Do we need HER-2/neu testing for all patients with primary breast carcinoma?

BACKGROUND: HER-2/neu is a valuable prognostic marker in primary breast carcinoma. Controversy surrounds the correlation between HER-2/neu expression and other prognostic markers, as has been discussed in preclinical and clinical studies. The objective of the current study was to investigate the probability, calculated using parameters that are assessed routinely in clinical practice, that patients with breast carcinoma had positive HER-2/neu status. METHODS: The authors evaluated HER-2/neu status in 923 consecutive patients with breast carcinoma by immunohistochemical methods. Correlations involving HER-2/neu status, estrogen receptor (ER) and progesterone receptor (PR) status, tumor grade, patient age, lymph node involvement, and tumor size were evaluated using the Mantel-Haenszel chi-square test and the Spearman correlation. The authors created a simple scoring system (i.e., the diagnostic instrument for validation of HER-2/neu score) to define subgroups of patients with breast carcinoma and to determine the likelihood of HER-2/neu positivity. RESULTS: HER-2/neu overexpression was correlated significantly with negative ER (P = 0.0001) and PR status (P = 0.0001), Grade 3 (G3) lesions (P = 0.0001), and young age (P = 0.006). The likelihood of HER-2/neu positivity in a patient with positive ER and PR status and G1/G2 disease was approximately 6.1%. CONCLUSIONS: The authors demonstrated in a large patient series that HER-2/neu overexpression was associated with negative hormone receptor status, G3, and young age. In a subgroup of patients presenting with hormone-responsive and G1/G2 tumors, the likelihood of HER-2/neu overexpression was very small. Therefore, the assessment of HER-2/neu status in this subgroup of patients with breast carcinoma may be considered unnecessary, unless the role of HER-2/neu status in adjuvant treatment has been proven.     

A comparison of five immunohistochemical biomarkers and HER-2/neu gene amplification by fluorescence in situ hybridization in white and Korean patients with early-onset breast carcinoma

BACKGROUND: The objective of this article was to compare five tumor markers between white women in the U.S. and native Korean women with early-onset breast carcinoma. METHODS: Sixty Korean women who were diagnosed with breast carcinoma at age 45 years or younger and 60 white women with breast carcinoma who were matched by age were selected for this study. The median age of both groups was 37 years. Paraffin embedded blocks of the primary tumor were processed for immunohistochemical staining of estrogen receptor (ER), progesterone receptor (PR), p53, cyclin D1, and HER-2/neu. RESULTS: The proportion of tumors that stained positive for ER, PR, p53, and cyclin D1 in the Korean women were 47.5%, 42.4%, 28.8%, and 40.9%, respectively; in the white women, the proportions were 43.9%, 52.6%, 21.1%, and 59.1%, respectively. The differences between the white patients and the Korean patients were not statistically significant with respect to any of those variables. A significant difference was found in the expression of HER-2/neu. Specifically, positive HER-2/neu status was observed in 47.5% of Korean women, compared with overexpression in only 15.8% of white women (P < 0.001). Fluorescence in situ hybridization analysis for HER-2/neu gene amplification on all HER-2/neu positive samples that scored 2 + and 3 + demonstrated a significant difference (P = 0.007) in gene amplification between the two populations. Differences in HER-2/neu positivity were observed for the entire cohort as well as among the subsets of patients with negative and positive lymph node status. No association was found between immunoreactivity for the five markers and axillary lymph node metastasis. CONCLUSIONS: The findings of high positivity of HER-2/neu expression and gene amplification in Korean women with early-onset breast carcinoma may have potential implications for local and systemic management of breast carcinoma, especially anti-HER-2/neu therapy for patients with hormone receptor negativity. Further research will be needed to identify biologic and genetic factors and their effects on the survival between different racial groups.     

Distribution of GPR30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression.

PURPOSE: The seven transmembrane receptor, GPR30, is linked to estrogen binding and heparan-bound epidermal growth factor release. Here, the significance of GPR30 in human breast cancer was evaluated by comparing its relationship to steroid hormone receptor expression and tumor progression variables. EXPERIMENTAL DESIGN: Immunohistochemical analysis of a National Cancer Institute-sponsored tumor collection comprised of 361 breast carcinomas obtained at first diagnosis (321 invasive and 40 intraductal tumors). Biopsies from 12 reduction mammoplasties served as controls. The distribution pattern of GPR30, estrogen receptor (ER), and progesterone receptor (PR) was correlated with clinicopathologic variables obtained at diagnosis. RESULTS: GPR30, ER, and PR were positive in all 12 normal controls. In contrast, GPR30 expression varied in breast tumors, in which 62% (199 of 321) of invasive tumors and 42% (17 of 40) of intraductal tumors were positive. Codistribution of ER and GPR30 was measured in 43% (139 of 321) of invasive breast tumors, whereas both receptors were lacking (ER-GPR30-) in 19% (61 of 321) of the tumors analyzed, indicating a significant association between ER and GPR30 (P<0.05). The coexpression of PR and ER did not influence GPR30 expression, yet coexpression of GPR30 and ER was linked to PR positivity. Unlike ER, which varied inversely with HER-2/neu and tumor size, GPR30 positively associated with HER-2/neu and tumor size. In addition, GPR30 showed a positive association with metastasis (P=0.014; odds ratio, 1.9). CONCLUSIONS: GPR30 and ER exhibited distinct patterns of association with breast tumor progression variables, including HER-2/neu, tumor size, and metastatic disease. Thus, these results support the hypothesis that GPR30 and ER have an independent influence on estrogen responsiveness in breast carcinoma.     

Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer

BACKGROUND: HER-2/neu, which encodes a receptor tyrosine kinase, is amplified and overexpressed in 20%-25% of human breast cancers. Such tumors are often resistant to hormone therapy. Despite a general inverse association between HER-2/neu amplification/overexpression and estrogen receptor (ER) and/or progesterone receptor (PR) expression, a fraction of patients are both HER-2/neu- and hormone receptor (HR)-positive. The efficacy of hormone therapy in this group is currently a matter of debate. To better understand the relationship between HER-2/neu positivity and HR expression, we analyzed HER-2/neu, ER, and PR as continuous variables in breast cancer cell lines and two cohorts of primary breast cancer patients. METHODS: HER-2/neu and ER/PR expression was analyzed by enzyme-linked immunosorbent assay (ELISA) and enzyme immunoassay (EIA), respectively, in 14 human breast cancer cell lines, some of which had been transfected with the HER-2/neu gene. For the clinical study population, HER-2/neu protein levels were assessed by ELISA (cohort A, n = 665), and HER-2/neu gene copy number was determined using fluorescence in situ hybridization (cohort B, n = 894). ER/PR expression was analyzed by EIA (cohort A) or radioligand binding (cohort B). Associations between HER-2/neu and ER/PR expression were analyzed using Spearman's rho correlation and the chi-square test, and absolute levels were compared using the Mann-Whitney U test. All statistical tests were two-sided. RESULTS: HR-positive human breast cancer cell lines transfected with the HER-2/neu gene expressed statistically significantly lower levels of ER and PR than parental lines. In the clinical cohorts, levels of HER-2/neu overexpression and gene amplification were inversely correlated with ER/PR levels (Cohort A [n = 112]: for ER, r = -0.34, P<.001; for PR, r = -0.24, P =.010. Cohort B [n = 188]: for ER, r = -0.39, P<.001; for PR, r = -0.26, P<.001). Among patients with HR-positive tumors, HER-2/neu-positive tumors had statistically significantly lower ER/PR levels than HER-2/neu-negative ones (Cohort A: for ER, median = 25 fmol/mg [interquartile range [IQR] = 13-78] versus median = 38.5 fmol/mg [IQR = 17-99] and P =.031; for PR, median = 35 fmol/mg [IQR = 12-119] versus median = 88.5 fmol/mg [IQR = 22-236] and P<.001. Cohort B: for ER, median = 44 fmol/mg [IQR = 13-156] versus median = 92 fmol/mg [IQR = 35-235] and P<.001; for PR, median = 36 fmol/mg [IQR = 13-108] versus median = 84 fmol/mg [IQR = 24-250] and P<.001). Patients with higher levels of HER-2/neu overexpression or amplification had statistically significantly lower levels of ER/PR than patients with lower levels of HER-2/neu overexpression or amplification. CONCLUSION: Because absolute HR levels are strongly related to response to hormone therapy in primary and advanced breast cancer, reduced ER/PR expression may be one mechanism to explain the relative resistance of HER-2/neu-positive:HR-positive tumors to hormone therapy.     

HER-2/neu Status: A Neglected Marker of Prognostication and Management of Breast Cancer Patients in India

Background: Categorizing breast tumors based on the ER, PR and HER/Neu 2 receptor status is necessary in order to predict outcome and assist in management of breast cancer. Herfe we assessed this question in South Indian patients. Materials and Methods: A total of 619 formalin fixed paraffin embedded breast tumor tissues were collected from pathology archives after receipt of ethical clearance. With the help of primary and secondary conjugated antibodies, expression status of ER, PR and HER2/neu was determined. All the experimental data were assessed for correlations with histopathological features of tumors and clinical presentation of the subjects. Results: In the present study, the ages ranged from 20-87 years with a mean of 50.0±12.q years, and majority of the tumors (84%) were of infiltrating duct cell carcinoma type. Assessment of ER, PR and Her-2/neu expression showed that 46% were triple negative. Interestingly, an inverse relation between ER, PR and HER-2/neu was apparent in 41.2% (p<0.0001) of the tumors, of which 24.5% (p<0.0001) were ER and PR co-negative but HER-2 positive. Conclusions: ER and PR positive tumors are less common (i.e<30%) compared to HER-2/neu positive tumors (i.e>50%) in Indian breast cancer patients, underlining the need for effective diagnostic screening and specific therapeutic managements in order to improve the survival rate of patients in low resource countries such as India.     

Association between HER-2/neu and the progesterone receptor in oestrogen-dependent breast cancer is age-related

Summary In oestrogen receptor-positive (ER⁺) breast cancer, HER-2/neu and the progesterone receptor (PR) are inversely associated. This explains a lower response to anti-oestrogens if ER⁺ breast cancers are HER-2/neu positive. One randomized study however, showed that premenopausal women with an ER⁺ breast cancer respond to anti-oestrogens independent of HER-2/neu. We therefore hypothesized an age-related association between HER-2/neu and PR in ER⁺ breast cancers. Receptors for ER, PR and HER-2/neu were analysed by immunohistochemistry (IHC). A uni- and multivariate analyses was carried out to assess this relationship in 1104 women with an ER⁺ breast cancer. We observed an inverse association between HER-2/neu and PR only after age 45. There were 173 women of age 45 and 931 of age >45 years. In multivariate analysis, only tumour grade (p=0.005) but not PR status was associated with HER-2/neu in women age 45 years. However, in age >45 years group, both PR status (p=0.001) and tumour grade (p = 0.001) were independently associated with HER-2/neu. In ER⁺ breast cancers from women age >45, PR was positive in 76.9% if HER-2/neu negative but in 53.4% if HER-2/neu positive (p<0.001) and the median quantitative PR levels are 150 and 75 respectively in HER-2/neu negative and HER-2/neu positive tumours (p=0.002). This age effect of HER-2/neu on the PR status was not seen in women age 45 years and the median quantitative PR levels are 200 and 220 respectively in HER-2/neu negative and HER-2/neu positive tumours (p = 0.518). The study confirms an age-related inverse relationship between HER-2/neu and PR only in women age >45 years but not in women age 45 years.     

Immunohistochemical Profile of Breast Cancer Patients at a Tertiary Care Hospital in South India

Aims: 1) To evaluate the estrogen receptor(ER), progesterone receptor (PR) and Her-2 /neu expression ininvasive breast carcinomas by immunohistochemistry and 2) to compare the pattern of expression with clinicopathologicalparameters like patient’s age, tumor size, mitotic index, histological type and grade and lymph nodemetastasis. Methods: This is a retrospective study of 321 female invasive breast carcinomas diagnosed in theDepartment of Histopathology, Apollo Speciality Hospital, Chennai from January 2009 to June 2010. Results:The age of the patients ranged from 24 to 99 years, with a mean of 53.8, and the majority of the tumors wereT2 (83.8% in range of 2-5 cms), predominantly histological grade 2 (57.3%), followed by grade 3 (33.3%). ER,PR and Her-2/neu expression was seen in 59, 51 and 27% of cases respectively. Triple-negative breast cancersconstituted 25 % of our cases. We also found characteristic associations between hormonal receptor and Her-2/neu expression and various clinico-pathological parameters. Conclusions: The hormonal receptor expressionappears to be lower in the Indian population compared to the West. A significant proportion of tumors in ourstudy with Her2/neu overexpression also showed ER and PR positivity. Triple-negative breast tumors were mostcommonly grade 3, in women aged more than 50 years.     

Ki67 Index in Breast Cancer: Correlation with Other Prognostic Markers and Potential in Pakistani Patients

Introduction: Breast cancer aggressiveness can be correlated with proliferation status of tumor cells, whichcan be ascertained with tumor grade and Ki67 indexing. However due to lack of reproducibility, the ASCO donot recommend routine use of Ki67 in determining prognosis in newly diagnosed breast cancers. We thereforeaimed to determine associations of the Ki67 index with other prognostic markers like tumor size, grade, lymphnode metastasis, ER, PR and HER2neu status. Methods: A total of 194 cases of newly diagnosed breast cancerwere included in the study. Immunohistochemical staining for ER, PR, HER2neu and Ki67 was performed bythe DAKO envision method. Associations of the Ki67 index with other prognostic factors were evaluated bothas continuous and categorical variables. Results: Mean age of the patients was 51.7 years (24-90). Mean Ki67index was 26.9% (1-90). ER, PR, HER2neu positivity was noted in 90/194 cases (46.4%), 74/194 cases (38.1%)and 110/194 cases (56.70%) respectively. Significant association was found between Ki67 and tumor grade,PR, HER2neu positivity and lymph node status, but no link was apparent with ER positivity and tumor size.There wasan inverse relation between Ki67 index and PR positivity, whereas a direct correlation was seen withHER2neu positivity. However, high Ki67 (>30%) was associated with decreased HER2neu positivity as comparedto intermediate Ki67 (16-30%). The same trend was established with lymph node metastasis. Conclusion: Ourstudy indicates that with high grade tumors, clinical utility of ki67 is greater in combination with other prognosticmarkers because we found that tumors with Ki67 higher than 30% have better prognostic profile comparedto tumors with intermediate Ki67 level, as reflected by slightly lower frequency of lymph node metastasis andHER2neu expression. Therefore we suggest that Ki67 index should be categorized into high, intermediate andlow groups when considering adjuvant chemotherapy and prognostic stratification.     

Prognostic value of plasma HER-2/neu in African American and Hispanic women with breast cancer.

We examined the significance of plasma HER-2/neu as a clinical or biological marker for assessing the progression of breast cancer in African American and Hispanic women with similar socioeconomic status, similar health insurance, and similar access to health care delivery. Base line studies show the following: average age of our breast cancer patients was 48 for Hispanic and 53 for African American women. Most of our patients presented invasive ductal carcinoma, and there was no ethnic difference. A larger number of Hispanic women had stage III/IV disease at the time of diagnosis. There was no significant difference in the number of African American or Hispanic patients with ER positive or negative receptors. However, a larger number of Hispanic women had PR positive tumors, and a larger number of African American women had PR negative tumors. In general, there was no difference in the levels of HER-2/neu between the two ethnic groups. Patients with tumors >5 cm had elevated plasma HER-2/neu. However, there was no ethnic difference between tumor size and HER-2/neu levels. In addition, regional node status had no impact on plasma HER-2/neu. Patients with stage III/IV tumors had elevated plasma HER-2/neu. No ethnic difference was observed at either stage I/II or III/IV. ER positive or negative status had no significant impact on plasma HER-2/neu in either ethnic group. In contrast, PR positive patients showed elevated plasma HER-2/neu. Plasma HER-2/neu (>60 U/ml) was the strongest predictor of overall survival, visceral site metastasis, and local recurrence.     

Pathology of borderline HER-2/neu breast carcinoma: a biologically distinct phenotype

SummaryPurpose The significance of HER-2/neu results obtained by immunohistochemical analyses (IHC) which are neither negative nor strongly positive is controversial. The incidence of fluorescence in situ hybridization (FISH) positivity in these tumors is small and the implication is that these borderline results represent laboratory misclassification. We analyzed the tumor characteristics of these HER-2/neu borderline tumors to determine if they represent a unique tumor type.Methods HER-2/neu status was determined by image analysis (IA) of IHC sections in 669 cases of invasive breast cancer. Borderline cases were reflexed to FISH to determine gene status. HER-2/neu results were compared to tumor morphology and other tumor markers.Results HER-2/neu was negative, borderline and positive in 69.5, 15.8, and 14.6% of cases, respectively. HER-2/neu amplification was present in 17.3% of borderline cases. The borderline group is significantly different from the HER-2/neu positive group for all parameters studied except Ki-67. Compared to the HER-2/neu negative group, the borderline group showed a significantly higher HER-2/neu gene copy number and a trend towards lower progesterone receptor expression (p=0.058). Compared to the HER-2/neu negative group, the HER-2/neu borderline/FISH-negative group showed significantly lower PR expression. Compared to the HER-2/neu positive group, the HER-2/neu borderline/FISH positive group showed significant differences with multiple parameters.Conclusion Borderline HER-2/neu tumors are a unique tumor type and do not represent laboratory imprecision. Hormone receptor alterations are associated with early changes in HER-2/neu expression. While IA is capable of detecting these changes, current FISH methodology is not.     

Prognostic Significance of HER-2/neu and Survival of Breast Cancer Patients Attending a Specialized Breast Clinic in Kolkata,Eastern India

Introduction: The worldwide incidence of breast cancer has increased rapidly in recent years. The scenarioof Eastern India is also showing the same trend. It is necessary to study the utility of HER-2/neu as a prognosticfactor in breast cancer survival. However, there have not been detailed studies in this respect with the breastcancer patients of Eastern India. Thus this study was conducted. Materials and Methods: In this hospital-basedstudy 86 breast cancer patients attending a breast clinic of a reputed institute of Eastern India and having invasiveductal carcinomas were observed for a period of 5 years after surgery. Associations between 5 years observedsurvival and status of ER, PR and HER-2/neu of the patients were critically evaluated. Results: There wasstatistically significant association between survival pattern for 5 years and the HER-2/neu status (p=0.00001).Better survival was observed for the patients with HER-2/neu negative tumors 67(100%) compared to HER-2/neupositive tumors 7(36.8%). Conclusion: There is strong interaction between survival and HER-2/neu expressionof breast cancer patients. Thus the patients with HER-2/neu positive tumors need to be treated aggressively.     

Correlation of Hormone Receptor and HER2/neu Expression with Clinicopathologic Parameters in Primary Breast Tumors

Background: Breast cancer (BC) is a major health issue worldwide as well as in Pakistan. All women belonging to any race, ethnicity or lineage are in danger of developing breast cancer. Significant factors influencing the development of breast malignancies are the genetic background, environmental conditions, reproductive parameters, the consequences of female hormones both intrinsic and extrinsic, alteration of immune status, and biologic determinants. Materials and Methods: Overall 150 biopsy proven patients were included in the study. Samples were submitted for histopathology and determination of estrogen and progesterone receptor expression and HER2/neu status. Associations with other characteristics like age, tumor stage, node involvement, histological grade were also studied. Results: Mean age at presentation was 46.7 years. The majority had invasive ductal carcinoma, 100 (84.7%), and were in stage pT3, 54 (45.7%). Important relationships (P<0.05) were found among ER, PR positivity, and Her 2 neu overexpression. However, no noteworthy link was identified amongst ER, PR, Her 2 neu and tumor grade, stage, age, lymph node involvement except for the menopausal status. Conclusions: In summary, breast cancer patients featured an advanced stage of disease, more lymph node involvement, and moderately high grade tumors and with more estrogen, progesterone receptor and HER2 positive tumors.     

Reproducible Immunohistochemical Criteria Based on Multiple Raters’ Judgments for Expression of Thymidine Phosphorylase in Breast Cancer Tissue

The role of HER-2/ neu in male breast cancer is not well defined. The purpose of the current study was to measure the frequency of HER-2/ neu expression in primary male breast cancer, to demonstrate HER-2/ neu gene amplification in cases found to be positive for protein overexpression, and to correlate HER-2/ neu positivity with clinicopathological variables. Formalin-fixed, paraffin-embedded archival material from 99 primary male breast carcinomas was evaluated by immunohistochemistry (IHC) using the HercepTest (DAKO Corp., Hamburg, Germany). Scoring was performed according to established guidelines. All cases demonstrating HER-2/ neu staining by IHC (1+/2+ and 3+) were analyzed for HER-2/ neu gene amplification by fluorescence in situ hybridization (FISH) utilizing the PathVysion assay (Vysis Corp., Downers Grove, Illinois) to assess HER-2/ neu amplification status. The immunohistochemical staining of the HER-2/ neu protein revealed HER-2/ neu positivity in 15/99 (15.1%) cases, eight tumors showed 2+ and 7 tumors 3+ staining. HER-2/ neu gene amplification was observed in 11/99 cases (11,1%), and all of the 3+ and 4/8 from the 2+ cases were amplified. HER-2/ neu gene amplification/protein overexpression did not correlate with tumor state, histological grade or estrogen/progesterone receptor status nor the axillary lymph node status. This is the first comprehensive study of HER-2/ neu gene amplification by FISH analysis in primary male breast cancer. Compared to female primary breast cancer the percentage of HER-2/ neu positivity in our study was lower. Our data provide first evidence for HER-2/ neu gene amplification in male breast cancer. Further studies should be addressed on the potential application of the monoclonal rhuMAB HER-2/ neu antibody for treatment of HER-2/ neu positive male breast cancer.     

HER-2,P53 and Hormonal Receptors Protein Expression as Predictive Factors in Breast Cancer Prognosis

Objective  Breast cancer is a heterogeneous disease with variable biological and clinical characteristics. We conducted a study to evaluate P53, HER-2/neu and hormonal receptor expression as predictors of prognosis in breast cancer. Methods  In a prospective study, we recruited 81 consecutive patients with primary operable breast cancer who were treated with mastectomy followed by locoregional radiotherapy or chemotherapy and studied the presence of P53, HER-2/neu and hormonal receptors (ER/PR) expression in tumor tissues by immunohistochemical staining. Associations between these markers expression and clinical outcomes, including local and regional recurrence and metastasis were evaluated. Statistical analysis was performed with the SPSS so ware. Results  The mean time of follow-up was (47.3 ± 4.6) months. Expression of P53, HER-2/neu, Estrogen receptors and progesterone receptors were observed in 31.1%, 38.5%, 31.8% and 51.7% of the patients, respectively. P53, HER-2/neu and Negative ER status were potent predictors of local-regional recurrence (P = 0.034, 0.038, 0.044, respectively). Also HER-2/neu, Negative ER and Negative PR status were strong predictors of metastasis (P = 0.001, 0.042, 0.054, respectively). Conclusion  P53 and HER-2/neu expression and also steroid receptors status (ER/PR status) have an important role in predicting the outcome of breast cancer and thus may be of value in selecting suitable therapeutic strategy and determining prognosis in these patients.     

Expression of Cyclin E and Its Relationship with the Prognosis of Patients with Breast Cancer

Objective： To investigate the expression of cyclin E in breast cancer tissues and its relationship with prognosis of the patients with breast cancer. Methods： The expression of cyclin E, HER-2/neu, nm23-H1 and actin was detected in 80 breast cancer tissues and 18 benign breast tumor tissues by immunohistochemical methods. The relationship between cyclin E and the remaining genes or the clinical data of the patients with breast cancer was analyzed. Results： The over expression rate of cyclin E in malignant tissues was obviously higher than that in benign tumor tissues （P〈0.01）. The over expression of cyclin E in later stage of disease was higher than that in early stage of disease （P〈0.05）. The expression of cyclin E in ER positive tissues was lower than that in ER negative tissues （P〈0.05）. The expression of cyclin E in PR positive tissues and PR negative tissues had no significant difference （P〉0.05）. The expression of cyclin E in HER-2/neu positive tissues was higher than that in HER-2/neu negative tissues （P〈0.05）. And the expression of cyclin E in ER, PR and HER-2/neu all positive tissues was much higher （P〈0.01）. There was no significant difference in the expression of cyclin E between nm23-H1 positive tissues and nm23-H1 negative tissues （P〉0.05）. The expression of cyclin E in actin positive and continuous distribution tissues was lower than that in actin negative or discontinuous distribution tissues （P〈0.05）. Conclusion： The expression of cyclin E has a strong correlation to the prognosis of the patients with breast cancer.     

ER阴性乳腺癌高表达乳腺癌干细胞标志物乙醛脱氢酶1

目的探讨85例乳腺浸润性导管癌中肿瘤干细胞标志物乙醛脱氢酶1(ALDH1)的表达情况及与临床病理特征的关系。方法采用免疫组化法检测乳腺组织芯片85例乳腺浸润性导管癌组织中ALDH1的表达并分析其临床意义。结果 ALDH1在雌激素受体(ER)阴性的乳腺癌中表达率(34.6%)显著高于ER阳性者(12.1%;P=0.024)。不同亚型乳腺癌中存在ALDH1表达的显著差异,其中三阴性乳腺癌中ALDH1的表达较高(50.0%,P=0.034)。ALDH1的表达在不同大小肿块的肿瘤中也存在差异,其中肿块小于2 cm的乳腺癌中ALDH1的表达率最高(50.0%;P=0.040)。而ALDH1的表达与患者年龄、肿瘤分级、淋巴结转移、疾病分期及PR、HER-2状态无关(P>0.05)。结论 ER阴性乳腺癌尤其是三阴性乳腺癌中ALDH1的表达率较高,提示ER阴性乳腺癌中存在较高比例的干细胞,进而有助于更好地理解其预后差的特点。     

Quantitative imaging of ps2 immunocytochemical assays in breast carcinomas

pS2 expression was studied in 212 breast carcinomas. Immunocytochemical assays (ICAs) were performed on frozen sections and evaluated by digital image analysis. pS2 immunostaining was compared in frozen sections and paraffin sections. The pS2 positivity was observed in 45% of the cases on frozen sections. But in pS2 positive tumors, the tumor surface which was immunostained was small (m=14.3%). In 22% of immunoreactive tumors the positive surface was 5% or less. In contrast to frozen sections, the pS2 positivity on paraffin sections could not be evaluated by image analysis system because of the background. No significant correlation was observed between pS2 expression and patient age, tumor size, histological type and grade, nor with lymph node status. The pS2 positivity was significantly correlated to ER and PR positive immunodetection on frozen sections. But pS2 was independent from pHER-2/neu and cathepsin expression whereas there was a significant inverse relationship between pS2 and Ki67. This study shows that pS2-ICAs on frozen sections and image analysis are optimal and standardized conditions for the evaluation of pS2 expression in breast carcinomas, and suitable for selecting patients for hormone therapy.     

Multivariate analysis of bcl-2, apoptosis,P53 and HER-2/neu in breast cancer: a short-term follow-up

BACKGROUND: Several molecular genetic alterations in breast cancer, including aneuploidy, altered apoptosis, aberrant expression of p53, HER-2/neu and Bcl-2, have been associated with poor prognosis in breast cancer patients. To determine the importance of molecular-genetic factors relative to more traditional surgical-pathological prognostic factors, multivariate analysis was performed. PATIENTS AND METHODS: Ninety-four fresh tissue samples of primary breast carcinoma were studied with flow cytometry for DNA ploidy. On the same specimens, steroid hormone receptors (ER and PR) were measured in the cytosol fraction using Abbott ELISA assays. HER-2/neu was determined in the membrane fraction and mutant p53 protein in the nuclear fraction, both, by Oncogene Science ELIZA procedures. Bcl-2 and apoptosis (cell death) were measured in cell lysates by Oncogene Science & Boehringer Mannheim ELISA assays. In addition, information regarding surgical-pathological features of the tumor was obtained. Multivariate analysis using an unconditional logistic regression model was done to identify variables predictive of poor prognosis. RESULTS: Using univariate analysis, histological grade, tumor stage, lymph node status, HER-2/neu and mutant p53 were predictive of poor short-term prognosis. By multivariate analysis, tumor stage, lymph node status and HER-2/neu were independent factors. Grade subgroup analysis versus time of relapse, illustrated a predictive value of Bcl-2 in only low-grade tumors while apoptosis was significant in high-grade type. CONCLUSION: Among a panel of molecular-genetic factors investigated, HER-2/neu was the most strongly predictive of poor short-term prognosis in breast cancer. Patients with HER-2/neu-positive tumors can benefit from Herceptin therapy.     

Selecting endocrine therapy for breast cancer: what role does HER-2/neu status play?

Most women with breast cancer that overexpresses either estrogen (ER+) or progesterone receptors (PR+) will be treated with an endocrine agent. Although ER and PR are the only validated predictive markers of response to hormonal therapy, many women with hormone receptor-positive (HR+) tumors will fail to respond to endocrine treatment or develop hormone resistant disease. Another tumor marker, HER-2/neu, is an oncogene whose amplification or protein overexpression predicts response to a monoclonal antibody targeting HER-2/neu, as well as to anthracycline-based chemotherapy. Preclinical and some clinical data suggest that HER-2/neu positivity may also predict for relative resistance to endocrine therapy. Interpretation of clinical data addressing this issue is confounded by largely retrospective study designs and considerable heterogeneity in patient populations and methods of marker detection and interpretation. At this writing, HER-2/neu expression should not influence the decision to use endocrine therapy.