category and a lack of prognostic significance expand the widely accepted image of breast cancer with non-inflammatory skin involvement. The highest T category, or Stage III, is not the appropriate classification for a considerable number of patients having this clinicopathologic entity.

Breast carcinoma with noninflammatory skin involvement (T4b): time to abandon an historic relic from the TNM classification.

BACKGROUND: In this study, the authors evaluated the clinical presentation of patients with T4b breast carcinoma, analyzed the impact of noninflammatory skin involvement on long-term survival, and addressed the question whether the T4 tumor category still has any justification. METHODS: The clinical course of a study group of 119 patients with skin involvement was compared with the outcome of a control group of 299 consecutive patients who had tumors of the same size but without skin involvement. All tumors were stratified into 1 of 4 subsets according to greatest tumor dimension, as follows: Group A, < or = 3.0 cm; Group B, 3.1-5.0 cm; Group C, 5.1-10.0 cm; and Group D, > 10.0 cm. RESULTS: The study group distribution of patients within the size subsets were as follows: Group A, 26.1%; Group B, 24.3%; Group C, 26.1%; and Group D, 23.5%. Differences in disease-specific survival between the tumor size subsets were significant (Groups A and B vs. Groups C and D; P < 0.0001). In contrast to large tumors (> 5.0 cm), carcinomas < or = 5.0 cm showed no statistical significant differences in disease-specific survival between study group patients and control group patients (Group A: P = 0.17; Group B: P = 0.31). CONCLUSIONS: There is a broad range of clinicopathologic breast carcinoma entities within the T4b category. For > 50% of patients with T4b breast carcinoma, the feature noninflammatory skin involvement had no significant prognostic impact. Approximately 25% of patients had an extent of disease similar to that observed in patients with Stage I-II disease and, thus, falsely were considered to have more advanced disease. Heterogeneity and a lack of prognostic significance suggest that a revision of the T4 category, a relic of historic tumor classifications, is necessary.

Expression of cytokeratins 17 and 5 identifies a group of breast carcinomas with poor clinical outcome.

While several prognostic factors have been identified in breast carcinoma, the clinical outcome remains hard to predict for individual patients. Better predictive markers are needed to help guide difficult treatment decisions. In a previous study of 78 breast carcinoma specimens, we noted an association between poor clinical outcome and the expression of cytokeratin 17 and/or cytokeratin 5 mRNAs. Here we describe the results of immunohistochemistry studies using monoclonal antibodies against these markers to analyze more than 600 paraffin-embedded breast tumors in tissue microarrays. We found that expression of cytokeratin 17 and/or cytokeratin 5/6 in tumor cells was associated with a poor clinical outcome. Moreover, multivariate analysis showed that in node-negative breast carcinoma, expression of these cytokeratins was a prognostic factor independent of tumor size and tumor grade.

Telomerase as a prognostic marker in breast cancer: high-throughput tissue microarray analysis of hTERT and hTR.

Telomerase activity (TA) has been shown to correlate with poor clinical outcome in various tumour entities, indicating that tumours expressing this enzyme may be more aggressive and that TA may be a useful prognostic marker. For breast cancer, however, TA is a controversial prognostic marker; whereas some studies suggest an association between TA and disease outcome, others do not find this association. This study used tissue microarrays (breast carcinoma prognosis arrays) containing 611 samples (each 0.6 mm in diameter) from the tumour centre of paraffin-embedded breast carcinomas to analyse the catalytic subunit of telomerase, human telomerase reverse-transcriptase (hTERT), and the internal RNA component (hTR), which are the core components of the telomerase holoenzyme complex. hTERT protein expression was obtained by immunohistochemistry (human anti-telomerase antibody Ab-2, Calbiochem), and hTR RNA was measured by radioactive in situ hybridization. hTERT and hTR expression were determined semi-quantitatively and graded (scores 1-4). Clinical data, such as histological subtype, pT stage, tumour diameter, pN stage, BRE grade, tumour-specific survival (in months), patient's age and others, were available for statistical analysis. A statistically significant correlation was found between tumour-specific survival (overall survival) and hTERT expression (p < 0.0001) or hTR expression (p = 0.00110). Tumours with higher scores (scores 3, 4) for hTR and/or hTERT were associated with a worse prognosis. In multivariate analysis, hTERT expression was an independent prognostic factor. Previous studies, focusing on analysis of TA in smaller numbers of fresh-frozen breast carcinomas by the TRAP assay, gave controversial results with respect to TA as a prognostic marker. Using tissue microarrays from 611 breast carcinomas, this study has demonstrated that increased expression levels of the telomerase core components, hTERT and hTR, are associated with lower overall survival. These findings suggest that TA should be included in future validation studies as a prognostic marker in breast cancer.