Study on the clinical usefulness of NCC-ST-439 in breast cancer

We investigated the usefulness of NCC-ST-439, a new tumor marker in breast cancer. The positive rate of NCC-ST-439 in cases of primary breast cancer was 46.9%. In cases of primary breast cancer, there were no significant differences in average and positive rate among each group of patient age, tumor size, number of metastatic node, clinical stage and status of hormone receptor (ER, PgR). The positive rate of NCC-ST-439 in early breast cancer was as high as that in advanced case. NCC-ST-439 had better sensitivity than CEA and CA15-3, and decreased in serum level after the curative operation. We concluded that NCC-ST-439 is useful as a screening marker for the detection of early breast cancer and as a post operative monitoring marker for the surveillance of the recurrence.     

Clinical evaluation of serum level of NCC-ST-439 as a new tumor marker for colorectal diseases--fluctuation of serum NCC-ST-439 in patients with colorectal cancers before and after surgery

Serum level of NCC-ST-439, a new tumor marker, was clinically evaluated in patients with benign and malignant colorectal diseases in comparison with serum CEA and CA 19-9. Fluctuation of serum levels of NCC-ST-439 in patients with colorectal cancers was especially studied. Serum level of NCC-ST-439 was determined by sandwich type NCC-ST-439 EIA kit, which was developed by Nippon Kayaku Co., Ltd., in 93 cases of primary colorectal cancers, 98 cases of recurrent colorectal cancers and 60 cases of benign colorectal diseases. Positive rate of serum NCC-ST-439 in patients with primary colorectal cancers was 8.6% in Dukes A cases, 14.3% in Dukes B cases, 37.5% in Dukes C cases and 78.9% in Dukes D cases. Positive rate in patients with recurrent colorectal cancers was 42.8%. On the other hand, false positive rate in patients with benign colorectal diseases was 5.0%, which was relatively low in comparison with serum CEA and CA 19-9. While serum NCC-ST-439 was well correlated with serum CEA and CA 19-9 in primary colorectal cancers, NCC-ST-439 value in benign colorectal diseases showed no correlation with serum CEA and CA 19-9. In patients with primary colorectal cancers, curative resection was applied for in 40 cases in which the value recovered to the normal range after resection. In contrast, all 8 cases, which received non-curative resection, showed the increase of serum NCC-ST-439 value. In cases of recurrent colorectal cancers, some cases, which responded against chemotherapy, obviously showed a decrease of NCC-ST-439 value. These facts indicated that serum level of NCC-ST-439 could monitor the clinical effects of surgical treatment, chemotherapy and radiation therapies and it could be used as a marker for colorectal cancers. In conclusion, determination of serum NCC-ST-439 value was clinically useful for the diagnosis and monitoring for patients with colorectal cancers as a new distinct tumor marker.     

Serum and immunohistochemical studies of NCC-ST-439 in breast cancer

It has been thought that NCC-ST-439 antigen (ST-439) is a tumor-related carbohydrate antigen. The authors conducted serum and immunohistochemical studies to investigate the clinical significance of ST-439 in breast cancer. The level of serum ST-439 was elevated in advanced and recurrent breast cancers. In comparison with CEA and CA15–3, ST-439 was superior in sensitivity but inferior in specificity to these markers. The level of serum ST-439 showed no correlation with the levels of CEA or CA15–3. In the combination assay of these three markers, 80.6% of recurrent cases and 33.8% of primary cases were positive. Immunohistochemically, the expression of ST-439 was observed in 28.1% of noncancerous mammary duct epithelium and in 38.1% of the cancerous portion. From the above, we concluded that ST-439 was a tumor-related antigen and could be a tumor marker with high sensitivity in breast cancer. © 1993 Wiley-Liss, Inc.     

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.     

Clinical significance of a tumor marker NCC-ST-439 in breast cancer--a comparative study with CA 15-3, CEA and TPA

We compared a new tumor marker NCC-ST-439 (ST-439) with CA 15-3, CEA and TPA for its clinical usefulness in 600 patients with breast cancer (81, primary; 49, recurrent; 470, non-recurrent), and confirmed the following results. The sensitivity of ST-439 (41.5%) was significantly higher (p less than 0.05) than that of CA 15-3 (26.2%), CEA (28.5%) and TPA (26.9%). The specificity of ST-439 (84.5%), however, was considerably lower (p less than 0.01) than these other three markers. In primary cases, the positive rate of ST 439 (34.6%) was significantly higher (p less than 0.05) than that of the other markers, and was remarkable in the early stage. As to the positive rate at the various metastatic sites, there were a few differences among these four markers. Because of no significant correlation among these markers, combination assay with ST-439, CA 15-3 and CEA showed an excellent sensitivity (57.7%). These results suggest that ST-439 is a useful tumor marker not only in monitoring the recurrence, but also in the diagnosis of primary cancer.     

Study on the clinical usefulness of NCC-ST-439 in cases of digestive tract cancer

NCC-ST-439 is a monoclonal antibody established from human stomach cancer xenografted nude mice. The values of NCC-ST-439 were measured in 139 cases with various digestive tract cancers and 294 cases with benign digestive tract diseases with the NCC-ST-439 EIA kit (Nihon Kayaku Co., Ltd.), and its clinical usefulness was compared with those of CA19-9 and CEA. The positive rates of NCC-ST-439 in cases of digestive tract cancer were high, i.e., 66.7% for cancer of the bile duct, 58.3% for pancreatic cancer and 52.9% for colorectal cancer. In the benign digestive tract diseases, the overall positive rate seen in case of cholelithiasis and cholangitis, chronic gastritis, benign colorectal diseases and hepatitis, was only 3.7%. The positive rate of NCC-ST-439 was lower than those for CA19-9 and CEA in cases of stomach cancer, colorectal cancer and liver cancer, but it was the same as that of CA19-9 and higher than that of CEA in cases of biliary tract cancer and pancreatic cancer. The false positive rate of NCC-ST-439 in benign diseases of the digestive tract was the lowest among the three markers. With respect to sensitivity, specificity and efficiency, CA19-9 showed the highest sensitivity, but NCC-ST-439 and CEA showed better specificity than CA19-9, and NCC-ST-439 showed the highest efficiency. In combination assays using combinations of NCC-ST-439, CA19-9 and CEA, the positive rates for ST-439 alone were 22.1% for stomach cancer, 52.9% for colorectal cancer, 15.0% for liver cancer and 58.3% for pancreatic cancer, while the combined rates increased to 51.9%, 70.6%, 75.0% and 66.7%, respectively. In an investigation of changes with time in NCC-ST-439 values during chemotherapy of various types of digestive tract cancer, there was a decrease in PR cases, no change in NC cases and a tendency to increase in PD cases. These results suggested that it was possible to apply NCC-ST-439 clinically.     

Significance of serum tumor markers in monitoring advanced breast cancer patients treated with systemic therapy: A prospective study

OBJECTIVE: The significance of serum tumor markers in monitoring advanced breast cancer patients is still controversial. To clarify this issue, the Tumor Marker Study Group of the Japanese Breast Cancer Society conducted a prospective study. METHODS: Patients with advanced breast cancer who were treated with systemic therapy between January and December 2002 were recruited from five collaborative institutes in Japan. The patients were monitored every four weeks using three serum tumor markers, CEA, CA 15-3 and NCC-ST-439 during the therapy. RESULTS: Findings from 108 eligible patients were analyzed. The pretreatment positivity rates were 51.9% for CEA, 50% for CA 15-3, and 34.3% for NCC-ST-439. The changes in each marker level at 8 and 12 weeks but not at 4 weeks after the start of therapy seemed to correlate with the response to therapy in pretreatment marker-positive patients but not in negative patients. The Cox proportional hazard model revealed a greater than 20% reduction in CEA, CA 15-3 or NCC-ST-439 levels at 4, 8 and/or 12 weeks after the start of therapy to be an independent predictive factor for longer time-to-progression (TTP) in pretreatment marker-positive patients. CONCLUSION: This prospective study supported the findings obtained from our previous retrospective study that in pretreatment marker-positive patients 1) the changes in serum tumor marker levels after the start of therapy correlate with the response to therapy; and 2) a greater than 20% reduction in the tumor marker levels was a favorable predictive factor for TTP during systemic therapy. When the pretreatment serum level of these markers is over the respective cut-off value, sequential measurement of them may be useful for evaluating the efficacy of treatment as well as monitoring the outcome of patients with advanced breast cancer.     

Clinical evaluation of a new tumor marker, CA 15-3, in breast cancer; a comparative study with CEA

Recently, a new RIA method has been developed by Centocor Co., utilizing the monoclonal antibody CA 15-3. We performed a clinical trial to evaluate its utility as a tumor marker for breast cancer in comparison with CEA. We set 15 U/ml as the cut-off value of serum CA 15-3 level from results acquired from controls; 10 volunteers and 17 patients with non-malignant diseases. The CA 15-3 positive rate among the cases of primary breast cancer was 13.3%, which was of poor diagnostic value. In the recurrent cases the positive rate of CA 15-3 was 72.0%, which was valuable compared with that of serum CEA, 52.0%. In the cases of primary cancers other than breast cancer, the positive rate of CA 15-3 was 6.9%.     

Tumor marker levels elevate false-positively in postsurgical Breast Cancer patients with high sgpt levels or with receiving oral 5-FU or its derivatives

Background  False elevation of tumor marker levels (TM) has been encountered in some postsurgical breast cancer patients. Methods  We investigated 33 postsurgical breast cancer patients whose TM (CEA, CA15-3, NCC-ST-439, or BCA225) measured every 3 months, showed elevation 3 times in a row in a 6-month period, and in whom metastases were not detected at the end of the 6-month period. Nine patients developed recurrence within 36 months of the end of the 6-month period and 24 patients did not develop recurrence for more than 36 months after the end of the 6-month period. Results  Seven patients who stopped treatment with oral 5-FU or its derivatives because of severe nausea and appetite loss did not develop recurrence. Normalization of TM (CEA, NCC-ST-439, or BCA225) manifested within 3 months of the interruption of the medication. Six patients who showed simultaneous increase in serum glutamic-pyruvic transaminase (sGPT) and TM (CEA or BCA225) in the initial 6 months did not develop recurrence. Three of 6 patients did not take any anti-cancer drugs. Correlation coefficiencies of sGPT with CEA in 4 patients were 0.467, 0.569, 0.738, and 0.910 and those of sGPT with BCA225 in 3 patients were 0.663, 0.826, and 0.840. Conclusions  A false-positive increase in CEA, NCC-ST-439 or BCA225 might be caused by treatment with oral 5-FU or its derivatives. CEA or BCA225 elevates false-positively in patients with high sGPT levels.     

A case of breast cancer metastatic to the head of the pancreas

A case of breast cancer that metastasized to the head of the pancreas 6 years and 8 months after mastectomy is reported. The pancreas head metastasis was associated with general fatigue and obstructive jaundice. The serum levels of CEA, CA15-3 and NCC-ST-439, tumor markers of breast cancer, were within normal limits, but CA15-3 was immunohistochemically demonstrated in the resected metastatic lesion, in a manner similar to lobular carcinoma of the breast.     

Sandwich Radioimmunometric Assay with Murine Monoclonal Antibody, NCC-ST-439, for Serological Diagnosis of Human Cancers

Sandwich radioimmunometric assay (RIA) for a new tumor-associated carbohydrate antigen defined by a monoclonal antibody (MoAb), NCC-ST-439, was developed and the antigen levels were determined in sera of normal donors, and patients with various malignant and non-malignant disorders. In normal donors, 97.0% (226/233) of sera were antigen-negative (less than 12 units/ml) except for 7 serum samples from young females. In patients with malignant disorders, 34.2% (82/240) were antigen-positive, in particular 64.0% (16/25) of patients with pancreatic carcinoma, 66.7% (16/24) of patients with recurrent colorectal carcinoma and 54,5% (6/11) of patients with recurrent breast carcinoma. In patients with non-malignant disorders, 6.0% (7/116) were antigen-positive. The positive rate in benign hepatobiliary disorders, including gallstones, hepatitis and liver cirrhosis, was especially low at 4.3% (1/23). We concluded that determination of serum NCC-ST-439 antigen would be useful in serodiagnosis of carcinoma patients.     

A case of breast cancer metastatic to the pituitary gland

A case of breast cancer that developed pituitary metastasis 22 years after mastectomy is reported. The pituitary metastasis was associated with hypopituitarism, impairment of the visual field and later diabetes insipidus. The serum levels of CA15-3 and NCC-ST-439, tumor markers of breast cancer, were increased, and CA15-3 (DF3) and NCC-ST-439 were demonstrated in the resected pituitary metastatic lesion immunohistochemically.     

C-erbB-2 protein in the sera of breast cancer patients

Summary The c-erbB-2 protein was measured in sera of patients with breast cancer or benign breast diseases to study the significance of this protein as a tumor marker. The mean value and positive rate for this protein (assuming 20 U/ml as the cut-off value) were 11.8 U/ml (0%) in benign breast disease (n=30), 11.8 U/ml (3.1%) in stage I/II primary breast cancer (n=64), 38.2 U/ml (29.4%) in stage III/IV primary breast cancer (n=17), 17.9 U/ml (33.3%) in locally recurrent breast cancer (n=12), 298.4 U/ml (51.0%) in recurrent breast cancer with distant metastases (n=51), and 12.9 U/ml (0%) in those with no evidence of recurrence (n=57). Thus, the serum c-erbB-2 protein level was significantly higher in the distant metastatic group. In patients with distant metastases, there was a close association between expression of c-erbB-2 protein in the primary tumor and the serum c-erbB-2 protein level. On the basis of these results, serum c-erbB-2 protein was thought to be useful as a tumor marker for postoperative monitoring of breast cancer, especially in patients positive for expression of this protein in primary cancer tissue.     

Serum c-erb B-2 in Breast Cancer Patients

The c-erb B-2 oncogene product in serum (serum c-erb B-2) was measured by an enzyme-im-munoassay kit. The 12 U/ml cut-off level was estimated as the mean plus two standard deviations for 250 healthy women. With this cut-off level increased serum c-erb B-2 was found in 12.0% of primary breast cancer cases (n = 25), in 4.9% of non-recurrent breast cancer patients (n = 82), and in 31.4% of patients with recurrent breast cancer (n = 35). In patients with primary and recurrent breast cancer, whose sera were assayed concurrently for serum c-erb B-2, CEA and CA15-3, the positive rates of these markers were fairly similar. However, their combined use significantly increased the sensitivity as compared to the use of any one marker alone.     

乳腺癌组织中Cath-D、c-erbB-2的表达及其与肿瘤标志物水平、淋巴结转移的相关性

目的观察乳腺癌患者病理组织中Cath-D、c-erbB-2的表达情况,并分析其与淋巴结转移、肿瘤标志物水平的相关性。方法选取接受手术治疗的乳腺癌患者为研究对象,同时选取同期接受手术治疗的乳腺纤维腺瘤患者为对照。观察乳腺癌(有、无淋巴转移组)、乳腺纤维腺瘤患者组织切片Cath-D、c-erbB-2阳性表达情况,比较乳腺癌(有、无淋巴转移组)、乳腺纤维腺瘤患者血清肿瘤标志物水平的差异,分析淋巴结转移的乳腺癌患者Cath-D、c-erbB-2阳性表达与肿瘤标志物水平的相关性。结果乳腺癌组患者的组织切片Cath-D、c-erbB-2阳性表达率均高于乳腺纤维腺瘤组(χ²=51.796、70.090,P均<0.001);有淋巴结转移的乳腺癌患者组织切片Cath-D、c-erbB-2阳性表达率高于无淋巴结转移组。乳腺癌组患者血清CEA、CA15-3、CA125水平高于乳腺纤维腺瘤组(t=52.270、58.784、76.349,P<0.001);乳腺癌组有淋巴结转移组患者血清CEA、CA15-3、CA125水平高于无淋巴结转移组(t=16.681、27.880、23.216,P<0.001)。有淋巴结转移的乳腺癌患者Cath-D、c-erbB-2阳性表达率与血清CEA、CA15-3、CA125水平正相关。结论乳腺癌患者病理组织中Cath-D、c-erbB-2阳性表达率较高,且与淋巴结转移和肿瘤标志物水平相关。     

核素骨显像联合肿瘤标记物检测对乳腺癌骨转移的诊断价值

目的：观察核素骨显像联合肿瘤标记物对乳腺癌骨转移的诊断价值。方法选择乳腺癌患者82例,按照核素骨显像结果分为转移组43例及未转移组39例,另选取40例健康体检女性作为对照组。观察核素骨显像以及肿瘤标记物检测结果,并对其诊断价值进行考察。结果转移组血清CA125、CA15-3及CEA表达水平及阳性率显著高于未转移组及对照组,骨转移灶数目≤2患者血清CA125、CA15-3以及CEA表达水平及阳性率均显著低于骨转移灶数目＞2的患者,差异均具有统计学意义（P＜0．05）。且随着骨转移分级程度的升高,患者乳腺癌相关肿瘤标记物CA125、CA15-3及CEA表达水平及阳性率均呈升高趋势,各分级间差异有统计学意义（ P＜0．05）。结论核素骨显像联合肿瘤标记物检测可提高诊断敏感性,对于乳腺癌骨转移的诊断具有重要的参考价值。     

Combined measurement of the c-erbB-2 protein in breast carcinoma tissues and sera is useful as a sensitive tumor marker for monitoring tumor relapse

c-erbB-2 protein levels in tissue extracts and sera were determined in a retrospective analysis of 158 patients who underwent surgical resection of breast carcinoma by means of a sandwich enzyme immunometric assay (EIA) using monoclonal antibodies (MAbs) directed to the extracellular domain of the c-erbB-2 oncogene protein (ErbB-2). In the analysis of tissue extracts, 48 samples (30.3%) showed ErbB-2 levels exceeding 18.0 ng/mg protein (group A), while in 110 samples these levels were below 18.0 ng/mg protein (group B). Immunohistochemical examination of resected tissues using anti-c-erbB-2 antibody revealed positive staining in 93.8% (45/48) in group A and 13.6% (15/110) in group B (p < 0.00001). The proportion of patients who preoperatively showed a serum ErbB-2 value above 5.4 ng/ml was 52.1% (25/48) in group A and 10.0% (11/110) in group B (p < 0.00001). Thus, the level of ErbB-2 in tissue extracts was significantly associated with immunohistochemistry and ErbB-2 levels in preoperative sera. During follow-up, 48 patients (30.3%) developed recurrent disease: 17 in group A (35.4%) and 31 in group B (28.2%). From an ROC analysis based on the postoperative serum ErbB-2 levels in patients either with or without relapse, the cutoff value of serum ErbB-2 for tumor relapse was determined to be 6.5 ng/ml. The sensitivity of serum ErbB-2 in patients with relapsed breast cancer was 58.3% (21/36) overall, 84.6% (11/13) in group A and 43.5% (10/23) in group B. In the analysis of serum samples taken before relapse, 90.9% (10/11) of the subjects in group A and 26.7% (4/15) of those in group B were shown to be positive for serum ErbB-2. Serum ErbB-2 in group A was a more sensitive marker than other tumor markers such as CEA, CA15-3, and NCC-ST-439. Thus, the determination of ErbB-2 in tissue extracts of breast carcinoma may be useful for assessing c-erbB-2 protein expression in the primary tissue and indicates that serum ErbB-2 may be a sensitive marker for monitoring tumor relapse.     

早期乳腺癌CEA mRNA阳性循环细胞检测及其临床意义

[目的]研究早期乳腺癌外周血中CEAmRNA阳性循环肿瘤细胞的临床意义。[方法]检测50例早期乳腺癌患者、24例乳腺良性疾病患者和20例健康志愿者外周血CEAmRNA阳性细胞。[结果]早期乳腺癌患者外周血CEAmRNA阳性率为14．0％,CEAmRNA阳性率与TNM分期（P=0．004）、肿瘤大小（P=0．027）、血清CEA（P=0．000）水平异常升高显著性相关。CEAmRNA阳性患者中位无瘤生存期为18个月,与阴性患者比较差异有统计学意义（P=0．000）。[结论]CEAmRNA阳性循环肿瘤细胞可能是早期乳腺癌患者监测复发转移的重要指标和独立的预后因素。     

Clinical evaluation of a combination assay of CEA, CA-19-9 and TPA in patients with colorectal cancer

The effectiveness of serum CEA (56 cases), CA-19-9 (53 cases) and TPA (48 cases) in patients with colorectal cancer has been evaluated. The preoperative sensitivity and specificity of CEA and CA 19-9 were found to be almost the same in level but the level of TPA was low. In 20 cases recurrent, the sensitivity of the marker was 66.7% in the liver, 60% in the lung, and 66.7% in the local recurrence of primary foci. In these recurrent cases, serum CEA in initially elevated to 65%, CA 19-9 to 25%, and TPA to only 10%. In diagnostic rate imaging or in our clinical findings, however, the frequency was almost the same as tumor markers.     

Clinical significance of serum CEA determination in the diagnosis of colo-rectal cancer

Serum CEA levels of 581 specimens obtained from 350 colo-rectal cancer patients and 61 specimens from 54 non-tumor subjects were determined by sandwich method of CEA-EIA McAb kit supplied by the Beijing Institute of Biological Products. In patients with primary colo-rectal cancer, the serum CEA level was 15.0 +/- 52.1 ng/ml and 37.9% of patients gave a CEA level greater than 5 ng/ml. In recurrent colo-rectal cancer patients, serum CEA increased to 124.2 +/- 454.8 ng/ml with a positive rate of 78.0%. Both the CEA value and the positive rate of patients in clinically tumor-free period after surgery were 2.9 +/- 2.2 ng/ml and 16.5%, respectively. Serial follow-up CEA assays in selected cases were helpful to reflect the clinical status. Generally, CEA is useful to predict prognosis and to guide follow-up management.