乳腺癌临床诊断中雌激素和孕激素受体表达的意义

目的探讨雌激素(ER)和孕激素(PR)受体的表达在乳腺癌临床诊断中的意义。方法选取2013年3月至2014年3月间大连大学附属中山医院收治的60例乳腺癌患者,另选取大连市红星社区体检健康人员60例为对照组。所有患者术前均进行ER和PR水平测定,分析彩色多普勒超声表现特征,采用免疫组织化学染色检测ER和PR在乳腺及其周围组织中的表达。结果年龄≥40岁的乳腺癌患者的雌二醇激素含量和孕酮激素含量均高于<40岁的患者,两者比较差异有统计学意义(P<0.05)。免疫组化反应测定中,与健康成年女性比较,乳腺癌患者ER和PR水平均高(均P<0.05),且集中分布于细胞质当中。乳腺癌肿块边缘性状和血流信号的分级与ER、PR均有统计学意义(均P<0.05)。结论年龄偏大,ER和PR水平高,彩色多普勒检查显示乳腺肿块边缘不清晰、周围组织血流不丰富,提示可能患有乳腺癌。     

Prognostic value of estrogen and progesterone receptors in primary breast cancer

Estradiol receptor alone or estradiol and progesterone receptors (ER, PgR) have been measured in tumors from 307 women who were treated for primary breast adenocarcinoma. Patients received adjuvant therapy in relation to tumor stage independently of receptor status. Over a relatively short follow-up, more recurrences are recorded in patients with ER+ tumors, but at 7 years the same proportion of recurrences are registered in both groups of patients whose tumors were ER+ or ER-. Patients whose tumors were processed for both ER and PgR (148 cases) have now been evaluated after 5 years follow-up. Among 56 patients with PgR+ tumors 5 recurred, versus 22/92 in the PgR- group. 21/87 patients who had 1 to 4 invaded nodes at the time of surgery relapsed: 17/54 had PgR- tumors versus 4/33 PgR+. 6 recurrences were recorded in the 61 patients with negative nodes: 5 of them occurred in patients with PgR- tumors. In addition, recurrences observed in patients with negative receptor status occurred after a shorter disease-free interval. Analysis of the incidence of recurrences in relation to the combined ER/PgR status in patients who did not receive adjuvant therapy suggests that tumor PgR content is a more significant criterion than ER for long-term prognosis.     

HER-2 amplification, steroid receptors and epidermal growth factor receptor in primary breast cancer

Amplification of HER-2 oncogene was analysed in DNAs obtained from 291 primary human mammary carcinomas. 52/291 (18%) were found to contain amplified HER-2 oncogene. Moderate amplification (2- to 5-fold) was noted in 36/291 (12%). Thirteen tumors (4.5%) had a copy number of 5 to 10. A 10- to 20-fold and greater than 20-fold amplification was observed in 2 and 1 patient, respectively. Sample sizes allowed the determination of estrogen receptor (ER) and progesterone receptor (PgR) levels in 253/291 primary breast cancers. HER-2 gene amplification was noted in 14% of ER+ patients and in 28% of ER- patients, respectively (P = 0.02). Similarly a significantly greater number of PgR- primary mammary carcinoma exhibited an amplification of the HER-2 gene compared to PgR+ cases (22% vs. 16%, P = 0.01). Although statistically not significant, tumors with HER-2 gene amplification were found to have lower levels of ER and PgR. No association of HER-2 amplification with the androgen receptor and EGF receptor was observed. Present data combine to suggest that tumor progression is more stringently controlled by the oncogene upon loss of hormone dependency. Differences found in HER-2 amplification between steroid receptor positive and negative tumors could be helpful to define a specific subset of women to whom adjuvant therapy should be directed.     

Immunohistochemical evaluation of human epidermal growth factor receptor 2 and estrogen and progesterone receptors in breast carcinoma in Jordan

Introduction  

Although breast carcinoma (BC) is the most common malignancy affecting Jordanian females and the affected population in Jordan is younger than that in the West, no information is available on its biological characteristics. Our aims in this study are to evaluate the expression of estrogen receptor (ER) and progesterone receptor (PR) and Her-2/neu overexpression in BC in Jordan, and to compare the expression of these with other prognostic parameters for BC such as histological type, histological grade, tumor size, patients' age, and number of lymph node metastases.     

Serum epidermal growth factor receptor and HER2 expression in primary and metastatic breast cancer patients

Background  

Breast tissue expression of the ERBB proto-oncogene family has been extensively studied. It was recently shown that expression of epidermal growth factor receptor (EGFR; c-erbB-1) and epidermal growth factor receptor (HER)2 (c-erbB-2) can be detected in the serum of breast cancer patients. The clinical relevance of this has not been fully established.     

Epidermal growth factor receptors and prognosis in primary breast cancer

A retrospective study was performed on 109 human breast tumors stored in liquid nitrogen in order to assess the prognostic value of epidermal growth factor receptor (EGF-R) (median patient follow-up 5 years). A significant inverse relationship was observed between EGF-R and both estrogen (ER) and progesterone receptors (PR). Univariate analysis showed a trend towards a shorter metastasis-free survival both in the overall population and in node-negative patients with EGF-R positive tumors. Multivariate analysis of the overall population showed that lymph-node involvement and PR status were the only significant variables in predicting metastasis-free survival. However, in patients receiving no adjuvant treatment (hormone therapy or chemotherapy), EGF was the only significant variable in the multivariate Cox analysis. No c-erbB-1 amplification was detected in these tumors.     

Epidermal growth factor receptor in human breast cancers: Correlation with estrogen and progesterone receptors

Epidermal growth factor receptor (EGFR), determined by the Scatchard curve method, was found in 22 cases of a random series of 100 patients with breast carcinoma. Two groups of patients were identified, one (n = 16) with a low concentration (0–50 fm/mg protein) of EGFR but with a high affinity (Kd = 3.2 nM), and the other (n = 6) with a high concentration (90–210 fm/mg protein) of EGFR but with a lower affinity (Kd = 6.3 nM).A significant inverse relationship was found between the presence of EGFR and receptors for estrogen (p<0.001) and progesterone (p = 0.001). EGFR was found in no (0/8) tumors with Grade I histoprognostic grade, 17% (10/58) Grade II, and 38% (11/29) Grade III (p<0.05). EGFR is present therefore in poorly differentiated tumors and associated with other factors of poor prognosis. Ourin vivo analyses confirm results found in tissue culture derived from human breast carcinoma cells.With the technical assistance of J. Barraque.     

Differential effects of phorbol ester on epidermal growth factor receptors in estrogen receptor-positive and -negative breast cancer cell lines

A previous study from this laboratory (Koga et al., Cancer Res., 48: 2734-2739, 1988) demonstrated that the growth inhibitory effect of 1,25-dihydroxyvitamin D3 in human breast cancer cells in vitro was associated with a decline in the concentration of epidermal growth factor receptor (EGF-R). In the present study experiments were undertaken with the phorbol ester, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), an agent known to decrease EGF-R binding, in order to further define the relationship between changes in EGF-R binding and changes in growth rates in 10 human breast cancer cell lines. Treatment with TPA decreased the rate of cell proliferation in all cell lines except BT 474 in which a slight increase in proliferation rate was observed. Sensitivity to TPA was unrelated to estrogen receptor (ER) status and a wide spectrum of sensitivities was apparent. The concentrations of TPA that produced a 25% decrease in cell number ranged from less than 0.25 nM for MCF 7M and BT 20 cells to greater than 10 nM for the HBL 100, T 47D, and ZR 75-1 cell lines. Growth inhibition was associated with a block in cell cycle progression in the G1 and G2 + M phases of the cell cycle. In all cell lines studied, except BT 474, TPA treatment resulted in a reduction in the ability of cells to bind EGF. Saturation analysis revealed marked differences between the effects of TPA on EGF binding in ER+ and ER- cell lines. In ER+ cell lines, 2-h treatment with 10 nM TPA resulted in a marked reduction in the number of high affinity EGF-R sites and a significant decrease in binding affinity. Among this group of cell lines there was a significant positive correlation between the ability of TPA to decrease cell growth and the TPA-induced decrease in the number of EGF-R sites/cell (r = 0.82, P less than 0.03). In ER- cell lines, TPA-induced growth inhibition and the minor changes in EGF-R concentration were unrelated. However, growth inhibition was negatively correlated with TPA-induced changes in apparent affinity of the EGF-R (r = 1.00, P less than 0.003) and in the same rank order as the EGF-R concentration in control cells. These data demonstrate differential relationships between TPA-induced changes in growth and EGF-R binding in ER+ and ER- breast cancer cells, thus supporting the view that growth regulatory pathways are markedly different in these two subtypes of human breast cancer.     

Comparison of estrogen receptor and epidermal growth factor receptor content of primary and involved nodes in human breast cancer

Estrogen receptors (ER) and epidermal growth factor receptors (EGFR) in the tumor cells of breast cancer tissues (primary tumors) and metastatic lymph nodes (involved nodes) were analyzed by immunocytochemical study in 19 patients; 12 were ER positive, and seven were ER negative. Microscopic study was used to determine the percentage of positive cells and the staining index. The percentage of EGFR-positive cells and the EGFR staining index were higher in the ER-negative primary tumors than ER-positive primary tumors. In ER-positive cases, both the number of ER-positive cells and ER content per cell was less in the involved nodes than in the primary tumors, whereas the number of EGFR-positive cells and EGFR content per cell was greater in affected nodes. On the other hand, in the ER-negative cases the number of EGFR-positive cells and EGFR content per cell remain almost unchanged between the primary tumors and involved nodes. The authors supposed a probability, in this study, that estrogen may exert inhibitory action on EGFR production through binding to ER.     

Human epidermal growth factor receptor-2 expression in primary and metastatic gastric cancer

Background

Amplification and overexpression of human epidermal growth factor receptor-2 (HER-2) has been shown in subgroups of gastric cancer, correlated to more aggressive disease and predictive for the treatment with HER-2 antibodies. In this study, we examined the prognostic value of HER-2 expression in primary gastric cancer and in associated lymph node metastases and confirmed the role of HER-2 in tumor angiogenesis by examining vascular endothelial growth factor (VEGF) expression.

Methods

Immunohistochemistry was used to detect HER-2 and VEGF expression in 110 gastric cancer specimens and associated lymph node metastases and in 96 specimens of normal gastric mucosa.

Results

The expression level of HER-2 in gastric tissues was significantly higher than in normal tissues (19.1 % vs. 8.3 %; P < 0.05). HER-2 overexpression was homogeneous in primary gastric cancer and metastatic lymph nodes (P = 0.607). There was a significant positive correlation of HER-2 expression and VEGF expression (P = 0.007). HER-2 overexpression in primary tumor correlated with lymph node metastasis, distant metastasis, and American Joint Committee on Cancer (AJCC) stage. Cox regression multivariate analyses confirmed that tumor size, histological grade, lymph node ratio, AJCC stage, chemotherapy, and HER-2 expression were all prognostic factors. Patients with HER-2 positivity in both primary and metastatic tissues (+/+) had the poorest survival (OS, 12.5 months; DFS, 11.0 months) (P < 0.01).

Conclusions

HER-2 was significantly overexpressed in gastric cancer versus normal tissue and correlated with VEGF expression. HER-2 in tumor or lymph nodes was an independent negative prognostic factor.     

Immunohistochemical detection of estrogen receptor,progesterone receptor,and human epidermal growth factor receptor 2 expression in breast carcinomas

BACKGROUND:

Fine‐needle aspiration (FNA) is a rapid and accurate procedure for the detection of breast carcinomas. The evaluation of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression by immunohistochemistry (IHC) is performed routinely on formalin‐fixed, paraffin‐embedded needle‐core (NC) or excision tissue block (TB) preparations, according to the American Society of Clinical Oncology/College of American Pathologist guidelines. In this retrospective study, the authors compared expression levels of ER, PR, and HER2 in ethanol‐fixed BC FNA cell block (CB) samples with expression levels in formalin‐fixed NC and TB samples.

METHODS:

Forty‐one breast carcinoma CB samples with concurrent or subsequent NC and TB samples were identified. Patients who had received neoadjuvant or adjuvant chemotherapy were excluded. CB samples initially were fixed in 50% ethanol (4‐12 hours), and this was followed by formalin fixation (minimum, 6 hours). NC samples were placed promptly in formalin for a minimum of 6 hours. Within 4 to 8 hours, TB samples were fixed in formalin for 6 to 48 hours. Fluorescence in situ hybridization (FISH) results were also compared.

RESULTS:

IHC for ER on alcohol‐fixed CB samples had good correlation with NC and TB samples. PR results on TB samples had excellent agreement with NC samples. A higher discordance rate wais observed when PR results were compared between CB samples and NC samples. HER2 detection on ethanol‐fixed CB samples resulted in a higher rate of positive and equivocal staining than NC or TB samples. HER2 IHC on TB samples demonstrated better correlation with FISH results than CB or NC samples.

CONCLUSIONS:

Alcohol fixation did not affect ER results in breast carcinoma, but it may alter tumor cell PR antigenicity. The authors concluded that CB samples could be used to triage patients for tamoxifen therapy, but they are not reliable for the assessment of HER2 status; therefore, CB results should be correlated with results from NC or TB samples. Cancer (Cancer Cytopathol) 2009. © 2009 American Cancer Society.     

Immunohistochemical image analysis of estrogen and progesterone receptors in breast cancer

Background  Recently objective quantification of immunohistochemical estrogen receptor (ER) and progesterone receptor (PgR) staining in breast cancer by image cytometry has been predominantly performed by measuring the area of positively stained cells. However, in sample preparations of immunostained hormone receptors, both the stained area and the intensity of staining vary. In this study, we performed quantification of the stained area by measuring, tailing intensity using image cytometry. Methods  Quantitative analysis of ER and PgR immunohistochemistry was performed using image cytometry. The obtained values were presented as % of positive staining (%PS). Comparison of %PS with values obtained by EIA and with clinicopathological features was performed. Results  The %PS values and the natural logarithm of the EIA levels of the hormone receptors showed a significant positive correlation for both ER and PgR. The concordance of the results obtained by the two methods was 96.3% for ER and 73.7% for PgR. The ER-%PS values of postmenopausal patients were significantly higher than those of premenopausal patients, whereas the PgR-%PS values of the former group were significantly lower than those of the latter group. Conclusions  The quantification of ER and PgR in immunostained preparations using %PS as a parameter was reproducible and showed a high correlation with values obtained by EIA. It was shown that only menopausal status affects hormone receptor levels when analyzing the relationship between %PS measurements and clinicopathological features.     

Expression of epidermal growth factor receptor mRNA and protein in primary breast carcinomas

The expression of epidermal growth factor receptor (EGFR) mRNA and protein has been determined in a group of breast carcinomas and compared to oestrogen and progesterone receptor (ER, PgR) status, as well as pathological features. In situ hybridization using a digoxigenin-labelled oligonucleotide probe was applied to formalin-fixed paraffin-embedded sections, and immunohistochemistry was used to determine EGFR protein.EGFR mRNA was detected in 66% of carcinomas with a third having labelling similar to normal breast tissue, 22% heterogeneous weak to strong labelling, and 11% strong labelling. EGFR protein was detected in 36% and these tumours had a strong correlation to lack of ER and high histological grade. The presence of EGFR protein was strongly correlated with more intense labelling for EGFR mRNA (p < 0.0001). This contrasted with normal breast in which both EGFR protein and mRNA were present with varying degrees in both tumours and a normal breast control. The ER-/PgR- carcinomas showed the full range of EGFR mRNA labelling. It is postulated that oestrogen or oestrogen regulated proteins are involved in regulation of EGFR mRNA and protein. In a proportion of tumours lacking steroid receptors regulation is lost, leading to EGFR overexpression.     

The relationship between somatostatin, epidermal growth factor, and steroid hormone receptors in breast cancer

The somatostatin (SS) and the epidermal growth factor (EGF) receptor content have been established in 36 primary breast cancers by receptor autoradiography on adjacent tissue sections. Iodine 125 (125I)-EGF was used as radioligand for EGF receptor visualization whereas an iodinated SS-28 analogue or an octapeptide SS analogue were used to measure SS receptors. Six of 36 tumors contained SS receptors, whereas ten of the 36 tumors were shown to contain EGF receptors. None of the tumor samples containing SS receptors were simultaneously EGF receptor positive. In contrast, all SS receptor-positive tumors simultaneously contained steroid receptors. The positive correlation between SS receptors and steroid receptors as well as the negative correlation between SS receptors and EGF receptors therefore suggest that the small percentage of SS receptor-positive breast tumors are a group of differentiated breast tumors with a good prognosis. In these cases, combined hormonetherapy including SS analogs may be of potential interest.     

Response to primary chemotherapy in breast cancer patients with tumors not expressing estrogen and progesterone receptors

Background:We recently demonstrated that in premenopausalpatients with estrogen receptors (ER)-absent tumors, early initiation ofsystemic chemotherapy after primary surgery might improve outcome. These dataindicate a different responsiveness to chemotherapy for tumors not expressinghormone receptors. To test this hypothesis we evaluated the responsiveness topreoperative chemotherapy in patients with ER and progesterone receptors(PgR)-absent tumors. Patients and methods:Patients with biopsy-provenT₂–T₃, N_0–2 breast cancertreated at a single institution from January 1995 to August 1999 withpreoperative chemotherapy were retrospectively evaluated. ER and PgR weredetermined immunohistochemically and classified for this purpose as absent(0% of the cells positive) or positive (1% of the cells). Results:On 117 evaluable patients 72 had an objective response(61%). A significant difference in response was observed for patientswith ER and PgR absent compared with those with ER and/or PgR-positive tumors(82% vs. 57%,P = 0.03 Fishers's exact test).Pathological complete remission rates were also significantly different in thetwo groups (23% vs. 7%, respectively; P = 0.04). Conclusions:The different degree of response according to hormonereceptors expression supports the hypothesis that tumors not expressing bothER and PgR might represent a different clinical entity in terms ofchemotherapy responsiveness.     

A clinical evaluation of nuclear estrogen receptors combined with cytosolic estrogen and progesterone receptors in breast cancer

Breast cancer tissue from 95 women was simultaneously assayed for three receptors: cytosolic estrogen (CER), cytosolic progesterone (CPR), and nuclear estrogen (NER). The main objective was to determine whether the addition of NER assay to the currently accepted practice with only CER and CPR could improve the predictive capacity of receptors. Forty-two patients were studied for response to hormone therapy and 95 patients were studied for survival; the median follow-up period was 73 months (range, 8 to 300 months). The incidence of CER+, CPR+, and NER+ was 74%, 70%, and 52%, respectively. Each receptor appeared more frequently, although not significantly so, in higher age groups. Forty percent of tumors had all three receptors positive and 14% had all negative; the remaining tumors showed all possible combinations of receptors. Both the rate of response and survival curves among 70 patients with CER+ did not show any significant difference whether NER was positive or negative. Also, among 38 patients with CER+, CPR+, and NER+, there was no significant difference in the clinical outcome as compared to 17 patients with CER+, CPR+, and NER-. Among 25 patients with CER- the rare occurrence of NER+ in only three patients did not suggest any clinical implication. It is concluded, therefore, that on overall clinical grounds the current series does not support the addition of NER assay whenever data is available on both CER and CPR.     

激素受体和人表皮生长因子受体2的表达与改良根治术后淋巴结阳性乳腺癌患者预后的关系

目的 探讨雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体2(Her-2)的表达情况与行改良根治术后腋窝淋巴结阳性乳腺癌患者预后的关系.方法 收集835例行改良根治术后腋窝淋巴结阳性乳腺癌患者的临床和随访资料.根据ER、PR和Her-2的免疫组化检查结果,将患者分为Rec-/Her-2-(三阴性)组、Rec-/Her-2+组、Rec+/Her-2+组和Rec+/Her-2-组,比较其局部区域复发率、远处转移率、无瘤生存率和总生存率.结果 835例患者中,三阴性组141例,Rec-/Her-2+组99例,Rec+/Her-2+组157例,Rec+/Her-2-组438例.Rec+/Her-2-患者的5年局部区域复发率为6.2%,低于其他患者(12.9%,P=0.004).与受体阳性组(Rec+/Her-2+和Rec+/Her-2-)比较,受体阴性组(Rec-/Her-2-和Rec-/Her-2+)有较高的5年远处转移率(26.4%和19.7%,P=0.0008)、较低的5年无瘤生存率(66.7%和75.6%,P=0.0001)和较低的5年总生存率(71.4%和84.2%.P=0.0000).多因素Cox回归分析结果显示,激素受体和Her-2的表达状态是乳腺癌患者局部区域复发、远处转移、无瘤生存和总生存的独立影响因素(均P<0.05),Rec+/Her-2-患者的局部区域复发风险低,受体阴性患者发生远处转移和死亡的风险高.结论 ER、PR和Her-2是改良根治术后腋窝淋巴结阳性乳腺癌患者的独立预后因素.