Yoshiatsu Sagara

Expression of maspin predicts poor prognosis in breast-cancer patients

The tumor suppressor gene maspin has been reported to inhibit the invasiveness and motility of breast cancer cells. It has been reported that maspin is expressed in normal human mammary epithelial cells but is downregulated during cancer progression, and that p53 could induce maspin expression by transcriptional activation. However, to date, the clinical significance of maspin expression and its correlation with p53 protein expression in human breast cancer patients have not been elucidated. One hundred and sixty‐eight female patients diagnosed with invasive ductal carcinoma, who had undergone a mastectomy (154 patients) or breast‐conserving surgery (14 patients), were followed up for 15–119 months (median: 87 months) postoperatively. Immunoreactivity for maspin and p53 antibodies with paraffin‐embedded carcinoma tissue was investigated using labeled streptavidin‐biotin methods. Tumors with more than 20% of positive cells were considered positive for the expression of maspin. The expression of maspin in carcinoma cells was found in 27.4% (46 of 168) and significantly correlated with larger tumor size (p = 0.008), higher histologic grade (p = 0.0001) and positive p53 status (p = 0.003). A significant inverse relationship was observed between the expression of maspin and estrogen receptor (p = 0.0004) or progesterone receptor status (p = 0.02). Univariate analysis by log‐rank test revealed a significant association between the expression of maspin and shorter relapse‐free survival (p < 0.0001) and overall survival (p < 0.0001). According to Coxs multivariate analysis, the expression of maspin had the most significant effect in relapse‐free survival (p < 0.0001) and overall survival (p < 0.0001) followed by lymph node status. In turn, the expression of maspin in 58 cases of ductal carcinoma in situ were also investigated to explore whether the downregulation of maspin through cancer progression are true or not. However, there were no positive cases in our series. These results seem to be contrary to previous reports defining maspin as a tumor suppressor gene. Although more precise characterization of the maspin expression, especially gene analysis is essential, the present investigation suggests that the expression of maspin is not downregulated through malignant progression and that the immunohistochemic detection of maspin in carcinoma cells may be helpful for selecting the group of breast cancer patients with an aggressive phenotype.

Co-expression of epidermal growth factor receptor and transforming growth factor-α predicts worse prognosis in breast-cancer patients

Epidermal growth factor receptor (EGF‐R) and its ligand, transforming growth factor‐α (TGF‐α), play an important role through the autocrine growth‐regulation system in several human cancers, including breast cancer. However, the clinical significance of co‐expression of EGF‐R and TGF‐α has not been elucidated. One hundred seventy‐three female patients diagnosed as invasive ductal carcinoma who had undergone a mastectomy (159 patients) or breast‐conserving surgery (14 patients) were followed up for 81 to 119 months (median 94 months) post‐operatively. Immunoreactivity for EGF‐R, TGF‐α, p53 and c‐erbB‐2 with paraffin‐embedded carcinoma tissue was investigated using labeled streptavidin‐biotin methods. Positive rates of carcinoma cells were 27%, 33%, 32% and 26% for EGF‐R, TGF‐α, p53 and c‐erbB‐2, respectively. Expression of EGF‐R only was observed in 16% (28/173), of TGF‐α only in 22% (38/173), of both EGF‐R and TGF‐α in 11% (19/173) and of neither in 51% (88/173). By univariate analysis, significant differences in overall survival and disease‐free survival were noted according to the co‐expression of EGF‐R and TGF‐α (p < 0.0001, p < 0.0001), co‐expression of EGF‐R and c‐erbB‐2 (p = 0.0029, p = 0.0028), nodal status (p = 0.0028, p = 0.0001), tumor size (p = 0.0001, p < 0.0001) and c‐erbB‐2 expression (p = 0.0034, p = 0.018), respectively. The status of p53 expression (p = 0.01), estrogen receptor (p = 0.042) and progesterone receptor (p = 0.046) showed significant differences in overall survival. According to Coxs multivariate analysis, co‐expression of EGF‐R and TGF‐α had the most significant effect on disease‐free survival (p < 0.0001) and overall survival (p < 0.0001), followed by nodal status. Co‐expression of EGF‐R and TGF‐α by immunohistochemical detection is an independent prognostic indicator, and it may be helpful for determining the group of breast‐cancer patients with an aggressive phenotype. Int. J. Cancer 89:484–487, 2000.

Overexpression of cyclinD1 predicts for poor prognosis in estrogen receptor‐negative breast cancer patients

CyclinD1 plays a critical role in regulating cell cycle progression. CyclinD1 mRNA and protein are overexpressed in approximately 50% of primary breast cancer cases. However, its clinical significance as a predictive factor remains unclear. One hundred and seventy‐three female patients diagnosed with invasive ductal carcinoma who had undergone a mastectomy (161 patients) or breast‐conserving surgery (12 patients) were followed up for 6–119 months (median 86 months) postoperatively. Immunoreactivity for monoclonal anti‐cyclinD1 antibody (clone DCS‐6) with paraffin‐embedded carcinoma tissues was investigated using a labeled streptavidin‐biotin method. Overexpression of cyclinD1 was found in 42% (73 of 173), and strongly correlated with estrogen receptor (ER) expression (p < 0.000001). Univariate analysis revealed no association between overexpression of cyclinD1 and overall survival or relapse‐free survival in all patient groups. However, in the ER‐negative subgroup (n = 75), overexpression of cyclinD1 was significantly correlated with shorter overall survival (p = 0.018) and relapse‐free survival (p = 0.014) as well as the lymph node status and tumor size. In contrast, there were no significant associations between overexpression of cyclinD1 and clinical outcome in the ER‐positive subgroup. According to Coxs multivariate analysis in the ER‐negative subgroup, overexpression of cyclinD1 had the most significant effect on overall survival (p = 0.02) and relapse‐free survival (p = 0.0058), followed by nodal status and histologic grade. These findings suggest that overexpression of cyclinD1 is an independent prognostic indicator in ER‐negative breast cancer patients.

Aldehyde dehydrogenase 1 expression predicts poor prognosis in triple-negative breast cancer

Ohi Y, Umekita Y, Yoshioka T, Souda M, Rai Y, Sagara Y, Sagara Y, Sagara Y & Tanimoto A
(2011) Histopathology59, 776–780

Immunohistochemical studies on oncogene products (EGF-R, c-erbB-2) and growth factors (EGF, TGF-α) in human breast cancer: their relationship to oestrogen receptor status, histological grade, mitotic index and nodal status

In this investigation, 83 human mammary carcinomas were examined for the expression of oestrogen receptor (ER), epidermal growth factor receptor (EGF-R), epidermal growth factor (EGF), transforming growth factor alpha (TGF-α), c-erbB-2, histological grade, mitotic index and nodal status, all of which are reportedly prognostically significant factors (Bloom and Richardson 1957; Baak et al. 1985; Wright et al. 1989). ER expression was biochemically recognized in 43.4% of mammary carcinomas, and EGF-R, EGF, TGF-α and c-erbB-2 were histochemically recognized in 25.3, 14.5, 27.7 and 18.0% of mammary carcinomas examined respectively, using conventional sections of buffered formalin-fixed, paraffin-embedded tissue and monoclonal or polyclonal antibodies. There were significant relationships between negative ER and positive EGF-R or TGF-α; positive EGF-R and TGF-α; positive EGF-R and c-erbB-2; and positive c-erbB-2 and TGF-α. The single changes which were the negative ER and the positive c-erbB-2 correlated with histological grade and mitotic index. Co-expression of EGF-R and TGF-α correlated with positive nodal status. Therefore, the present investigation indicates that the negative ER, single expression of c-erbB-2 and co-expression of EGF-R and TGF-α are important markers which contribute indirectly to prognosis, which reconfirms previous findings on the former two while adding the new finding that immuno-histochemical demonstration of expression of EGF-R and TGF-α may provide useful information for selecting the appropriate treatment.

Aldehyde dehydrogenase 1 expression is a predictor of poor prognosis in node-positive breast cancers: a long-term follow-up study

Yoshioka T, Umekita Y, Ohi Y, Souda M, Sagara Y, Sagara Y, Sagara Y, Rai Y & Tanimoto A
(2011) Histopathology58, 608–616
Aldehyde dehydrogenase 1 expression is a predictor of poor prognosis in node‐positive breast cancers: a long‐term follow‐up study

Expression of wild-type estrogen receptor β protein in human breast cancer: Specific correlation with HER2/neu overexpression

Expression of estrogen receptor β (ERβ) protein in human breast cancer and correlation with clinicopathological factors have been reported by many investigators, but many of them used ERβ antibodies that react with both wild‐type ERβ (ERβwt) and splicing variant isoform. Therefore, the frequency and correlation with clinicopathological factors of ERβwt expression remain to be established. In the present study a monoclonal antibody EMR02, specific for ERβwt, was used in formalin‐fixed paraffin‐embedded sections from 225 female primary breast cancer patients diagnosed as having invasive ductal carcinoma. Expression of ERα, progesterone receptor (PgR) and HER2/neu were also investigated by immunohistochemistry. For ERβwt, ERα and PgR, positivity was defined as nuclear staining in >10% of the cancer cells. HER2/neu overexpression was defined as a Hercep test score 3+. Positivity for ERβwt, ERα, PgR and HER2/neu overexpression was 55%, 74%, 61% and 25%, respectively. The expression of ERβwt had a positive correlation with ERα (P = 0.018) and PgR (P = 0.02). There was significant positive correlation between ERβwt expression and HER2/neu overexpression (P < 0.0001). According to multivariate logistic regression analysis the most significant association was between ERβwt expression and HER2/neu overexpression (P < 0.0001). These results suggest that clinical significances of ERβwt expression in human breast cancer patients may be more complex.

Estrogen Receptor Mutations and Changes in Estrogen Receptor and Progesterone Receptor Protein Expression in Metastatic or Recurrent Breast Cancer

To investigate the frequency of estrogen receptor (ER) gene mutation in metastatic or recurrent breast cancer, metastatic lymph nodes or recurrent breast cancer tissue from 35 patients with ER‐positive primary tumors were screened for mutations in the hormone‐binding domain of the ER gene by sequence analysis. Four missense mutations, Val316Ile, Gly344Val, Ala430Val and Gly494Val, were identified in these lesions. Second, to clarify whether there is any disparity in hormone receptor status between primary and metastatic or recurrent tumors, we immunohistochemically studied 117 specimens including the above 35 specimens obtained from metastatic or recurrent breast cancer patients using monoclonal anti‐ER and progesterone receptor (PgR) antibodies. Although hormone receptor status, especially ER, was highly maintained through disease progression, negative change in PgR expression at relapse (33%) was identified more frequently than in metastatic lymph nodes (6.7%). Therefore, it was suggested that development of PgR‐negative phenotype might correlate with disease progression in some breast cancer patients. These results suggest that ER mutations in metastatic or recurrent breast cancer may be more frequent than in primary lesions, irrespective of high maintenance of ER protein expression through disease progression.

Clinical significance of occult micrometastases in axillary lymph nodes in "node-negative" breast cancer patients.

The most important subgroup of breast cancer patients for whom reliable prognostic indicators are needed is women without axillary lymph node metastases. We evaluated the clinical significance of occult micrometastases in axillary lymph nodes in 148 consecutive “node‐negative” breast cancer patients. The median age of the patients at surgery was 52 years and the median follow‐up period after surgery was 98.5 months. Occult micrometastases were detected in 21 of 148 patients (14.2%) by means of immunohistochemical analysis using AE1/3 antibody and a single unstained section after routine histopathological examination. Log‐rank tests indicated that the 7–year disease‐free survival (DFS) and overall survival (OS) rates by Kaplan‐Meier methods were significantly better in patients without occult micrometastases than in patients with occult micrometastases [DFS, 93% versus 71% (P=0.0009); OS, 96% versus 76% (P=0.0001)]. According to Coxs multivariate analysis, the presence of occult micrometastases had the most significant effect on DFS (P=0.0053) and OS (P=0.0035). These findings suggest that the presence of occult micrometastases is an independent and significant predictor of clinical outcome, and that their immunohistochemical detection after routine histopathological examination is useful for selecting the “node‐negative” breast cancer patient subgroup at high risk for relapse and death.

Mucocele-like lesions of the breast: a long-term follow-up study

BackgroundMucocele-like lesions (MLL) of the breast were originally described as benign lesions composed of multiple cysts lined by uniform flat to cuboidal epithelium with extravasated mucin, but subsequent reports described the coexistence of columnar cell lesions (CCL), atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS). Several reports have investigated whether core biopsy can diagnose MLL reliably; however, there is only one report with a long-term follow-up after excision of MLL. We report here 15 surgically excised MLL with a long-term follow-up.FindingsFifteen lesions diagnosed as MLL from 13 patients who had undergone excisional biopsy between January 2001 and December 2006 were retrieved and followed-up for 24-99 months (median 63.8). Two lesions were accompanied with CCL, 5 with ADH and 3 with low grade DCIS. Four lesions (2 ADH, 2 DCIS) were additionally resected and their histology revealed 2 ADH, one DCIS and one MLL with CCL. Of 4 lesions (3 ADH, one DCIS) without additional resection, one lesion (ADH) relapsed accompanied with DCIS at 37 months after excision.ConclusionsMLL were frequently accompanied with CCL, ADH or low grade DCIS. Complete resection may be recommended in case of MLL with ADH or DCIS because of intralesional heterogeneity and the probabilities of relapse.