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An epidermal growth factor receptor (EGFR) has been reported to be associated with a poor clinical outcome in breast cancer, while its prognostic value remains controversial. Immunohistochemical staining for EGFR was performed on frozen sections of primary breast cancer from 1029 patients with a mean follow-up duration of 46months. EGFR was positive in 277 (26.9%) of 1029 cases, which inversely correlated with the estrogen receptor (ER) status. A univariated analysis indicated that EGFR had a significant prognostic value in both the disease free survival (DFS) and the overall survival (OS), while the same effect was also found in node negative as well as node positive breast cancer. A multivariate analysis indicated that EGFR was an independently significant prognostic factor for DFS (p=0.0174) and OS (p=0.0105) in all patients, but that EGFR demonstrated a prognostic significance only for DFS (p=0.0241) in node negative and only for OS (p=0.0333) in node positive breast cancer. When all patients were stratified for EGFR and ER, a multivariate analysis indicated that the combination of EGFR(+)/ER(–) was an independently significant factor for both DFS and OS in node negative as well as node positive breast cancer. In conclusion, the prognostic value of EGFR was demonstrated by a multivariate analysis in a large series of breast cancer patients, but the value of EGFR was somewhat insufficient to achieve statistical significance for both DFS and OS in the subgroups divided by nodal status. On the other hand, the prognostic value of combination of EGFR and ER was sufficient to achieve statistical significance based on a multivariate analysis for both DFS and OS in the subgroups of node negative as well as node positive breast cancer patients.     

原发性乳腺癌组织中人乳腺珠蛋白的表达及意义

目的研究人乳腺珠蛋白（hMAM）在乳腺组织中表达的特异性, hMAM 的表达与各临床病理特征以及与乳腺癌预后的关系。方法运用免疫组织化学的方法分析142 例原发性乳腺癌组织,103例其他肿瘤组织,30 例正常乳腺组织,30 例乳腺良性肿瘤中的hMAM表达情况,并结合乳腺癌患者的临床病理资料和生存情况进行分析。结果hMAM只在乳腺组织中表达,在原发性乳腺癌中有70.4%的阳性表达。hMAM的表达与年龄、临床分级分期、肿块大小、腋淋巴结状态、病理类型、PR、HER2 状态均无相关性,与ER呈正相关。生存分析显示,hMAM 阳性患者预后明显好于hMAM 阴性患者,Cox回归示年龄、临床分期、ER、hMAM状态均对乳腺癌的术后生存时间有影响。结论hMAM具有理想的乳腺组织表达特异性,在原发性乳腺癌组织中有较高的表达率同时具备较高的敏感度和特异性。生存分析显示hMAM 可以作为评估原发性乳腺癌患者预后的重要参考指标。     

Prognostic value of c-erbB2 expression in breast cancer

BACKGROUND AND OBJECTIVES: An overexpression of c-erbB2 has been reported to be associated with a poor clinical outcome in breast cancer, however, its prognostic value remains controversial especially in patients with node negative breast cancer, and regarding the estrogen receptor (ER) status. METHODS: Immunohistochemical staining for c-erbB2 was performed on the primary breast cancer from 698 Japanese patients with a mean follow-up duration of 54 months. RESULTS: The c-erbB2 expression was positive in 120 (17.2%) of 698 cases, which inversely correlated with the ER status. Both univariate and multivariate analyses indicated the c-erbB2 expression to be a significant prognostic factor for the disease-free survival (DFS) and overall survival (OS), while the same effect was also seen in the patient groups with node negative as well as node positive breast cancer. A univariate analysis also indicated a subgroup with the positive c-erbB2 and negative ER to have both a worse DFS and OS than the other subgroups. The patients with positive c-erbB2 had a significantly worse DFS and OS than the patients with negative c-erbB2 in all patient groups stratified according to the adjuvant therapies, while the prognostic significance of c-erbB2 on DFS was also found in the patients with the node negative breast cancer who received adjuvant tamoxifen alone. CONCLUSIONS: The c-erbB2 expression is an independent significant factor for breast cancer and the prognostic significance remains in the node negative as well as node positive breast cancer, while the same effect was also found in all subgroups stratified according to the adjuvant therapies. In addition, the combination of c-erbB2 and ER made it possible to identify the subgroup with the worst clinical outcome.     

The epidermal growth factor receptor as a prognostic marker: Results of 370 patients and review of 3009 patients

Summary Epidermal growth factor receptor (EGFR) and estrogen receptor (ER) were assayed by ligand binding in tumors from 370 patients with primary breast carcinoma with a median follow up of 18 months. Forty seven percent (175/370) and 57% (210/370) of tumors had >20 fmol/mg and >10 fmol/mg of EGFR and ER respectively. There was a highly significant inverse relationship between EGFR and ER (p=0.0032). There was also a significant association between EGFR and patient age (p=0.0006) but no correlation between EGFR and lymph node status, tumor grade, or tumor size (p=0.104, p=0.198, and p=0.085 respectively). In a univariate analysis of all patients, EGFR expression was not associated with a significant reduction in overall survival (OS). However, there was a significant decrease in relapse-free survival (RFS) and OS in node negative EGFR positive patients (p=0.03 and p=0.05 respectively). In a multivariate analysis (Cox proportional hazard model) of all patients, lymph node status was an independent prognostic indicator for OS and RFS (p<0.00005 and p=0.00005 respectively), ER status for RFS (p=0.0006), and EGFR (in the node negative model) for RFS (p=0.03). When all patients were stratified for EGFR and ER, there was a significant difference in RFS and OS such that EGFR positive and ER negative had the worst prognosis (p=0.0034 and p=0.005 respectively). A similar relationship was observed for OS in node negative patients (p=0.004) and for RFS in node positive patients (p=0.009). In a review of 3009 patients with follow-up, 11/16 series showed high EGFR was associated with shorter RFS or OS in univariate analysis, and 4 showed this in multivariate analysis. However, most series had inadequate follow-up time and most did not include multivariate analysis. This highlights the need for uniform criteria of reporting trials of prognostic factors.     

Progesterone receptor is a significant factor associated with clinical outcomes and effect of adjuvant tamoxifen therapy in breast cancer patients

Estrogen receptor status in breast cancer is associated with response to hormonal therapy and clinical outcome. The additional value of progesterone receptor (PR) has remained controversial. We examine the value of PR for prognosis and response to tamoxifen on a population-based series of 4,046 invasive early stage breast cancer patients. Clinical information for age at diagnosis, stage, pathology, treatment and outcome was assembled for the study cohort; the median follow-up was 12.4 years. PR status was determined by immunohistochemistry using a rabbit monoclonal antibody on tissue microarrays built from breast tumor surgical excisions. Survival analyses, Kaplan–Meier functions and Cox proportional hazards regression models were applied to assess the associations between PR and breast cancer specific survival. Progesterone receptor was positive in 51% of all cases and 67% of estrogen receptor positive (ER+) cases. Survival analyses for both the whole cohort and ER+ cases given tamoxifen therapy showed that patients with PR+ tumors had 24% higher relative probability for breast cancer specific survival as compared to PR− patients, adjusted for ER, HER2, age at diagnosis, grade, tumor size, lymph node status and lymphovascular invasion covariates. Higher PR expression showed stronger association with patient survival. Log-likelihood ratio tests of multivariate Cox proportional hazards regression models demonstrated that PR was an independent statistically significant factor for breast cancer specific survival in both the whole cohort and among ER+ cases treated with tamoxifen. PR adds significant prognostic value in breast cancer beyond that obtained with estrogen receptor alone.     

Survivin is an independent predictor of short-term survival in poor prognostic breast cancer patients

Established clinico-pathological factors can place patients with breast cancer into good and poor prognostic categories, but even within these groups behaviour and response to treatment can differ. This study examined the value of cell cycle and apoptotic regulatory proteins in predicting behaviour in a poor prognostic group. A total of 165 patients, all of whom had died of breast cancer with duration of survival 12-127 months, median 38 months, were examined using immunohistochemistry for proliferation, apoptosis, p53, phosphorylated p53, p21, checkpoint kinase 2 (Chk2), bcl-2, bax, survivin and XIAP. All had received chemotherapy and/or hormonal therapy and were predominantly T2, node positive, grade III with only half oestrogen-receptor (ER) positive. High proliferation, phosphorylated p53, Chk2 and survivin expression correlated with grade III and lack of ER, whereas low proliferation, p21 and bcl-2 related to better grade and presence of ER. On univariate analysis grade, proliferation, phosphorylated p53, bcl-2, ER and survivin related to duration of survival. In multivariate analysis, grade (P=0.001) and survivin (P=0.005) were independent prognostic factors, grade III and presence of survivin relating to shorter survival. The latter was particularly for those patients receiving neoadjuvant therapy and adjuvant chemo- and hormonal therapy. The presence of the inhibitor of apoptosis protein survivin is a highly significant independent predictor of shorter duration of survival of patients with poor prognostic features, and merits investigation as a marker in other prognostic groups.     

EGFR expression correlates with decreased disease-free survival in triple-negative breast cancer: a retrospective analysis based on a tissue microarray

The aim of this study was to analyze the prognostic value of EGFR expression for patients with triple-negative breast cancer (TNBC). Clinical data of these patients were collected and analyzed, and immunohistochemical staining for EGFR was performed on tissue microarrays of operable breast cancer from 287 patients with TNBC, who were treated at Sun Yat-sen University Cancer Center from January 1995 to December 2008. EGFR expression was found in 36.2% of the cases with TNBC. A significant correlation was found between EGFR expression and disease-free survival (DFS). Univariated analysis indicated that EGFR expression had a significant prognostic value in TNBC patients, whereas multivariate analysis indicated that EGFR was a significant independent prognostic factor of DFS (P = 0.011) in all patients. Our results suggested that EGFR was an independent prognostic factor of DFS in patients with TNBC. Therefore, EGFR could become a good therapeutic target in the treatment of TNBC.     

Prognostic significance of expression of c-ERBB-2 oncoprotein in breast cancer patients]

The c-erbB-2 oncogene, is a member of tyrosine kinase oncogene family and expected to play a role in the regulation of cell growth. In the present study, prognostic significance of the expression of c-erbB-2 oncoprotein was investigated by immunocytochemical assay with 130 primary breast cancer patients. The positive expression of c-erbB-2 oncoprotein was found in 53 out of 130 patients (40.8%). There was no significant correlation between expression of c-erbB-2 oncoprotein and conventional prognostic factors, estrogen receptor (ER), axillary lymph node metastasis and epidermal growth factor receptor (EGFR). Relapse free survival rate of the patients with positive c-erbB-2 expression was significantly worse than those with negative at 49 month after operation. Similar result was found in overall survival rate but the difference was not significant. Furthermore, when patients were stratified by regional nodal status, in the patients with lymph node metastasis, the prognosis of the patients with positive c-erbB-2 expression was significantly worse than those with negative, while no significant difference was found in the patients without lymph node metastasis. These results suggest that c-erbB-2 oncoprotein may act as a prognostic factor independently, predicting the prognosis of breast cancer patients.     

284例原发乳腺癌c-erbB2蛋白的表达及其与预后的关系

目的探讨c-erbB2癌蛋白在原发乳腺癌组织中的表达情况及其与预后的关系。方法采用免疫组化SP法检测284例原发乳腺癌组织的c-erbB2表达,并用统计学分析其与预后的关系。结果284例原发乳腺癌c-erbB2的阳性表达率为26．8％（76／284）,其表达与淋巴结转移数目（P=0．003）密切相关。单因素分析表明,c-erbB2是总生存时间（OS,P=0．002）和无病生存时间（DFS,P=0．024）的重要预后因素;多因素分析表明,c-erbB2是影响Os（P=0．023）的独立预后因素。此外,c-erbB2阳性的肿瘤患者较阴性者更易于发生内脏转移。而对于不同的淋巴结转移和ER状态,c-erbB2也有不同的预后价值。结论c-erbB2是影响原发乳腺癌患者OS的独立因素;在不同的淋巴结转移和ER状态下,其预后价值不同。     

Prognostic Factors of Locally Advanced Breast Cancer PatientsReceiving Neoadjuvant and Adjuvant Chemotherapy

Background: Neoadjuvant chemotherapy is known to be beneficial for down-staging patients with locallyadvanced breast cancer. Clinical stage, degree of cell differentiation and expression of estrogen/progesteronereceptors and HER2/neu are all prognostic factors that may effect survival of patients with locally advancedbreast cancer. The present study was conducted to determine their influence in a series of Indonesian patientsMaterials and Methods: The subjects were a total of 52 patients with locally advanced breast cancer in SardjitoGeneral Hospital Yogyakarta, from January 2003 to June 2006. Survival analysis with Kaplan Meier was testedfor age, clinical stage, degree of histological differentiation, estrogen-progesterone receptor (ER/PR), HER-2expression and neoadjuvant as well as adjuvant chemotherapy. To find the most important influencing factors,significant variables were tested with multivariate Cox regression. Result: Of the 52 patients with locallyadvanced breast cancer, most were between 40-60 years old (41, 78%), almost half were stage IIIA (23 ,44%),and the majority were negative for ER and PR (32, 61%). Her2 positivity was found in 29 patients (55%) and amoderate histological grade in 26 (50%). Thirty-nine patients were alive at the end of the study period (75%).There were no significant differences in survival between patients with and without adjuvant and neoadjuvantchemotherapy. Tumor characteristics that did influence survival were advanced stage (p<0.001) and histologicalgrade (p<0.001), while HER-2 and ER/PR hormonal status had no effect. Conclusion: Clinical stage and degreeof histological grade are the most significant prognostic factors for Indonesian locally advanced breast cancercases, while hormonal status and HER-2 did not appear impact on our patient’s survival.     

Role of epidermal growth factor receptor expression in primary breast cancer: results of a biochemical study and an immunocytochemical study

Summary We have conducted two series of studies, a biochemical study and an immunocytochemical study, to investigate the role of epidermal growth factor receptor (EGFR) expression in primary breast cancer patients. In the biochemical study, a consecutive 115 patients were included and EGFR was measured by a competitive binding assay with multipoint Scatchard analysis. In the immunocytochemical study comprising 126 patients, EGFR status was determined by immunostaining with anti-EGFR antibody EGFR1. Several agreements were found from these two studies. EGFR status was inversely correlated with estrogen receptor (ER) status. No significant correlation was found between EGFR status and tumor size, nodal metastases, or the expression of c-erbB-2 protein. Ki-67 immunoreactivity, a cellular proliferation marker, was enhanced in EGFR positive tumors over EGFR negative tumors, suggesting a linkage of EGFR expression to cellular proliferative activity. Post-operative follow up showed that relapse-free survival for EGFR positive patients was significantly worse than that for EGFR negative patients, particularly in node-positive patients. Multivariate analysis demonstrated a significance of EGFR status as an independent prognostic indicator in primary breast cancer. The group expressing EGFR and c-erbB-2 protein indicated a particularly high risk for relapse.     

Prognostic significance of transforming growth factor beta receptor II in estrogen receptor-negative breast cancer patients.

PURPOSE: The role of transforming growth factor beta (TGF-beta) in breast cancer is ambiguous; it can display both tumor suppressing and enhancing effects. Activation of the TGF-beta signal transduction system is subject to hormonal regulation. This study was conducted to further analyze the role of TGF-beta receptors in breast cancer and to evaluate their significance as prognostic markers. EXPERIMENTAL DESIGN: Expression of TGF-beta receptor I (TbetaRI) and TGFbeta receptor II (TbetaRII) was retrospectively analyzed by immunohistochemistry in 246 breast cancer patients. RESULTS: Expression of TbetaRI was strongly correlated with tumor size (P < 0.001) and nodal status (P = 0.012) but only weakly with overall survival (P = 0.056). In contrast, TbetaRII was prognostic for overall survival in univariate analysis (P = 0.0370). In estrogen receptor (ER) -negative patients TbetaRII expression was correlated with highly reduced overall survival (P = 0.0083). In multivariate analysis TbetaRII proved to be an independent and highly significant prognostic marker with a hazard ratio of 6.8. Simultaneous loss of both ER and TbetaRII was associated with longer overall survival times comparable with those of ER-positive patients. CONCLUSIONS: The results of this exploratory study show that TbetaRII is an independent, highly significant prognostic indicator for overall survival in ER-negative patients. In addition our results are supportive of a mechanism of breast cancer progression in which a selective loss of the tumor inhibitory action of TGFbeta takes place, whereas tumor- promoting aspects remain intact.     

Human breast cancer: prognostic significance of the c-erbB-2 oncoprotein compared with epidermal growth factor receptor, DNA ploidy, and conventional pathologic features.

PURPOSE: A study was undertaken to define the prognostic value of the expression of the c-erbB-2 oncoprotein in a series of breast cancer patients when compared by multivariate analysis with expression of the epidermal growth factor receptor (EGFR), DNA ploidy, and conventional clinicopathologic features. PATIENTS AND METHODS: Prognostic indicators were analyzed in 165 primary breast cancers. The c-erbB-2 oncoprotein was recognized by the polyclonal antibody 21N using an immunocytochemical method. Expression of the EGFR was stated immunocytochemically using the monoclonal antibody EGFR1. DNA ploidy was assessed in paraffin-embedded sections using a standard flow-cytometric method. RESULTS: Overall, 27% of carcinomas had membrane 21N-staining and were classified as c-erbB-2-positive. Overexpression of the c-erbB-2 oncoprotein was poorly associated with EGFR expression and the conventional pathologic features, and it was weakly associated with DNA ploidy and nodal status. Univariate analysis showed that c-erbB-2 expression, nodal status, DNA ploidy, and EGFR provided significant prognostic information concerning 4-year relapse-free survival (RFS) with the odds ratios (ORs) of not relapsing of 2.94, 2.83, 2.34, and 2.20, respectively. Regarding overall survival (OS) at 4 years, only nodal status and DNA ploidy had prognostic significance, with the ORs of not dying of 2.68 and 2.80, respectively. Applying multivariate analysis to RFS, 21N when adjusted for nodal status, EGFR, and DNA ploidy (full model) failed to retain prognostic value (P = .202), whereas nodal status was the most significant indicator of relapse (P = .027) followed by DNA ploidy (P = .056) and EGFR (P = .093). CONCLUSIONS: This study suggests that overexpression of the c-erbB-2 oncoprotein appears to be an important indicator of relapse in stage I-II breast cancer when singly evaluated. Multivariate analysis shows that the determination both of nodal status and DNA ploidy improves our ability to identify subsets of patients with different prognoses, and allows for a better selection of patients for systemic adjuvant treatments.     

Long term survival and the prognostic factors of advanced breast cancer patients treated with adreno-oophorectomy

Summary Longer survival data are necessary to elucidate the prognostic factors for survival in advanced breast cancer patients. Univariate and multivariate analyses were performed in 159 patients treated with adreno-oophorectomy alone as the first-line treatment for advanced or recurrent breast cancer, between 1972 and 1983. Nine clinical factors included age, menopausal status, estrogen (ER)- and progesterone receptors (PgR) in recurrent tumors, disease-free interval (DFI), number of metastatic organs, performance status, and adjuvant therapy performed. Response was evaluated according to the UICC criteria. A 31% (50/159) response with 16 CR, 34 PR, 48 NC, and 61 PD was obtained. The logistic regression model of the factors showed that ER was the single affecting factor for the response. According to the Cox proportional hazard model, ER and the dominant site of metastasis were indicated to be significant for survival. According to the landmark method, the response significantly correlated to survival. Using the backward elimination procedure of the Cox proportional hazard model in the patient group defined by the landmark time of 3 months after therapy, the survival of the patients with advanced breast cancer was shown to be primarily influenced by the tumor response which was solely affected by ER status, and the dominant site, particularly the presence of liver metastasis, independently modified the survival length. These results may be useful in future studies of total estrogen blockade trials for breast cancer.     

Hormone receptors (ER, PgR) as a prognostic factor in breast cancer

To investigate the significance of the hormonal receptors (ER: estrogen receptors; PgR: Progesterone receptors) as prognostic factors in breast cancer, 213 patients with breast cancer (stages I-III) who were examined for both receptors and had not received adjuvant hormonal therapy have been studied so as to determine a disease-free survival rate. In stage I, the status of the hormonal receptors failed to show any statistically significant differences with regard to the disease-free curve. However, in patients in advanced stage, the presence of either PgR or both receptors positively correlated with the disease-free survival curve. In comparing the ER with the PgR as prognostic factors, the presence of the PgR seemed to be more important than the presence of the ER. These data suggest that the status of the hormonal receptors is considered to have prognostic significance.     

The prognostic significance of transforming growth factors in human breast cancer.

Transforming growth factor alpha (TGF alpha) and Transforming growth factor beta-1 (TGF-beta 1) are growth regulatory for breast cancer cell lines in vitro and several studies have suggested that levels of the receptor for TGF alpha, the epidermal growth factor (EGFR) in tumour biopsies predict relapse and survival. We have examined the prognostic significance of TGF alpha, TGF-beta 1 and EGFR mRNA expression in a series of patients with primary breast cancer with a median follow up period of 60 months. In 167 patients the expression of TGF-beta 1 was inversely correlated with node status (P = 0.065) but not ER status, tumour size or menopausal status. Patients with high levels of TGF-beta 1 had a longer disease free interval with a significantly longer probability of survival at 80 months although the overall relapse free survival was not increased. EGFR mRNA expression was measured in 106 patients and was inversely correlated with ER status (P = 0.018). EGFR levels did not predict for early relapse or survival. TGF alpha mRNA levels were measured in 104 patients, no correlation was seen tumour size, node status, Er status, or clinical outcome.     

表皮生长因子受体表达与乳腺癌激素受体水平和预后的关系

应用免疫组化ＡＢＣ方法研究７５例乳腺癌冰冻组织表皮生长因子受体（ＥＧＦＲ）的表达，结合临床资料和ＥＲ、ＰＲ测定结果进行分析，探讨ＥＧＦＲ表达与乳腺癌预后的关系。结果表明，ＥＧＦＲ阳性３０例（４０％），ＥＧＦＲ表达与肿瘤大小、腋淋巴结状况，临床分期和年龄无关，与ＥＲ、ＰＲ存在着显著的负相关（Ｐ＜０．００５）。全组中位随诊时间为６０个月，ＥＧＦＲ阳性组术后总生存率明显低于阴性组（Ｐ＜０．００１）。在无腋淋巴结转移的病例中，ＥＧＦＲ阳性组和阴性组术后生存情况也有显著差异（Ｐ＜０．０１），提示ＥＧＦＲ表达与乳腺癌不良的预后有关。调整分析乳腺癌有关的预后因素，各组病例中均以ＥＧＦＲ表达阳性组的预后为差，说明ＥＧＦＲ对乳腺癌预后具有独立的作用，不受其他因素的影响。经Ｃｏｘ模型多因素分析显示，ＥＧＦＲ和腋淋巴结受累与否是对乳腺癌术后生存情况有显著性影响的两个因素。