Molecular forms of prostate-specific antigen in the serum of women with benign and malignant breast diseases.

Using a highly sensitive immunofluorometric procedure, we measured the total prostate-specific antigen (PSA) concentration in 632 sera obtained from female blood donors and women with idiopathic hirsutism, breast cancer or benign breast diseases. A total of 50 sera with total PSA > 15 ng l(-1) were fractionated by high-performance liquid chromatography (HPLC) in order to resolve the two immunoreactive molecular forms, i.e. free PSA (approximately 30 kDa) and PSA bound to alpha1-antichymotrypsin (PSA-ACT, 100 kDa). We found that breast cancer patients have presurgical serum total PSA levels similar to those of blood donors. Total serum PSA concentration decreases with age in women with idiopathic hirsutism, in cancer patients and in patients with benign breast diseases. The major molecular form of PSA in the serum of all normal and hirsute women (n = 15) is PSA bound to the proteinase inhibitor alpha1-antichymotrypsin. The major molecular form in 44% of presurgical cancer patient sera is free PSA. A total of 58% of benign breast disease patients also have in their serum mainly free PSA. We conclude that about half the patients with breast cancer or benign breast diseases have free PSA as the major molecular form in their serum, whereas patients without breast pathologies (normal blood donors, idiopathic hirsutism) have PSA bound to alpha1-antichymotrypsin as the major molecular form. The ratio of PSA/PSA-ACT may have value as a simple biochemical test for diagnosis of breast pathologies including breast cancer.     

The lady with raised prostate specific antigen: do we need to worry?

Background: Prostate specific antigen (PSA) is generally considered a biological marker of prostate cancer although raised values may also be observed in benign prostatic diseases. PSA can be secreted in females from skeine’s periurethral gland but at low levels. This case - control study aimed at the evaluation of relation of PSA with different diseases in women. Method: A total of 297 patients were included, 107 with breast cancer, 90 with benign breast disease (BBD) and 100 controls (patients attending our surgery department for non-breast diseases). PSA was measured in the serum of all and a statistical analysis was conducted. Result: An association of raised PSA with breast diseases was observed. Total PSA was more sensitive for benign breast diseases, whereas breast cancer showed a predilection towards increase in free PSA. PSA decreased after surgery. Conclusion: PSA can be used as a diagnostic and prognostic marker of breast cancer in women, therefore helping secondary prevention of breast cancer.     

Serum total and free prostate-specific antigen for breast cancer diagnosis in women.

Prostate-specific antigen (PSA) is a serine protease expressed at high levels in prostate epithelium, and elevated PSA in serum is a well-established marker of prostate cancer. Recently, the relative proportions of free PSA and PSA complexed to the serine protease inhibitor alpha 1-antichymotrypsin have become important variables in distinguishing between prostate cancer and benign prostatic hyperplasia. Numerous studies have demonstrated the production of PSA in female tissues such as the breast, and low levels of PSA are present in female sera. The objective of this study was to measure and compare the relative proportions of free PSA and PSA complexed to the serine protease inhibitor alpha 1-antichymotrypsin in the serum of women with breast cancer or benign breast disease or women with no known malignancies. PSA was measured with an established immunoassay for total PSA and a novel immunoassay for free PSA, both of which had a detection limit of 0.001 microgram/liter (1 ng/liter). The percentage of breast cancer patients with free PSA as the predominant molecular form (> 50% of total PSA) in serum was five times higher than that of healthy women or women with benign breast disease, and PSA decreased in the serum of breast cancer patients after surgery. The diagnostic use of free PSA for breast cancer is limited at this point, due to the low diagnostic sensitivity (approximately 20%); however, free PSA as the predominant molecular form shows a high diagnostic specificity (approximately 96%) in comparison to women free of breast cancer or with benign breast disease. These results suggest that the clinical applicability of free PSA for breast cancer diagnosis and the biological mechanism behind its increase should be further investigated.     

蛋白芯片技术检测肿瘤标志物对乳腺癌的诊断价值

目的探讨应用蛋白芯片技术检测肿瘤标志物对乳腺癌的诊断价值。方法采用多肿瘤标志物蛋白芯片诊断系统,检测90例乳腺癌患者、60例乳腺良性病变者和100名健康体检者12种血清肿瘤标志物,采用SPSS13．0统计软件进行数据分析。结果乳腺癌组CEA、CA125、FER、CA153水平,均显著高于良性病变组和对照组（P〈0．01）：良性捐变组CEA、CA125、FER、CA153水平与对照组比较,差异无显著性意义（P〉0．05）;而CA199、NSE、CA242、HCG、AFP、f-PSA、PSA、HGH在三三组间比较均未见统计学意义（P〉0．05）;乳腺癌组与对照组的logistic回归方程P=1／1＋e^-（-1.29＋2.25×cea＋3.12×CA125＋10.59×CA153）;ROC曲线中,CA125、CA153、CEA、FER联合检测的AUC大于各项肿瘤标志物单项检测的AUC（P=0．000）。结论蛋白芯片技术检测肿瘤标志物对乳腺癌的有较高的临床诊断价值;血清CA125、CA153、CEA、FER是乳腺癌辅助诊断的理想指标,其联合检测有利于提高乳腺癌的诊断率;CA199,NSE,CA242,HCG,AFP,f-PSA,PSA,HGH这些指标对乳腺癌诊断价值较低;作为1种统计手段,logistic回归可改善诊断的灵敏度和特异性。     

Prostate-specific antigen in serum of women with breast cancer.

Prostate-specific antigen (PSA) was recently found in 30% of female breast tumours. In this study we have examined if PSA circulates in the blood of breast cancer patients and if serum PSA has any clinical application. We have compared serum PSA levels between women with and without breast cancer, between women with PSA-positive and PSA-negative breast cancer and between women with breast cancer before and after surgical removal of the tumour. We found that for women > or = 50 years, there is no difference in serum PSA between normal or breast cancer patients. We also could not find any difference in presurgical or post-surgical serum PSA between women who have PSA-positive or PSA-negative breast cancer. We found no correlation between PSA concentrations in matched presurgical and post-surgical sera, between presurgical sera and tumour cytosols and between post-surgical sera and tumour cytosols. High-performance liquid chromatography has shown that PSA in normal male serum consists mostly of PSA bound to alpha 1-antichymotrypsin (molecular weight approximately 100,000), and PSA in breast tumours and presurgical and post-surgical serum consists mostly of free PSA (molecular weight approximately 33,000). These data suggest that female serum PSA is not associated with tumour PSA levels. We speculate that most of the circulating PSA in women originates from the normal breast. It appears that serum PSA in women does not have potential for breast cancer diagnosis or monitoring, but our previous data are consistent with the view that tumour PSA concentration is a favourable prognostic indicator in women with breast cancer.     

乳腺癌患者血清内IL-6和CCL-18的表达及临床意义

目的:定量检测乳腺癌患者血清内IL-6和CCL-18的表达,并分析其表达与临床病理因素的相关性,以评估IL-6和CCL-18作为乳腺癌诊断和预后指标的可行性。方法:ELISA定量检测来自于58名乳腺癌患者,41名乳腺良性肿瘤患者和30名健康人血清内IL-6和CCL-18的表达。Wlicoxon test检测各组间差异。结果:与健康组相比,肿瘤组IL-6和CCL-18表达水平明显升高,但与良性肿瘤组相比,肿瘤组CCL-18表达水平则处于边界值（P=0.05）。而良性肿瘤组与健康组相比,CCL-18和IL-6的表达水平均明显升高。此外,两种细胞因子的表达水平与病人年龄、肿瘤大小、组织学类型、淋巴结转移及组织学分级均无关。IL-6在ER阳性及发生转移的乳腺癌患者血清内表达明显升高,而CCL-18在晚期乳腺癌患者血清内表达明显升高。结论:IL-6和CCL-18可以用来区别乳腺癌患者和健康人群。IL-6的高度表达可能导致ER阳性乳腺癌患者预后较差,而CCL-18的表达与另一个预后参数Ki67的高表达相关。     

Benign and malignant breast disease: initial study results of serum and breast fluid analyses of endogenous estrogens

Design, methods, and study population of a long-term multidisciplinary investigation of benign and malignant breast disease were reported. This initial report focused on the relation of menstrual, reproductive, and other factors to serum and breast fluid estrogen measures [estradiol (E2), estrone (E1), percent free estrogen, and sex hormone binding globulin] among control women. After adjustment for the factors found to be related to the various estrogen measures, estrogen levels in women with benign and malignant disease were compared to those of controls. Findings were as follows: a) little evidence of any relation of most breast cancer risk factors with the various serum estrogen parameters studied; b) differences in breast fluid estrogen levels that may be relevant to the protective effect of parity on breast cancer risk; c) markedly higher levels of E2 and E1 in breast fluid than in serum and no evidence of a correlation of serum with breast fluid measures; d) no support for the hypothesis that breast cancer patients have higher serum percent free E2 than controls or women with benign breast disease; and e) higher breast fluid E2 and E1 levels in women with biopsied benign breast disease than in controls.     

Study on carbohydrate antigen NCC-ST-439 in breast cancer

We evaluated the clinical significance of serum NCC-ST-439 (ST439) in sera from 20 healthy women, 8 patients with benign breast disease and 105 patients with breast cancer (79 primary, 26 recurrent) by using enzyme immuno-assay (EIA). No false positive case was noted in the measuring of ST439 for healthy women and patients with benign breast disease. The positive rates of ST439 were 23% (18/79) in primary breast cancers and 50% (13/26) in recurrent breast cancers. The serum levels of ST439 in stage I breast cancer was significantly higher (p less than 0.05) than those in healthy women, but there was no significant difference among each stage. The serum levels of ST439 were not significantly different among the subsets such as T, n, m and histological types. The high levels of serum ST439 were observed in two cases with mucinous carcinoma. Although there were no relation between ST439 and receptor status, the higher serum levels of ST439 were observed in postmenopausal patients than premenopausal ones. The positive frequency of serum ST439 in stage I and II breast cancers was higher than that of CEA, TPA or CA15-3, while the positive rate in recurrent breast cancer was the lowest among 4 tumor markers. These results suggest that ST439 is a useful tumor marker for not only detecting the recurrence of breast cancer but also diagnosing primary breast cancer in early stage.     

Prostate specific antigen in breast cancer,benign breast disease and normal breast tissue

Prostate specific antigen (PSA) is a tumor marker used widely for the diagnosis and monitoring of prostatic adenocarcinoma. Recently, we provided evidence that PSA may also be produced by breast tumors. In this report we examined quantitatively the PSA levels in 199 breast tumors, 48 tissues with benign breast disease (BBD, 34 fibroadenomas), and 36 normal breast tissues. Significant amounts of PSA (≥ 0.030 ng of PSA per mg of total protein) were found in 28% of breast tumors, 65% of BBD tissues, and 33% of normal breast tissues. PSA positivity in breast tumors was highest in stage I disease (34%) and decreased with disease stage (24% in stage II and 18% in stage III–IV). Using polymerase chain reaction amplification we have shown PSA mRNA presence in patients with PSA protein-positive tissues (benign and malignant) but not in patients with PSA protein-negative tissues. Our data suggest that PSA is expressed frequently by normal breast tissue, by tissue of benign breast diseases, and by breast cancer tissue. Highest expression is seen in benign breast disease and lowest expression in advanced stage cancerous tissue. As PSA production is mediated by steroid hormones and their receptors, we propose that PSA may be a new marker of steroid hormone action in the normal or diseased female breast. The role of this enzyme in the development of breast diseases including breast cancer is currently unknown.     

血清T-PSA和F-PSA检测在乳腺癌诊断中的意义

目的:检测术前乳腺癌患者血清中T-PSA和F-PSA的含量,探讨其和乳腺癌临床生物学行为的关系及在诊断中的价值.方法:利用微粒子酶免分析法,检测85名女性乳腺癌患者和30名健康女性血清中T-PSA和F-PSA的含量.结果:乳腺癌患者血清中F-PSA水平明显高于健康女性(P＜0.05),F-PSA优势患者占37.6%,而健康女性中仅占3.3%.女性乳腺癌患者的T-PSA和F-PSA阳性率分别为23.5%和27.1%.T-PSA阳性患者中,淋巴结转移者较多(70%,P＞0.05),而F-PSA优势患者中,早期(Ⅰ、Ⅱ期)发病率较高(68.8%,P＞0.05).结论:血清检测T-PSA和F-PSA对乳腺癌的诊断及预后判断有一定意义.     

乳腺癌患者血清her-2/neu水平及相关性研究

目的　研究乳腺癌患者血清her 2 /neu的水平、影响因素及临床意义。方法　采用酶联免疫吸附 (ELISA)方法检测 10例正常人、3 1例乳腺良性病变患者、53例可手术乳腺癌及 2 6例晚期转移性乳腺癌患者血清her 2 /neu的水平。结果　正常人和乳腺良性病变患者血清her 2 /neu阳性率均为 0。 53例可手术乳腺癌患者中 ,10例血清her 2 /neu水平高于正常 ,血清her 2 /neu水平与肿瘤大小有相关性 (P <0 .0 5) ,与淋巴结、受体状况无关。 2 6例晚期转移性乳腺癌患者中 ,16例血清her 2 /neu阳性 ,但阳性率 (61.5% )与转移部位无明显相关。结论　血清her 2 /neu的水平与肿瘤良恶性、肿瘤分期及瘤负荷有关 ,并有可能用于指导复发转移性乳腺癌的治疗     

Serum oestradiol in women with and without breast disease

It has been suggested that the percentage of non-protein-bound or free oestradiol (E2) is abnormally high in patients with breast cancer. In this study, the serum oestradiol profiles of a large group of women were analysed to determine whether a significant correlation could be found between serum oestradiol and various breast diseases. In addition oestradiol levels were measured in relation to sex hormone binding globulin (SHBG), albumin levels, oestrogen receptor status and family history of breast cancer. Serum samples were taken from a total of 300 women who had either no breast disease, benign breast disease or breast cancer. The percentage of free oestradiol was found to be highest in women with breast cancer, lowest in the control group and intermediate for the women with benign breast disease. These differences were most marked in post-menopausal women. The absolute values for total and free oestradiol were not statistically different in the three groups studied. There did not appear to be a correlation between oestrogen receptor (ER) concentration in breast cancer tissue and free E2 percentage levels. Women who had a family history of breast cancer did not appear to have higher percentage levels of free E2 than those with no such history. The presence of elevated proportions of free oestradiol in the serum of women with breast cancer may be significant in regard to understanding the aetiology of breast neoplasia. There also may be important implications for the use of this measurement in the earlier diagnosis and detection of breast cancer.     

Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen

The assessment of angiogenesis in breast cancer is of importance as a key indicator of survival and response to therapy. Circulating vascular endothelial growth factor (VEGF) measurements may provide a less subjective analysis than microvessel density (MVD) or immunohistochemical analysis of VEGF expression; however, most studies have used serum, which is now known to largely reflect platelet-derived VEGF concentrations. This study examined for the first time both plasma (VEGFp) and serum (VEGFs) VEGF concentrations in 201 blood samples from pre- and postmenopausal healthy controls and from patients with benign breast disease, localized breast cancer, breast cancer in remission, or metastatic breast cancer and related these to other clinicopathological markers. VEGFp but not VEGFs concentrations of patients with localized disease were significantly elevated compared with normal controls (P = 0.016). Patients with metastatic disease had higher VEGFp and VEGFs levels than normal controls (P < 0.001, P = 0.044 respectively), and higher VEGFp, but not VEGFs, than patients with benign disease (P = 0.009) and patients with localized disease (P = 0.004). However, the highest VEGFp and VEGFs concentrations were seen in patients in remission compared with normal controls (P < 0.001 and P = 0.008, respectively). VEGFp concentrations in patients in remission were also higher than in patients with benign disease (P = 0.01) or patients with localized disease (P = 0.005). Tamoxifen treatment was significantly associated with higher circulating and platelet-derived VEGF levels. Circulating VEGF did not correlate with any clinicopathological factor, including MVD or VEGF expression. VEGF expression was significantly correlated with estrogen receptor status and inversely correlated with tumor grade. MVD correlated with tumor size. Tamoxifen-induced increases in VEGF may be important in clinical prognosis or associated pathologies.     

Retrospective assessment of menstrual cycle length in patients with breast cancer, in patients with benign breast disease, and in women without breast disease

The length of the menstrual cycle was compared in women with breast cancer, women with benign breast disease, and controls. Older women in general tended to report shorter menstrual cycles (P less than 0.05). After correction for the age difference, breast cancer patients still reported a shorter average menstrual cycle length than benign breast disease patients and controls (P less than 0.006). Very short cycles (less than or equal to 21 days) were present in 20% of the breast cancer patients compared to 8% of the patients with benign breast disease and 4% of the controls (P less than 0.0001). Long cycles (less than or equal to 30 days) were not a feature of breast cancer patients (2%), whereas 20% of the patients with benign breast disease and 20% of the controls reported such long cycles (P less than 0.0001). Irregular menstrual cycles were more common in benign breast disease patients (20%) than in cancer patients (10%) and controls (8%) (P less than 0.001).     

Oestrogen binding and risk factors for breast cancer

Although women with breast cancer tend to have a greater proportion of their circulating oestradiol non-protein bound and albumin bound, and less SHBG-bound, than controls, it remains uncertain whether this has an aetiological role or is an effect of the tumour. Oestradiol and its binding to serum proteins was investigated: (a) in relation to risk factors for breast cancer in a normal population; (b) in women with proliferative benign breast disease as a risk group for breast cancer, and women with non-proliferative benign breast disease as a low risk group, as well as breast cancer patients. The strongest associations were with body mass index; the greater the body mass the greater the bioavailability of oestradiol. Changes in relation to age at menarche and menopause could have been a function of body mass. An interesting change with age was noted with a fall in bioavailability over the menopausal years. There was no relationship apparent for parity, age at first full term pregnancy, family history or country of birth. Similar differences in oestradiol binding between cases and controls were seen for patients with breast cancer, benign epithelial hyperplasia and fibrocystic disease without proliferative changes, but these were not significant. This study provides limited support for the concept that oestradiol binding has an aetiological role in the development of breast cancer.     

Nipple aspirates of breast fluid and the epidemiology of breast disease

Epidemiologic data were obtained, and nipple aspiration attempted, from 289 healthy women, 548 women currently having or with a history of benign breast disease, 153 untreated women with breast cancer, and 106 women previously treated by mastectomy. Breast duct fluid was produced in detectable amounts by 59% of the controls and patients with benign or untreated malignant breast disease; in 35% the volume was in excess of 10 microliters. There were more secretors aged 30 to 50 years (72%), than either those who were younger (52%), or older (44%). Overall, 57% of premenopausal women were secretors, compared with 38% of postmenopausal women. Healthy women who had their menarche before age 13 years were more likely to be secretors. Neither parity, age at first completed pregnancy, nor body weight affected secretor status. There was a trend for the 141 benign breast disease patients aged 40 to 49 years to include more women yielding greater than 10 microliter of fluid (57%) compared with 46 controls (39%). Although breast cancer per se did not appear to influence secretor status, postmastectomy patients were more likely to secrete large fluid volumes, an effect that was particularly pronounced after menopause. Hormonal factors related to age and fibrocystic disease risk and endocrine activity after mastectomy may be the principal determinants influencing the secretion of breast duct fluid.     

The diagnostic and prognostic utility of prostate-specific antigen for diseases of the breast

Although prostate-specific antigen (PSA) is the most valuable tumor marker for the diagnosis and management of prostate carcinoma, it is widely accepted that PSA is not prostate specific. Numerous studies have shown that PSA is present in some female hormonally regulated tissues, principally the breast and its secretions. In this review, we summarize the findings of PSA in the breast, and focus on its potential for clinical applications in breast disease. PSA is produced by the majority of breast tumors and is a favorable indicator of prognosis in breast cancer. Low levels of PSA are released into the female circulation, and while the level of serum PSA is elevated in both benign and malignant breast disease, the molecular form of circulating PSA differs between women with and without breast cancer. These findings indicate that PSA may have potential diagnostic utility in breast cancer. PSA may also have a clinical application in benign breast disease, as both the level and molecular form of PSA differ between Type I and II breast cysts. High levels of PSA have been reported in nipple aspirate fluid (NAF) and recent studies have shown that the concentration of PSA in NAF is inversely related to breast cancer risk, indicating that NAF PSA may represent a clinical tool for breast cancer risk assessment. Thus, PSA represents a marker with numerous potential clinical applications as a diagnostic and/or prognostic tool in breast disease.     

血清瘦素水平及体质指数与乳腺癌发生的相关性研究

  目的 探讨血清瘦素水平及体质指数与乳腺癌发生的相关性，为乳腺癌的防治寻找科学依据。方法 收集术前乳腺癌患者90例，乳腺良性疾病患者32例，健康对照103例血清，采用放射免疫分析法测定瘦素水平，并进行体质指数的测量与计算。采用SPSS软件包进行统计学处理。结果 乳腺癌组血清瘦素水平与体质指数明显高于乳腺良性疾病和健康对照组，差异均具有统计学意义（P＜0.01）；三组人群瘦素水平与体质指数均呈正相关，相关系数分别为0.327（P＜0.001），0.416（P＜0.001），0.525（P＜0.001）；Logistic回归分析，血清瘦素水平的升高是乳腺癌发生的危险因素，OR值为1.14（95 %CI：1.076 ~ 1.209）。结论 血清瘦素水平、体质指数升高可能与乳腺癌发生有关。     

A complex between prostate-specific antigen and alpha 1-antichymotrypsin is the major form of prostate-specific antigen in serum of patients with prostatic cancer: assay of the complex improves clinical sensitivity for cancer.

We have studied the forms of prostate-specific antigen (PSA) in serum of patients with prostatic cancer and benign prostatic hyperplasia. Fractionation of serum by gel filtration and assay of the fractions for PSA showed that a considerable part of the PSA immunoreactivity in serum consisted of complexes that were larger than PSA. The complexes were assayed by time-resolved immunofluorometric assays based on an antibody against PSA on the solid phase and europium-labeled antibodies against various protease inhibitors as indicator antibodies. In addition to its monomeric form, PSA was found to occur in complex with alpha 1-antichymotrypsin. The proportion of the alpha 1-antichymotrypsin complex was a major form of PSA and it increased with increasing PSA concentrations, being over 85% at PSA levels exceeding 1000 micrograms/liter. A complex with alpha 1-protease inhibitor was also observed in serum of patients with prostatic cancer and very high levels of PSA. Complexes with alpha 2-macroglobulin and inter-alpha-trypsin inhibitor were detected, but their concentrations were low and similar in sera of cancer patients, normal men, and normal women, suggesting that they were not prostate derived. Commercial immunoradiometric assays for PSA were found to measure free PSA and its complexes with alpha 1-antichymotrypsin but not the complexes with alpha 2-macroglobulin and inter-alpha-trypsin inhibitor. The proportion of the PSA-alpha 1-antichymotrypsin complex was higher in patients with prostatic cancer than in those with benign hyperplasia. Therefore, assay of the complex had a higher sensitivity for cancer than assay of total PSA immunoreactivity.     

c-erbB-2 protein level in tissue and sera of breast cancer patients: a possibly useful clinical correlation

AIMS AND BACKGROUND: The aims of this study were to assess the clinical utility of circulating preoperative HER-2 extracellular domain p105 detected by enzyme immunoassay (ELISA), to compare the tissue expression of HER-2/neu determined by immunohistochemistry (IHC), to correlate prognostic factors including tumor size, nodal involvement, and hormone receptor status, and to analyze the prognostic significance of the marker in relation to clinical outcome as measured by disease-free and overall survival. METHODS: In this study, we enrolled 108 consecutive patients with breast carcinoma, and obtained serum samples and frozen tumor tissues. We compared them with 57 women with fibroadenoma and 63 healthy women as controls. RESULTS: Univariate ANOVA analysis showed no relationship between HER-2/neu in tissue and serum. Preoperative serum levels of p105 were significantly higher in breast cancer patients than in women with benign disease or healthy women. Concerning the correlation between p105, HER-2/neu tissue expression, and the other prognostic factors, a statistically significant correlation between high serum p105 levels and ER-negative status in breast cancer patients was found. Kaplan-Meier analysis confirmed that patients with positive HER-2/neu tissue expression had a significantly shorter survival than those with negative expression. Analysis with the Cox model demonstrated that tumor size was the only significant independent prognostic factor. CONCLUSIONS: This research failed to demonstrate a relationship between preoperative tissue overexpression and circulating HER-2/neu, suggesting that p105 does not represent a valid alternative to predict a worsened prognosis in breast cancer, but it could be a diagnostic marker to discriminate healthy subjects from breast cancer patients.