Sustained complete response in lung metastasis of breast cancer by goserelin--report of two cases

We report two patients with lung metastasis of breast cancer who had durable complete responses (CR) with goserelin. The first patient was a 48-year-old woman diagnosed with left breast cancer (T1N0M0, Stage I) at the age of 40, for which she underwent mastectomy. The tumor was estrogen receptor (ER) and progesterone receptor (PgR) positive. She received tamoxifen for 2 years as adjuvant therapy. After 8 years and 7 months, a lung metastasis was found by chest X-p, and treatment with goserelin was started. After 11 months of this treatment a CR was achieved, and the response lasted 3 years and 5 months. The second patient was a 38-year-old woman with a diagnosis of lung metastasis. She underwent right mastectomy at the age of 29 for breast cancer (T2N1M0, Stage IIB), and the tumor was ER and PgR positive. She received tamoxifen and doxifluridine for 2 years as adjuvant therapy. Eight years and 6 months after the mastectomy, a lung metastasis was found by chest X-p, and goserelin treatment was started. After 8 months of this treatment, chest X-p and CT revealed a complete regression of the lung metastasis, and response lasted 1 years and 7 months. Serum estradiol levels were suppressed below 10 pg/ml during the treatment in both patients. These results indicate the usefulness of LH-RH agonist in the treatment of recurrent breast cancer.     

Clinical evaluation of new serum tumor markers CA M26 and CA M29 in patients with primary breast cancer

Serum CA M26 and CA M29 values were determined in 125 women: 46 patients with primary breast cancer, 49 patients with benign breast disease, and 30 controls. The mean CA M26 and CA M29 values in breast cancer patients were higher than in patients with benign breast disease and in control subjects. When we set the cut-off level at 40 kU/1 for CA M26, 15/46 (33%) of all breast cancer patients, 11/20 (55%) of breast cancer patients with axillary node involvement, 1/1 breast cancer patient with distant metastases, 4/49 (8%) of patients with benign breast disease, and 7/30 (23%) of control subjects were above this cut-off level. For comparison, at the cut-off level of 10 kU/1 the CA M29 test was positive in 30/46 (65%) cancer cases, in 16/20 (80%) of cancer patients with nodal involvement, in 9/49 (18%) of the patients with benign breast disease, and in 10/30 (33%) of control subjects. Patients with axillary nodal metastasis showed higher values than patients without metastasis in both tests. When we used a cut-off level of 15 kU/1 for CA M29, 24% (11/46) of all breast cancer patients, 35% (7/20) of breast cancer patients with axillary node involvement, 4% (2/49) of patients with benign breast disease, and 0% of control subjects were above this cut-off level. The combination of CA M26 at the 40 kU/l cut-off level and CA M29 at the 10 kU/l cut-off level reached the diagnostic sensitivity of 0.65, specificity of 0.78, and efficiency of 0.72. In breast cancer detection among patients with breast problems serum marker CA M29 reached the sensitivity of 0.65 at the specificity level of 0.82. Our results suggest that the CA M29 marker alone is as good as the panel of two markers (CA M26, CA M29) in breast cancer diagnostics. Thus it seems that CA M29 is a promising serum tumor marker in breast cancer.     

The surgical management of patients following neoadjuvant chemotherapy for locally advanced breast cancer

The aim of this study was to evaluate the role of surgery in patients who achieve a complete clinical response (cCR) to neoadjuvant chemotherapy for locally advanced breast cancer. A retrospective study of patients with either large central (T2 >30 mm, N0 or N1, M0) or locally advanced (T3, N0 or N1, M0) tumours who received neoadjuvant chemotherapy followed by surgery to the breast and axilla and postoperative radiotherapy. All patients had operable disease at presentation. A total of 133 patients were included. Overall, 43 (32%) patients achieved a cCR following chemotherapy. Of these, 19 patients had no pathological evidence of disease in the breast (pCR) or on imaging or core biopsy and these patients received only adjuvant radiotherapy to the breast. A further 5 patients had no pathological evidence of cancer following breast surgery. 126 patients had an axillary clearance. Increasing response to chemotherapy was related to fewer pathologically involved nodes, but 7 of 24 (29%) patients with a pCR still had evidence of axillary metastases. This is the principal conclusion of the study at the present time. The patients were followed-up for a median of 30 months (range 5–83 months) with a local recurrence rate of 3.8%. There was no difference in either distant recurrence-free or overall survival between patients experiencing a pCR and the remainder.     

外周血循环肿瘤细胞在不同阶段和不同类型肺癌中的价值研究

目的 探讨外周血循环肿瘤细胞(CTC)在不同阶段、不同类型肺癌中的价值.方法 选取148例肺癌患者为肺癌组,79例肺部良性疾病患者为肺部良性疾病组,15例健康者为健康对照组.采用免疫磁珠阴性富集法捕获外周血中CTC;采用流式细胞仪检测免疫荧光染色后的CTC,并分析其与肺癌患者临床特征的关系.结果 肺部良性疾病组与健康对照组的CTC检出率比较,差异无统计学意义(P﹥0.05);肺癌组的CTC检出率明显高于肺部良性疾病组和健康对照组(P﹤0.01).临床分期为Ⅲ~Ⅳ期、M分期为M1期的肺癌患者的CTC检出率分别高于临床分期为Ⅰ~Ⅱ期、M分期为M0期的患者(P﹤0.05),而不同性别、年龄、组织学类型、T分期和N分期的肺癌患者的CTC检出率比较,差异均无统计学意义(P﹥0.05).结论 大部分肺癌中均存在CTC,其检出率与肺癌患者的临床分期及远处转移情况有关,早期检测CTC有利于肺癌患者的病情评估.     

Quintuple carcinomas with metachronous triple cancer of the esophagus, kidney, and colonic conduit following synchronous double cancer of the stomach and duodenum

A patient who had undergone radical gastrectomy for synchronous gastric cancer (T(1)N(0)M(0), stage I) and duodenal cancer (Tis, stage 0) in November 1987 was found to have esophageal cancer in November 1994, and underwent radical thoracolaparotomy at our hospital (T(1)N(0)M(0), stage I). After follow-up for about 3.5 years, renal cancer was detected in April 1998, and radical nephrectomy was performed (T(1)N(0)M(0), stage I). Two years later, in April 2000, the patient was found to have a polypoid lesion in the colonic conduit used for reconstruction after esophagectomy, and endoscopic mucosal resection was performed (Tis, stage 0). The patient remains under careful follow-up, including observation of the colonic conduit and the residual large intestine.     

TPS in breast cancer--a comparative study with carcinoembryonic antigen and CA 15-3.

The serum levels of tissue polypeptide antigen were determined using the M3 monoclonal antibody (TPS) and compared with the serum levels of carcinoembryonic antigen (CEA) and breast carcinoma antigen 15-3 (CA 15-3) in 96 patients with benign breast tumors, in 25 breast cancer patients with no evidence of disease, in 139 preoperative breast cancer patients and in 298 samples of 25 breast cancer patients during therapy monitoring (4-22 samples per patient). The 95th percentile of TPS in 89 apparently healthy females was 51 U/l. The 95th percentile of TPS in patients with benign breast tumors was 55 U/l. The maximum TPS level in breast cancer patients with no evidence of disease was 56 U/l. In preoperative breast cancer the number of patients with TPS levels above the 95th percentile of TPS in benign breast tumors was significantly higher in stage III breast cancer as compared with stage I+II. This was not established for CEA and CA 15-3. During therapy monitoring TPS followed the course of the disease faster than CEA and CA 15-3 in patients with bone metastases, liver metastases, lung metastases and pleural effusion, with one exception. TPS levels could be correlated with progression of disease in patients with normal and steady levels of CEA and/or CA 15-3.     

Assesssment of the effect of pretreatment with neoadjuvant therapy on primary breast cancer.

Patients with invasive cancer of the breast (T1-4, N0-2, M0) were assigned to pretreatment based on oestrogen receptor (ER) status; patients with ER-negative tumours received chemotherapy [mitozantrone, methotrexate and mitomycin C (MMM)] for 3 months, patients with ER-positive tumours underwent endocrine therapy [luteinising hormone releasing hormone (LHRH) agonist goserelin (leuprolide-premenopausal) or 4-hydroxyandrostenedione (formestane-post-menopausal)] for 3 months. Of the first 100 patients assessed at 3 months, 47 with ER-positive tumours had a 40.4% response (premenopausal 53.8%; post-menopausal 35%) and 53 with ER-negative tumours had a 60% response (premenopausal 57%; post-menopausal 63%). Patients with early breast cancer (T1/T2) had a complete clinical resolution in 41% (16/39) of cases after MMM and in 20% (7/35) of cases following endocrine therapy compared with 14% (2/14) advanced tumours (T3/T4) following MMM and (0/12) following endocrine therapy. However, in those patients achieving a complete clinical response, subsequent appropriate surgery showed that 16 of 19 patients (84%) had evidence of residual viable tumour on histological examination.     

Prediction of response to neoadjuvant chemotherapy in breast cancer patients by circulating apoptotic biomarkers nucleosomes,DNAse, cytokeratin-18 fragments and survivin

Biomarkers predicting response to neoadjuvant chemotherapy in locally confined breast cancer (LBC) are highly needed. We prospectively assessed serial blood levels of apoptotic biomarkers nucleosomes, DNAse activity, cytokeratin-18 fragments (M30) and survivin in 51 LBC patients and correlated them with response to neoadjuvant treatment and established tumor markers. As controls, we used 31 healthy subjects, 13 patients with benign diseases and 28 with metastatic breast cancer (MBC). Levels of nucleosomes and survivin were elevated in LBC and MBC while M30, CEA and CA 15-3 levels were only elevated in MBC. During neoadjuvant chemotherapy, LBC patients with no change of disease (N = 13) had significantly higher pretherapeutic levels of nucleosomes than patients with remission (N = 38). We conclude that apoptotic biomarkers bear valuable information for diagnosis and therapy response prediction in LBC patients.     

Anti-malignin antibody in serum and other tumor marker determinations in breast cancer

In this study, 154 healthy volunteers and 76 patients were tested using the anti-malignin antibody in serum (AMAS) test. Of the 154 volunteers, three were AMAS positive. After further examination, two were positive for cancer and one had a history of ulcerative colitis. Tumor biopsies of 43 suspicious mammography patients revealed that 32 were cancerous and 11 were benign by pathology. For the cancer patients, 31/32 were positive for the AMAS test, while 4/11 of the pathological benign cases were AMAS positive. In comparison to cancer antigen tests, AMAS was more sensitive (97%) in detecting breast cancer than CEA (0%), CA 15-3 (10%), CA 19-5 (5%) or CA 125 (16%) in the same patients.     

Latent heterogeneity of prognosis among cancer patients

There is a considerable variation in individual lifespan among cancer patients with identical diagnosis. We used damped exponential approximation, which includes both single- and double-compartment extension, for radiobiological assessment of survival curves among cases of breast, lung and oro-pharyngeal cancer. It was shown that in certain cases (breast--T2N1-2M0T3N1-2M0 and oro-pharyngeal cancer--T2-4N1-3M0) the curves can be identified with the two compartments which in turn are associated with different rates of mortality. The remaining curves represented either the slow rate (breast cancer--T1N1-2M0) or the fast one (non-small lung cancer) alone. The mean values of the fast or slow mortality differed 7-fold with high probability; they were stable and almost independent of tumor site or therapeutic modality. The double-rate curves pointed to a possible wide range of prognosis prior to treatment.     

Expression of S100A4 and Met: potential predictors for metastasis and survival in early-stage breast cancer

BACKGROUND: To formulate individually tailored therapy for patients with early-stage breast cancer, it is necessary to identify biomarkers for predicting metastasis and survival. METHODS: A homogeneous cohort of 92 T1-2N0M0 breast carcinoma patients with a long-term follow-up were divided into two groups: the metastasis group (n = 41) and the disease-free group (n = 51). We evaluated the ability of risk discrimination of six biomarkers, including S100A4, Met, bcl-2, p53, survivin, and HER-2/neu, in early-stage breast cancer. RESULTS: In multiple logistic regression analysis, only S100A4 expression (odds ratio = 5.37, p = 0.008) and Met expression (odds ratio = 6.91, p = 0.002) were independent predictors of distant relapse. Multivariate Cox models showed S100A4 and Met expressions were associated with 10-year disease-free survival (DFS) (risk ratio 3.2 and 4.0, respectively); however, tumor size and histological grade were not significant predictors. The 10-year DFS of T1-2N0M0 patients was 55.4%. T1-2N0M0 patients with S100A4-positive tumors had a significantly worse 10-year DFS than those with S100A4-negative tumors (29.0 vs. 68.9 %, p = 0.001). The 10-year DFS in T1-2N0M0 patients with Met-negative tumors was 82.4 vs. 39.7% if Met expression was positive (p = 0.0002). S100A4, but not Met, was still a significant predictor of 10-year DFS in T1N0M0 breast carcinoma patients (p = 0.02). For the T2N0M0 subgroup, both S100A4 and Met were significantly correlated with survival. The 10-year DFS of T2N0M0 patients with S100A4-negative and Met-negative tumors was 92.3%; in those with S100A4-positive and Met-positive tumors, however, it was only 11.8%. CONCLUSIONS: S100A4 expression is an indicator of a poor prognosis for T1N0M0 breast cancer. In addition, the combination of S100A4 and Met expression gives the best risk group discrimination in the T2N0M0 subgroup. S100A4 expression appears to be an earlier step in the metastatic progression compared to Met expression in early-stage breast carcinoma.     

Breast cancer skin test antigens of increased sensitivity prepared from vesicular stomatitis virus-infected tumor cells

Crude membrane (CM) extracts were prepared from five cultured breast tumor lines (MDA-MB-157, MDA-MB-231, ZR75-1, HS0578T, and MCF-7) which had been infected with vesicular stomatitis virus (VSV) to augment their antigenicity. In skin test trials, CM extracts of uninfected MCF-7 cells elicited positive response in 0 of 13 (0%) tests in breast cancer patients, while VSV-MCF-7 elicited positive responses in 11 of the same 13 patients (84.6%). CM extracts of VSV-ZR75-1 and VSV-MCF-7 elicited greater delayed hypersensitivity responses (mm induration at 48 hr) in breast cancer patients than in patients with lung carcinoma or melanoma. Although the sensitivity of VSV-ZR75-1 was too low (ten of 28, or 35.7% of tests positive) to be useful as a skin test antigen, VSV-MCF-7 elicited positive responses in 30 of 38 (78.9%) tests in breast cancer patients, as compared to two of 15 (13.3%) and two of 13 (15.4%) of tests in patients with lung carcinoma and melanoma, respectively. The "virus-augmented" CM extract of cultured MCF-7 cells exhibited markedly greater sensitivity as compared to control MCF-7 extracts (P less than .005), with a high degree of specificity for breast cancer patients as compared to patients with the other neoplasms (P less than .00001). The results of skin testing with VSV-MCF-7 CM extracts demonstrated antigenic cross-reactivity with a large number of breast cancer patients, a finding of great importance for any potential immunotherapy and/or immunodiagnosis.     

A Phase II trial of Zoladex combined with CEF chemotherapy as neoadjuvant therapy in premenopausal women with hormone-responsive,operable breast cancer

The purpose of this study was to evaluate the efficacy and safety of Zoladex combined with CEF chemotherapy as neoadjuvant therapy in hormone-responsive, premenopausal, operable breast cancer. One hundred and nineteen patients with hormone-responsive, premenopausal, operable breast cancer were enrolled in the study. Zoladex at 3.6 mg was given by subcutaneous injection every 4 weeks for 3 cycles. CEF (cyclophosphamide, 600 mg/m², epirubicin, 60–90 mg/m², and fluorouracil 500 mg/m²) was administered every 3 weeks for 4 cycles as neoadjuvant therapy. The primary objective was a pathologic complete response (PCR) rate in the breast. Thirty-one patients (26.1%) achieved a clinical complete response, and 76 patients (63.9%) achieved a clinical partial response; the clinical response rate was 90.0%. Fourteen patients (11.8%) achieved a pathologic complete response (T0/Tis, N0), and 20 patients (16.8%) achieved a pathologic complete response (T0/Tis, Nx). When stratified by the clinical lymph node status, the clinical partial response rate in the clinical lymph node negative group was significantly higher than in the clinical lymph node positive group (P = 0.02). When stratified by hormonal status, the clinical partial response rate in the ER and PR + group was significantly better than the ER or PR− group (P = 0.0471). There were no treatment-related deaths and no grades 3 or 4 toxicity. The most common adverse event was nausea (grade 1 65.5%, grade 2 18.5%), vomiting (grade 1 58.8%, grade 2 13.4%), and alopecia (grade 1 45.4%, grade 2 54.6%). Zoladex combined with CEF chemotherapy was effective as neoadjuvant therapy in hormone-responsive, premenopausal breast cancer. This regimen was particularly effective in the clinical lymph node negative group and in the ER/PR double positive group. (ClinicalTrials.gov number, NCT00488722).     

血清蛋白质谱诊断模型在乳腺癌辅助诊断中的价值

目的 建立乳腺癌的血清蛋白质谱诊断模型,评价其在乳腺癌辅助诊断中的价值.方法 应用表面增强激光解析电离飞行时间质谱(SELDI-TOF-MS)技术检测113例乳腺癌患者、103例乳腺良性肿瘤患者及92例健康女性的血清蛋白质谱,采用Biomarker Pattern(BPS)软件分析蛋白质谱,建立分类树模型,然后对模型进行盲筛验证.结果 比较乳腺癌患者与健康女性的血清蛋白质谱,筛选出12个差异蛋白质峰.经验证,所建立的分类树模型Ⅰ诊断乳腺癌的灵敏度为91.9%,特异度为81.2%.比较乳腺良性肿瘤患者与健康女性的血清蛋白质谱,筛选出11个差异蛋白质峰.经验证,所建立的分类树模型Ⅱ诊断乳腺良性肿瘤的灵敏度为87.9%,特异度为81.2%.比较乳腺癌与乳腺良性肿瘤患者的血清蛋白质谱,筛选出2个差异蛋白质峰.经验证,所建立的分类树模型Ⅲ诊断乳腺癌的灵敏度为81.8%,特异度为78.3%.应用这些差异蛋白及分类树模型,分别对93例CA15-3阴性乳腺癌患者与36例乳腺良性疾病患者的血清、20例CA15-3阳性乳腺癌患者与36例乳腺良性疾病患者的血清进行盲筛,诊断乳腺癌的敏感度和特异度分别为80.6%和91.7%、75.0%和91.7%,明显高于传统的乳腺癌标志物CA15-3,而CA15-3阴性与CA15-3阳性乳腺癌未见明显的差异蛋白质峰.结论 应用SELDI-TOF-MS技术可筛选出乳腺癌、乳腺良性肿瘤和健康女性血清蛋白质谱存在的差异蛋白质峰,据此建立的诊断模型可用于乳腺癌的辅助诊断.     

Differential levels of soluble intercellular adhesion molecule-1 (sICAM-1) in early breast cancer and benign breast lesions

To date, no soluble markers can discriminate benign from malignant breast lesion; therefore, to assess the diagnostic potential of circulating intercellular adhesion molecule-1 (sICAM-1), serum concentrations of sICAM-1 were quantitated in 230 consecutive patients that underwent surgery for breast neoplasias, utilizing an enzyme-linked immunosorbent assay. Histological diagnosis revealed that 177 patients had breast cancer and 53 had a benign breast disease. In the cancer patient group, 90 subjects had pTl tumors without (pT1N0M0, n=46) or with (pT1N1M0, n=41; pT1N2M0, n=3) regional lymph node metastases. Mean levels of serum sICAM-1 of patients with pT1 breast cancer, without or with regional lymph node involvement, were significantly (P<0.05) higher than those of patients with benign breast lesions and of 49 age-matched control subjects. Elevated levels of serum sICAM-1 were detected in 27/90 (30%) pTl breast tumors and in 1/53 (2%) benign breast lesions; thus, among subjects with high levels of sICAM-1, 96% had breast cancer. No significant correlation was found between levels of serum sICAM-1 and breast cancer progression. These observations, altogether, suggest that in the presence of a suspicious breast neoplasm the quantitative analysis of serum sICAM-1 can orient clinical diagnosis towards malignancy.     

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。     

Evaluation of serum CA 125 as a tumor marker in non-small cell lung cancer.

Serum CA 125 levels were evaluated in 130 healthy subjects and 133 patients with untreated pulmonary lesions. These were 33 patients with benign pulmonary conditions and 100 with lung cancer. The mean concentration of CA 125 was higher in patients with lung cancer (37 +/- 81 U/ml) than in those with nonmalignant disease (4.2 +/- 5.7 U/ml) (P less than 0.01). In the healthy control group CA 125 concentrations were significantly lower (0.63 +/- 1.5 U/ml) (P less than 0.001). In patients with lung cancer the concentration of this tumor marker was related to the tumor-node-metastasis (TNM) stage. At a cut-off value of 15 U/ml, CA 125 had a sensitivity of 44%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 65% with respect to healthy subjects; in patients with benign pulmonary conditions, these values were 44%, 94%, 94%, and 31%, respectively. At this cut-off value, a correlation between the respectability prognosis and the likelihood of survival 24 months posttreatment was observed. These findings suggest that CA 125 can be used as an adjunctive test in the management of patients with lung cancer patients.     

Predicting aggressive outcome in T1N0M0 breast cancer

Despite the excellent overall prognosis, unpredictable breast cancer recurrences and deaths also occur among T1N0M0 patients. We have evaluated clinically applicable methods for identifying aggressive outcome in T1N0M0 breast cancer. The material is based on aggressive T1N0M0 invasive ductal and lobular carcinomas diagnosed in Turku University Hospital and Jyv?skyl? Central Hospital, Finland, during 1987-1997. We studied all the T1N0M0 breast cancers that had led to recurrency or death (n=21, 95% T1cN0M0) during the follow-up period (4-14 years). The study is based on statistical analyses of matched case-control data in which the prognostic factors of each individual patient with aggressive disease were compared with control patients (n=45) individually matched by tumour size, age at diagnosis, histological type of tumour and length of follow-up. The cancer cases were examined for clinically applicable conventional and immunohistochemical pathologic prognostic factors. High Ki-67 immunopositivity was the strongest prognosticator of breast cancer death or recurrence in T1N0M0 breast cancer. Also, high p53 immunopositivity, low oestrogen receptor immunopositivity and Her-2/neu oncogene amplification by chromogen in situ hybridisation were reliable indicators of unfavourable outcome. Our statistical methods also allowed us to determine for the present material a range of clinical significance for each immunohistochemical prognostic feature with the associated relative risk for breast cancer death and recurrence. The paper suggests guidelines for predicting aggressive outcome in T1N0M0 breast cancer.