Coexpression of HER-2/neu and p53 in breast cancer identifies a subset with an aggressive biopathological profile.

AIMS AND BACKGROUND: Amplification/overexpression of HER-2/neu and inactivation of p53 may be reliable parameters for the prognostic assessment of breast carcinomas. Several studies have addressed the prognostic significance of simultaneous expression of these gene abnormalities with controversial results. METHODS: In this study we analyzed the biopathological profile of 45 breast cancers with both HER-2/neu and p53 overexpression and compared their features with those of 45 randomly selected cases negative for these gene products. RESULTS: Tumors with HER-2/neu and p53 coexpression were found in younger patients, were more often multifocal and/or multicentric, were poorly differentiated in 55% of cases and lymph node-positive in 57%, showing a statistically significant difference compared to tumors with neither alteration (11% and 28%, respectively). Moreover, they were prevalently negative for estrogen (71% vs 22%) and progesterone receptors (78% vs 40%) and showed a higher proliferative activity. CONCLUSIONS: Our data demonstrate that the coexpression of p53 and HER-2/neu is an additive effect in terms of genetic instability reflected by both morphological and biological adverse features; patients with such coexpression should be assigned to specific therapeutic and follow-up protocols.

Detection of HER-2/neu (c-erbB-2) overexpression and amplification in breast carcinomas with ambiguous immunohistochemical results. A further contribution to defining the role of fluorescent in situ hybridization.

BACKGROUND: The assessment of HER-2/neu status is a prerequisite in the clinical management of patients with breast cancer in order to obtain prognostic and predictive information, including Herceptin sensitivity. Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) are the techniques recommended to detect HER-2/neu alterations and considerable attention is currently being focused on the standardization of these techniques. Intrinsic limitations of IHC, such as antigen preservation and antibody specificity, may make it difficult to score the membrane staining thereby resulting in inconclusive results. PATIENTS AND METHODS: In this study, 65 invasive breast carcinomas, with doubtful IHC results using the monoclonal antibody CB11, were reanalyzed with two recently licensed assays, the Hercep Test (IHC) and the Path Vision (FISH). RESULTS: IHC with Hercep Test detected HER-2 protein overexpression in 72% of cases, including nine (14%) strongly positive (3+), 13 (20%) medium positive (2+) and 25 (38%) weakly positive (1+) specimens. FISH testing, with interpretable results in 48 cases, showed a moderate HER-2 gene amplification in only 22% of carcinomas with 2+ or 3+ overexpression. CONCLUSION: These data indicated an excessive sensitivity of the Hercep Test and suggested that, in the case of indeterminate results after standard IHC, the FISH technique is the best approach to establish HER-2 status.

HER2 overexpression as a predictive marker in a randomized trial comparing adjuvant cyclophosphamide/methotrexate/5-fluorouracil with epirubicin in patients with stage I/II breast cancer: long-term results.

BACKGROUND: HER2 overexpression/amplification has been reported to be a predictor of prognosis in breast cancer and a potential marker for selecting the optimal adjuvant chemotherapy. PATIENTS AND METHODS: HER2 expression and its interaction with treatment were retrospectively evaluated in 266 of 348 patients in a trial comparing adjuvant CMF (cyclophosphamide/methotrexate/5-fluorouracil) with weekly epirubicin in stage I/II breast cancer. HER2 expression was determined by immunohistochemistry (IHC) using the monoclonal antibody CB11. Initially, any cell showing definite membrane staining was counted, and HER2 overexpression was analyzed as a continuous variable and as a dichotomous variable, with a cutoff of > 50% of positively stained cells. Subsequently, the same slides were reanalyzed with the HercepTest. RESULTS: Of the 266 tumors immunostained for HER2, 34% exhibited nearly homogeneous staining with > 50% positive cells. When the HercepTest was applied, 8% of tumors were IHC 3+ and 8% were IHC 2+. At 8 years, no statistically significant difference in relapse-free survival (RFS) and overall survival (OS) was observed between the treatment arms in patients with low versus high HER2 overexpression, although the number of events is low. The OS was statistically shorter in patients with high HER2 overexpression in the CMF arm, whereas no difference was observed in the epirubicin arm, suggesting that patients whose cancer overexpresses HER2 could benefit more from anthracycline-based therapy. CONCLUSION: HER2 overexpression was associated with a poorer OS but not a poorer RFS. However, a Cox regression model did not confirm the prognostic role of HER2 for OS.

Biopathologic profile of breast cancer core biopsy: is it always a valid method?

For breast cancer management biopathologic profile and particularly the expression of estrogen receptor (ER) and progesterone receptor (PR) is considered essential. In advanced cases, core biopsy results are the only data available. To evaluate reliability of data, results of ER, PR, MIB1, p53 and c-erbB2 on core biopsy were compared with those on surgical specimens. Results showed a statistically significant concordance for ER and PR in pT1 but not in pT2 tumors, possibly due to breast cancer heterogeneity. MIB1 results were worse with no significant concordance even for pT1 group. There was statistically significant concordance in pT1 and pT2 groups for p53 and c-erbB 2, probably due to the high number of negative cases for these markers. We recommend more core biopsies for larger tumors since core biopsy has a high probability for giving unreliable data in these cases. In conclusion, this study showed that core biopsy has a high probability for not very reliable data in bigger tumors where the results obtained might be the only data available. A higher number of core biopsy is recommended in those cases.

Primary cutaneous leiomyosarcoma: a clinicopathological and immunohistochemical study of 7 cases.

Primary cutaneous leiomyosarcomas are rare tumors, few series being reported in the current literature. A retrospective study of 7 cases was undertaken to understand the clinicopathological characteristics of these neoplasms and some of their molecular mutations. Histologically, a well-differentiated proliferation of cells of smooth muscle derivation was evident in all cases. The number of mitoses was considered the most important criterion of malignancy (more than 2 for 10 HPF). Smooth muscle actin, desmin, and vimentin were positive in all cases. Immunohistochemical analysis also revealed a positivity for p53 in 3 cases and no reaction for retinoblastoma protein. Research for Epstein-Barr virus was negative in all cases. Three patients developed local recurrences owing to incomplete surgical excision. Recurrent tumors were more atypical and located deeper. No distant metastases were observed. Our results emphasize that cutaneous leiomyosarcomas have an indolent biological course if treated by surgical excision with wide margins. Molecular abnormalities involving tumor suppressor genes are probably involved.

The clinical relevance of Bcl-2, Rb and p53 expression in advanced non-small cell lung cancer.

PURPOSE: The aim of this study was to evaluate the impact of Bcl-2, retinoblastoma (Rb) and p53 proteins on overall survival of 102 patients with locally advanced and metastatic NSCLC who underwent cisplatin-based chemotherapy. MATERIALS AND METHODS: Paraffin-embedded bronchial biopsy and fine-needle biopsy specimens were evaluated by an immunostaining method. RESULTS: Median age of analyzed patients was 61 years. Male/female ratio was 88/14. There were 10 (10%) patients with stage IIIA, 37 (36%) with stage IIIB and 55 (54%) with stage IV NSCLC. Only 15 (15%) tumor specimens had no detectable alterations for analyzed factors. Forty-six samples (45%) had positive immunostaining for p53, 61 (60%) had negative immunostaining for Rb and 8 (8%) had positive immunostaining for Bcl-2. Median and 5-year survival of analyzed population was 12 months and 6%, respectively. In univariate analysis Bcl-2 overexpression, stage (III versus IV) and normal lactate dehydrogenase (LDH) serum levels were associated with better overall survival (P<0.02, 0.001 and 0.03). In multivariate analysis, only stage was identified as an independent predictive factor. CONCLUSION: High frequency of Rb and Bcl-2 loss was detected in patients with advanced NSCLC. P53, Rb and Bcl-2 have not been shown to be independent predictors of survival even if Bcl-2 might have a particular relevance in patients with advanced NSCLC and should be better explored in this setting.

The correlation of protein peroxidation with morphological changes in experimental oestradiol-induced carcinogenesis.

Oestradiol-induced male Syrian hamster carcinogenesis is a well-known experimental model of human cancer of the breast, ovary and uterus. The pathomechanism postulated in this model is 4-hydroxylation of oestradiol and further free radical formation. The same process is suspected in human breast cancer. Dynamic changes in protein peroxidation were reported during the tumour induction. In this paper we try to correlate the protein peroxidation markers with the histopathological progression of the changes. The biochemical and histopathological evaluations were performed after 1, 3, 6 and 9 months of the hormone exposition. Significant protein peroxidation was observed as soon as after 1 month and increased further until the 6th month. After 9 months however, it was not significantly different from the control. The discrete histopathological changes after 1 month, progressed into tubular and interstitial hyperplasias after 3 and 6 months. After 9 months several dysplastic areas, sometimes with features of carcinoma in situ, were observed. The severe 9-month histopathological changes did not correlate with the protein peroxidation.

Relevance of p53, bcl-2 and Rb expression on resistance to cisplatin-based chemotherapy in advanced non-small cell lung cancer.

PURPOSE: Tumors with p53 overexpression have been associated with enhanced resistance to cisplatin-based chemotherapy in a few and small studies involving non-small cell lung cancer. The relationships and interactions between p53, Rb and bcl-2 immunostaining, clinical parameters and response to cisplatin-based chemotherapy were evaluated in the present study. EXPERIMENTAL DESIGN: Histological specimens obtained by bronchial or fine-needle biopsy from patients who underwent cisplatin-based chemotherapy between 1992 and 1999 were evaluated by immunostaining. RESULTS: There were 102 patients, 88 men. Median age was 63 years; 47 had stage III and 55 stage IV disease. Forty-six tumor samples (45%) had positive immunostaining for p53, 61 (59%) had negative immunostaining for Rb and 8 (8%) had positive immunostaining for bcl-2. The response rate of the group with p53 positive immunostaining was 26% versus 57% of the p53 negative group (P=0.004). In multivariate analyses p53 positive immunostaining was identified as an independent predictive factor for resistance to cisplatin-based chemotherapy (P=0.006). CONCLUSIONS: Our study confirmed an association of p53 immunostaining and response rate of patients treated with cisplatin-based chemotherapy.