Serum amyloid A (SAA): a novel biomarker for uterine serous papillary cancer

Background:

Uterine serous papillary carcinoma (USPC) is a biologically aggressive variant of endometrial cancer. We investigated the expression of Serum Amyloid A (SAA) and evaluated its potential as a serum biomarker in USPC patients.

Methods:

SAA gene and protein expression levels were evaluated in USPC and normal endometrial tissues (NEC) by real-time PCR, immunohistochemistry (IHC), flow cytometry and by a sensitive bead-based immunoassay. SAA concentration in 123 serum samples from 51 healthy women, 42 women with benign diseases, and 30 USPC patients were also studied.

Results:

SAA gene expression levels were significantly higher in USPC when compared with NEC (mean copy number by RT–PCR=162 vs 2.21; P=0.0002). IHC revealed diffuse cytoplasmic SAA protein staining in USPC tissues. High intracellular levels of SAA were identified in primary USPC cell lines evaluated by flow cytometry and SAA was found to be actively secreted in vitro. SAA concentrations (μg ml⁻¹) had a median (95% CIs) of 6.0 (4.0–8.9) in normal healthy females and 6.0 (4.2–8.1) in patients with benign disease (P=0.92). In contrast, SAA values in the serum of USPC patients had a median (95% CI) of 15.6 (9.2–56.2), significantly higher than those in the healthy group (P=0.0005) and benign group (P=0.0006). Receiver operating characteristics (ROC) analysis of serum SAA to classify advanced- and early-stage USPC yielded an area under the ROC curve of 0.837 (P=0.0024).

Conclusion:

SAA is not only a liver-secreted protein but is also a USPC cell product. SAA may represent a novel biomarker for USPC to assist in staging patients preoperatively, and to monitor early-disease recurrence and response to therapy.     

Serum amyloid A is elevated in the serum of lung cancer patients with poor prognosis

Background:

Lung cancer is known as the top cancer killer in most developed countries. However, there is currently no promising diagnostic or prognostic biomarker for lung cancer. This study aims to discover non-invasive differential markers in the serum of lung cancer patients, to determine the protein identity of the candidate biomarker(s), and to investigate any clinical implication of the biomarker(s) concerned.

Methods:

Blood specimens were collected from 154 pre-operative patients with lung cancer and 35 healthy blood donors with no evidence of lung cancer. Fractionated serum samples were processed by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (MS). Candidate biomarker was identified using sodium dodecyl sulphate polyacrylamide gel electrophoresis and tryptic digestion followed by tandem MS fragmentation analysis, which was subsequently validated with immunoassay.

Results:

A differential protein with m/z 11.6 kDa was detected and identified as an isoform of human serum amyloid A (SAA). It was significantly increased by 1822% in lung cancer patients when compared with the healthy controls, which gave an area under the receiver operator characteristic curve of 0.88. In addition, the protein was also significantly elevated by 77% in lung cancer patients with survival <5 years when compared with patients with survival ⩾5 years.

Conclusion:

There are several functions of the SAA protein, described in the context of inflammation, that are compatible with the mechanism of tumour invasion and metastasis. Our study not only detected increased SAA level in the serum of lung cancer patients but also identified that elevated SAA level may be a non-invasive biomarker useful for the prediction of lung cancer prognosis.     

Elevated levels of the acute‐phase serum amyloid are associated with heightened lung cancer risk

BACKGROUND:

The authors investigated whether early stage lung cancer could be identified by proteomic analyses of plasma.

METHODS:

For the first case‐control study, plasma samples from 52 patients with lung cancer and from a group of 51 controls were analyzed by surface‐enhanced laser desorption/ionization time‐of‐flight mass spectrometry. In a second case‐control study, a classifier of 4 markers (mass‐to‐charge ratio, 11,681, 6843, 5607, and 8762) also was tested for validation on plasma from 16 consecutive patients with screen‐detected cancer versus 406 healthy individuals. The most relevant marker was identified, and an enzyme‐linked immunosorbent assay‐based analysis revealed that signal intensity was correlated with concentration.

RESULTS:

The classifier had a sensitivity of 94.23% and a specificity of 76.47% in the first study but lost predictive value in the second study. Nevertheless, the 11,681 cluster, which was identified as serum amyloid protein A (SAA), resulted in a multiple logistic regression model that indicated a strong association with lung cancer. When both studies were considered as a together, the odds ratio (OR) for an SAA intensity ≥0.5 was 10.27 (95% confidence interval [CI], 4.64‐22.74), whereas an analysis restricted to stage I cancers (TNM classification) revealed an OR of 8.45 (95% CI, 2.76‐25.83) for T1 lung cancer and 21.22 (95% CI, 5.62‐80.14) for T2 lung cancer.

CONCLUSIONS:

SAA levels were predictive of an elevated risk of lung cancer, supporting the general view that inflammation is implicated in lung cancer development. Cancer 2010. © 2010 American Cancer Society.     

Serum amyloid A as indicator of distant metastases but not as early tumor marker in patients with renal cell carcinoma

The aim of the present study was to evaluate the clinical significance of the concentration of serum amyloid A (SAA) in patients with renal cell carcinoma (RCC). SAA protein was determined with enzyme-linked immunosorbent assay in serum samples of 55 healthy controls and 98 RCC patients subdivided into groups with localized tumor (N0M0, n=40), with lymph node metastases (N1M0, n=13), and distant metastases (M1, n=45). SAA concentrations in controls and N0M0 group of RCC were not different while SAA concentrations were significantly elevated in M1 patients compared to the N1M0 and N0M0 patients. In this respect, SAA provided an accurate detection of distant metastases with the area under the ROC curve of 0.86. SAA was identified as a significant independent factor of survival in RCC patients using the multivariate Cox proportional hazards regression model. SAA could be a useful analyte in predicting the survival outcome of RCC patients.     

Serum amyloid A 1 induces suppressive neutrophils through the Toll‐like receptor 2–mediated signaling pathway to promote progression of breast cancer

Immune inflammation plays a key role in breast cancer development, progression, and therapeutic efficacy. Neutrophils are crucial for the regulation of the suppressive tumor microenvironment and are associated with poor clinical survival. However, the mechanisms underlying the activation of suppressive neutrophils in breast cancer are poorly understood. Here, we report that breast cancer cells secrete abundant serum amyloid A 1 (SAA1), which is associated with the accumulation of suppressive neutrophils. High expression of SAA1 in breast cancer induces neutrophil immunosuppressive cytokine production through the activation of Toll‐like receptor 2 (TLR2)‐mediated signaling pathways. These include the TLR2/myeloid differentiation primary response 88 (MYD88)‐mediated PI3K/nuclear factor‐κB signaling pathway and p38 MAPK‐associated apoptosis resistance pathway, which eventually promote the progression of breast cancer. Our study shows a mechanistic link between breast cancer cell secretion of SAA1 and suppressive neutrophils that potentiate tumor progression. These findings provide potential therapeutic targets for breast cancer.     

Serum Amyloid A is a Novel Prognostic Biomarker in Hepatocellular Carcinoma

Purpose: To investigate the prognostic value of serum amyloid A (SAA) in patients with hepatocellularcarcinoma (HCC) undergoing surgery. Materials and Methods: Preoperative serum samples of 328 patients withHCC who underwent curative resection and of 47 patients with benign liver lesion were assayed. Serum levelsof SAA were measured by enzyme-linked immunosorbent assay and its correlations with clinicopathologicalcharacteristics and survival were explored. Results: Levels of SAA were significantly higher in patients withHCC than those with benign liver lesion. There were strong correlations between preoperative serum SAA leveland tumor size and more advanced BCLC stage. On univariate analysis, elevated SAA was associated withreduced disease-free survival and overall survival (p=0.001 and 0.03, respectively). Multivariate analyses showedthat serum SAA level was an independent prognostic factor for overall survival (hazard ratio 2.80, p=0.01).Conclusions: High SAA serum level is a novel biomarker for the prognosis of HCC patients.     

淋巴瘤患者血清淀粉样蛋白A水平的变化及其临床意义

目的:探讨淋巴瘤患者血清淀粉样蛋白A(SAA)水平的变化及其临床意义。方法:回顾279名淋巴瘤患者临床参数,其中非霍奇金淋巴瘤(NHL)191人,霍奇金淋巴瘤(HL)88人。同期90例健康成人作为对照。比较不同人群间SAA差异。分析SAA浓度与淋巴瘤类型、分期、IPI评分和肿瘤负荷是否存在相关性。根据疗效进行分组,对比SAA浓度变化。结果:NHL的SAA浓度为13.2(4.9～60.5)mg/L,HL患者的SAA浓度为71.2(19.6～139.2)mg/L,二者均高于正常对照组6.14(3.9～18.91)mg/L。SAA在淋巴瘤临床特征中有显著差异,且随着疾病的不同阶段而动态变化。在治疗后NHL患者的SAA浓度能更好地反映预后。而HL患者无论是否达到缓解,SAA水平均有下降的趋势。结论:和正常人对比,NHL和HL患者中SAA浓度明显升高,且NHL患者中SAA可辅助反映预后。     

JMJD2A在子宫内膜癌中的表达及意义

目的:探讨组蛋白去甲基化酶JMJD家族中的JMJD2A在正常子宫内膜以及子宫内膜癌中的表达及临床意义.方法:收集临床手术标本,包括子宫内膜癌组织56例,正常子宫内膜组织20例.采用免疫组化的ElⅣisionTM法检测标本中JMJD2A抗体的表达,分析其表达水平与临床病理参数之间的关系,探讨其临床意义.结果:JMJD2A在子宫内膜癌组织中的表达高于正常子宫内膜组织(P<0.05),JMJD2A的表达与年龄、子宫内膜癌的组织学分级和临床病理分期无相关(P>0.05).结论:JMJD2A可能是一个与子宫内膜癌相关的癌基因,高表达提示子宫内膜癌.     

Serum amyloid a as an independent prognostic factor for renal cell carcinoma--a hospital based study from the Western region of Nepal

Objective: The objective of our present study was to assess the role of serum amyloid A (SAA) in stages andprognosis of renal cell carcinoma. Material and Methods: It was a hospital based retrospective study carriedout in the Department of Medicine and Biochemistry of Manipal Teaching Hospital, Pokhara, Nepal between1st January 2008 and 31st December 2011. The variables collected were SAA, CRP. Approval for the study wasobtained from the institutional research ethical committee. Quantitative analysis of human SAA and C-reactiveprotein (CRP) was performed by radial immune diffusion (RID) assay for all cases. Results: Of the 422 total casesof renal cell carcinoma, 218 patients had normal and 204 abnormal SAA. SAA levels were grossly elevated in T3stage (122.3 ± SD35.7) when compared to the mean for the T2 stage (84.2 ± SD24.4) (p value: 0.0001). Similarly,SAA levels were grossly elevated in M1 stage (190.0 ± SD12.7) when compared to the M0 stage (160.9±SD24.8)(p: 0.0001). There was no significant association with elevated CRP levels (209.1 ± SD22.7, normal 199.0 ±SD19.5) . Conclusion: The validity of SAA in serum as being of independent prognostic significance in RCC wasdemonstrated with higher levels in advanced stage disease.     

肝细胞癌的相关血清标志物

HCC的早期诊断是其治疗的关键，HCC血清标志物的检测又为其诊断提供了有利的途径，并且操作简单，敏感性高和特异性强。目前常用的血清标志物为AFP、AFP变异体、AFP mRNA、AFU、GGT、DCP、AIF、GPC3等。这些标志物的联合使用有助于HCC的诊断及预后。     

Serum Protein and Genetic Tumor Markers of Gastric Carcinoma

The high incidence of gastric cancer and consequent mortality pose severe threats to human health. Earlyscreening, diagnosis and treatment are the key to improve the prognosis of the patients with gastric cancer.Gastroscopy with biopsy is an efficient method for the diagnosis of early gastric cancer, but the associateddiscomfort and high cost make it difficult to be a routine method for screening gastric cancer. Serum tumormarker assay is a simple and practical method for detection of gastric cancer, but it is limited by poor sensitivityand specificity. Therefore, people have been looking for novel serum markers of gastric cancer in recent years.Here we review the novel serum tumor markers of gastric cancer and their diagnostic significance, focusing onthe discoveries from serum proteomics analyses and epigenetics researches.     

Activated macrophages promote invasion by early colorectal cancer via an interleukin 1β‐serum amyloid A1 axis

Submucosal invasion and lymph node metastasis are important issues affecting treatment options for early colorectal cancer (CRC). In this study, we aimed to unravel the molecular mechanism underlying the invasiveness of early CRCs. We performed RNA‐sequencing (RNA‐seq) with poorly differentiated components (PORs) and their normal counterparts isolated from T1 CRC tissues and detected significant upregulation of serum amyloid A1 (SAA1) in PORs. Immunohistochemical analysis revealed that SAA1 was specifically expressed in PORs at the invasive front of T1b CRCs. Upregulation of SAA1 in CRC cells promoted cell migration and invasion. Coculture experiments using CRC cell lines and THP‐1 cells suggested that interleukin 1β (IL‐1β) produced by macrophages induces SAA1 expression in CRC cells. Induction of SAA1 and promotion of CRC cell migration and invasion by macrophages were inhibited by blocking IL‐1β. These findings were supported by immunohistochemical analysis of primary T1 CRCs showing accumulation of M1‐like/M2‐like macrophages at SAA1‐positive invasive front regions. Moreover, SAA1 produced by CRC cells stimulated upregulation of matrix metalloproteinase‐9 in macrophages. Our data suggest that tumor‐associated macrophages at the invasive front of early CRCs promote cancer cell migration and invasion through induction of SAA1 and that SAA1 may be a predictive biomarker and a useful therapeutic target.     

Expression and Effects of JMJD2A Histone Demethylase in Endometrial Carcinoma

Previous studies have demonstrated that JMJD2A is a potential oncogene and is overexpressed in humantumors. However, its role in the endometrial carcinoma remains largely unknown. In this study, we discoveredthat JMJD2A was overexpressed in endometrial carcinoma, using immunohistochemistry, quantitative realtimepolymerase chain reaction, and western blotting. Downregulation of JMJD2A led to reduced endometrialcarcinoma RL95-2 and ISK cell proliferation, invasion and metastasis as asessed with cell counting kit-8, cellmigration and invasive assays. Collectively, our results support that JMJD2A is a promoter of endometrialcarcinoma cell proliferation and survival, and is a potential novel drug target.     

Utility of serum tumor markers during surveillance for stage I seminoma

BACKGROUND:

The serum tumor markers α‐fetoprotein (AFP), β‐human chorionic gonadotropin (HCG), and lactate dehydrogenase (LDH) are often measured as part of surveillance protocols in patients with stage I seminoma. In this study, the authors evaluated the utility of routine measurement of these markers in the detection of disease relapse.

METHODS:

Data were gathered from a prospectively maintained database of patients who underwent surveillance for stage I testicular seminoma diagnosed between 1982 and 2005 at Princess Margaret Hospital. Patients were followed on a predefined schedule with physical examination (PE), serum tumor markers, abdominopelvic computed tomography, and chest x‐rays. The records of patients who relapsed were examined for details of imaging and serum tumor markers throughout the period of follow‐up until the time of relapse.

RESULTS:

Of the 527 patients who were managed by surveillance, 75 patients (14%) relapsed at a median follow‐up of 72 months. Of these, 65 patients relapsed within the first 3 years and had routine serum tumor markers measured. In total, 11 patients had abnormal tumor markers at the time of relapse (AFP, 0 patients; HCG, 6 patients; LDH, 4 patients; and HCG and LDH, 1 patient). Only 1 patient had an elevated tumor marker (LDH) before relapse, as defined by an abnormal imaging study (n = 64) or physical examination (n = 1), for which the treatment and outcome were not affected.

CONCLUSIONS:

Serum tumor marker levels did not aid in the early diagnosis of disease relapse in patients with stage I seminoma who were managed with surveillance. The current results indicated that routine measurement of serum tumor markers can be discontinued safely in seminoma surveillance schedules. Cancer 2012. © 2012 American Cancer Society.     

非小细胞肺癌患者血清淀粉酶A浓度与放射治疗生存时间及放射性肺炎相关性研究

目的 血清淀粉酶A(serum amyloid A,SAA)是一种非特异性急性时相反应蛋白,肿瘤患者血清中浓度可较健康人群明显增高.本研究旨在探索接受胸部放疗的非小细胞肺癌(non small cell lung cancer,NSCLC)患者的SAA浓度与总生存时间(overall survival,OS)和发生放射性肺炎相关性.方法 华中科技大学同济医院2012-07-15-2015-06-01共入组115例不可手术切除的或者局部晚期的NSCLC患者,并接受单纯胸部放疗或者同步放化疗.分别于放疗开始前(基线)、放疗2周、放疗4周及放疗完成后3个月内采血,并采用ELISA法检测SAA浓度.放疗完成后1年内根据CT-CAE 4.0标准记录患者放射性肺炎的发生情况.OS的计算方法为放疗开始至患者死亡或者至2016-03-31研究截止.采用SPSS 18.0及GraphPad Prism 5.0进行统计分析,检验水准α=0.05.结果 共114例患者进入数据分析,中位随访时间为17.1个月.全组患者基线SAA浓度中位值为101.4 μg/mL.＜和≥此中位浓度患者的中位OS分别为25.8和14.3个月,χ2 =5.519,P=0.019.多因素分析显示,性别、放疗剂量及基线SAA是OS延长的独立预后因素.放疗后SAA浓度(142.6 μg/mL)较放疗前明显降低(420.1 μg/mL),差异有统计学意义,t=3.50,P=0.001.放疗后出现≥2级和＜2级放射性肺炎患者的基线SAA平均浓度分别为476.7和113.0 pg/mL,两者相比差异有统计学意义,t=2.72,P=0.009.结论 在接受胸部放疗的局部晚期NSCLC患者中,SAA有可能作为预测放射性肺炎和预后的分子生物学指标.     

Serum Tumor Marker Levels might have Little Significance in Evaluating Neoadjuvant Treatment Response in Locally Advanced Breast Cancer

Background: To determine the potential value of serum tumor markers in predicting pCR (pathologicalcomplete response) during neoadjuvant chemotherapy. Materials and Methods: We retrospectively monitoredthe pro-, mid-, and post- neoadjuvant treatment serum tumor marker concentrations in patients with locallyadvanced breast cancer (stage II-III) who accepted pre-surgical chemotherapy or chemotherapy in combinationwith targeted therapy at Fudan University Shanghai Cancer Center between September 2011 and January 2014and investigated the association of serum tumor marker levels with therapeutic effect. Core needle biopsy sampleswere assessed using immunohistochemistry (IHC) prior to neoadjuvant treatment to determine hormone receptor,human epidermal growth factor receptor 2(HER2), and proliferation index Ki67 values. In our study, therapeuticresponse was evaluated by pCR, defined as the disappearance of all invasive cancer cells from excised tissue(including primary lesion and axillary lymph nodes) after completion of chemotherapy. Analysis of variance ofrepeated measures and receiver operating characteristic (ROC) curves were employed for statistical analysisof the data. Results: A total of 348 patients were recruited in our study after excluding patients with incompleteclinical information. Of these, 106 patients were observed to have acquired pCR status after treatment completion,accounting for approximately 30.5% of study individuals. In addition, 147patients were determined to be Her-2positive, among whom the pCR rate was 45.6% (69 patients). General linear model analysis (repeated measuresanalysis of variance) showed that the concentration of cancer antigen (CA) 15-3 increased after neoadjuvantchemotherapy in both pCR and non-pCR groups, and that there were significant differences between thetwo groups (P=0.008). The areas under the ROC curves (AUCs) of pre-, mid-, and post-treatment CA15-3concentrations demonstrated low-level predictive value (AUC=0.594, 0.644, 0.621, respectively). No significantdifferences in carcinoembryonic antigen (CEA) or CA12-5 serum levels were observed between the pCR andnon-pCR groups (P=0.196 and 0.693, respectively). No efficient AUC of CEA or CA12-5 concentrations wereobserved to predict patient response toward neoadjuvant treatment (both less than 0.7), nor were differencesbetween the two groups observed at different time points. We then analyzed the Her-2 positive subset of ourcohort. Significant differences in CEA concentrations were identified between the pCR and non-pCR groups(P=0.039), but not in CA15-3 or CA12-5 levels (p=0.092 and 0.89, respectively). None of the ROC curves showedunderlying prognostic value, as the AUCs of these three markers were less than 0.7. The ROC-AUCs for theCA12-5 concentrations of inter-and post-neoadjuvant chemotherapy in the estrogen receptor negative HER2positive subgroup were 0.735 and 0.767, respectively. However, the specificity and sensitivity values were at oddswith each other which meant that improving either the sensitivity or specificity would impair the efficiency ofthe other. Conclusions: Serum tumor markers CA15-3, CA12-5, and CEA might have little clinical significancein predicting neoadjuvant treatment response in locally advanced breast cancer.     

Vitronectin and dermcidin serum levels predict the metastatic progression of AJCC I–II early‐stage melanoma

Like many cancers, an early diagnosis of melanoma is fundamental to ensure a good prognosis, although an important proportion of stage I–II patients may still develop metastasis during follow‐up. The aim of this work was to discover serum biomarkers in patients diagnosed with primary melanoma that identify those at a high risk of developing metastasis during the follow‐up period. Proteomic and mass spectrophotometry analysis was performed on serum obtained from patients who developed metastasis during the first years after surgery for primary tumors and compared with that from patients who remained disease‐free for more than 10 years after surgery. Five proteins were selected for validation as prognostic factors in 348 melanoma patients and 100 controls by ELISA: serum amyloid A and clusterin; immune system proteins; the cell adhesion molecules plakoglobin and vitronectin and the antimicrobial protein dermcidin. Compared to healthy controls, melanoma patients have high serum levels of these proteins at the moment of melanoma diagnosis, although the specific values were not related to the histopathological stage of the tumors. However, an analysis based on classification together with multivariate statistics showed that tumor stage, vitronectin and dermcidin levels were associated with the metastatic progression of patients with early‐stage melanoma. Although melanoma patients have increased serum dermcidin levels, the REPTree classifier showed that levels of dermcidin <2.98 μg/ml predict metastasis in AJCC stage II patients. These data suggest that vitronectin and dermcidin are potent biomarkers of prognosis, which may help to improve the personalized medical care of melanoma patients and their survival.     

血AFP、CEA、CA-50、CA-199联合检测对原发性肝癌的诊断价值

目的　探讨肿瘤标志物AFP、CEA、CA -5 0、CA -199联合检测对原发性肝癌的诊断价值。方法　选择原发性肝癌 32例 ,行血清AFPRIA、CEARIA、CA -5 0IRMA、CA -199IRMA检测。结果　原发性肝癌 32例血AFP、CEA、CA -5 0、CA -199四项联合检测阳性符合率 10 0 % ,而各单项检测AFP为 6 8 8% (P <0 0 1) ,CEA 15 6 % (P <0 0 0 1) ,CA -5 0 78 1% (P <0 0 5 ) ,CA -19975 % (P <0 0 5 )。在原发性肝癌AFP阴性 10例中 ,血CEA值增高 2例 (2 0 % ) ,血CA -5 0值增高 9例 (90 % ) ,血CA -199值增高 8例 (80 % )。结论　血AFP、CEA、CA -5 0、CA -199四项标志物联合检测优于各单项检测 ,CA -5 0、CA -199对血AFP阴性原发性肝癌阳性符合率高 ,血CEA原发性肝癌诊断性符合率低 ,诊断意义较小。     

64排螺旋CT联合血清淀粉样蛋白A对直肠下段癌术前分期的临床价值

[目的]探讨64排螺旋CT联合血清淀粉样蛋白A(SAA)评估直肠下段癌术前分期的临床价值。[方法]2008年7月～12月于四川大学华西医院肛肠外科住院的119例直肠癌下段患者(肿瘤下缘距齿状线≤7cm),随机分为A组(58例)和B组(61例),A组术前行MSCT和SAA联合评估,B组术前只行MSCT评估。分别比较两组术前分期与术后病理分期。[结果]A组的术前T、N、M、TNM分期的准确度分别为89.7%、86.2%、100.0%和86.2%,B组分别为86.9%、70.5%、100.0%和67.2%。两组间N分期和TNM分期准确度的差异有统计学意义,P值分别为0.038和0.015。[结论]MSCT和SAA联合术前评估,能够提高直肠下段癌患者术前分期的准确性。     

Serum VEGF levels in women with a benign breast tumor or breast cancer

Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis and vascular permeability. Many types of malignant human tumors have been shown to produce VEGF. Recently, increased serum concentrations of VEGF (S-VEGF) have been reported in patients with various types of cancer, and high S-VEGF levels have also been associated with unfavorable prognosis. We have now measured S-VEGF in sera taken from 105 patients with a benign breast tumor or breast cancer. None of the women with a benign breast tumor had S-VEGF higher than 328 pg/ml (median, 57 pg/ml) whereas S-VEGF levels in metastatic breast cancer ranged from 7 to 1347 pg/ml (median, 186 pg/ml P=0.0018), and in locoregional breast cancer from 11 to 539 pg/ml (median, 104 pg/ml P=0.13). S-VEGF was higher in patients with locoregional ductal cancer (median, 107 pg/ml) than in those with locoregional lobular cancer (median, 44 pg/ml; P=0.029) or in patients with benign breast tumor (median, 57 pg/ml; P=0.033). Patients with metastatic cancer undergoing therapy had lower S-VEGF than those who had symptomatic treatment only (P=0.021). The results indicate that dissemination of breast cancer may be accompanied by an elevation of circulating VEGF and that primary ductal cancers are associated with higher S-VEGF levels than lobular cancers or benign breast lesions.