MIB1 proliferation index in breast infiltrating carcinoma: comparison with other proliferative markers and association with new biological prognostic factors

AIMS: In breast invasive carcinoma our objectives were I) to compare cellular proliferation determined by MIB1 index with S-phase fraction (SPF) assessed by flow cytometry and with mitotic index, and II) to examine the association of MIB1 index with classical and with new biological prognostic factors [bcl-2, p53, c-erbB-2 and cathepsin D (CD)]. METHODS AND RESULTS: From 102 cases of breast invasive carcinoma, 5-microm thick serial sections were cut from formalin-fixed, paraffin-embedded tissue blocks, and processed for detection of CD, c-erbB-2, p53, bcl-2, Ki-67 antigen MIB-1 and estrogen receptors (ER) and progesterone receptors (PR). SPF was measured by flow cytometry in fresh-frozen tissue samples taken from the carcinoma in each patient. MIB1 index was correlated with SPF (rho=0.45, p<0.0001) and with mitotic index (rho=0.42, p<0.0001). The MIB-1 index was positively associated with the histological grade (p=0.001), tumor size (p=0.04) and the presence of metastases in axillary lymph nodes (p=0.01). MIB1 was associated directly with p53 (p=0.045) and inversely with bcl-2 (p=0.0002). The MIB-1 index was not statistically associated with c-erbB-2. There was a weak association between MIBI index and stromal cell CD. The median MIB1 index was higher in tumors with moderate to strong CD staining of stromal cell, but the difference did not reach statistical significance (p=0.09). CONCLUSIONS: MIB1 index correlates with well established methods for assessing tumor proliferation and with parameters of an aggressive phenotype of tumor. MIB1 index is an effective and readily accessible method for assessing tumor proliferation in breast carcinoma.     

Prognostic factors affecting disease-free survival rate following surgical resection of primary breast cancer.

In order to identify the prognostic factors that significantly influence the disease-free survival rate after surgical resection of primary breast cancers, we determined tumour and lymph node grades, and immunohistochemical staining for estrogen and progesterone receptors (ER and PR), c-erbB-2, p53, bcl-2, bax and PCNA in 76 patients. Univariate analysis showed that increased grade of tumour and lymph nodes, negative immunostaining for ER, positive immunostaining for c-erbB-2, and a high PCNA index (> or = 30%) negatively influenced the disease-free survival rate, but PR, p53, bcl-2 and bax had no predictive value. Although p53 was not an independent prognostic factor by itself, the combination of p53, bcl-2, and bax proved to correlate with the disease-free survival, with the best prognosis noted in tumours negative for p53 and positive for both bcl-2 and bax, intermediate prognosis in tumours negative for p53 and positive for either bcl-2 or bax and worst prognosis in tumors negative for p53 as well as bcl-2 and bax. Tumour grade correlated positively with PCNA index, while positive staining for ER correlated negatively with tumour grade as well as with PCNA index, although this was statistically insignificant. Immunostaining of breast cancers for bcl-2 correlated negatively with tumour grade and PCNA index. Immunostaining for c-erbB-2 correlated positively with PCNA but not with tumour grade. Immunostaining for p53 tended to correlate positively with PCNA, but not with tumour grade. Immunostaining for PR and bax did not correlate with tumour grade and PCNA index. These results suggest that in addition to tumour size and lymph node involvement, immunostaining for ER, c-erbB-2, and a high PCNA index are important prognostic factors in human breast cancer. Wild-type p53 with preserved bcl-2 and bax gene products is also a favorable prognostic factor indicating breast cancer at an early stage of cancer progression.     

The Levels of Ki-67 Positive are Positively Associated with Lymph Node Metastasis in Invasive Ductal Breast Cancer

Breast cancer is the most common cancer in women worldwide. In this study, we evaluate the potential risk factors for lymph node metastasis in invasive breast cancer patients with axillary dissection. 147 patients were included into this prospective study. The prognostic biomarkers including Ki-67, human epidermal growth factor receptor 2 (HER-2), hormone receptor status, p53, and lymph node involvement were determined by immunohistochemistry. The association between lymph node metastasis and these biomarkers was analyzed. Lymph node metastasis was found in 62 patients out of 147 patients. The high levels of Ki-67 positive (greater than 20 %) were positively correlated with a higher incidence of lymph node metastasis, including the numbers of lymph nodes that contain tumor cells and the lymph node metastatic rate. The high rate of positive lymphovascular invasion (LVI) is associated with lymph node metastasis. However, the levels of Ki-67 positive were not correlated with the positive rate of LVI. There was also no association between lymph node metastasis and other prognostic biomarkers, such as HER-2, estrogen receptor, progesterone receptor, and p53. In addition, apart from p53, the levels of Ki-67 positive were correlated with other prognostic biomarkers. Our data suggest that Ki-67 positivity has value as a prognostic and predictive biomarker in breast cancer and may be a valuable proliferation marker in routine diagnosis of breast cancer.     

Breastfeeding and Immunohistochemical Expression of ki-67, p53 and BCL2 in Infiltrating Lobular Breast Carcinoma

Background/Aim

Invasive lobular breast carcinoma is the second most common type of breast cancer after invasive ductal carcinoma. According to the American Cancer Society, more than 180,000 women in the United States find out they have invasive breast cancer each year. Personal history of breast cancer and certain changes in the breast are correlated with an increased breast cancer risk. The aim of this work was to analyze breastfeeding in patients with infiltrating lobular breast carcinoma, in relation with: 1) clinicopathological parameters, 2) hormonal receptors and 3) tissue-based tumor markers

Materials and Methods

The study included 80 women with ILC, 46 of which had breastfeed their children. Analyzed parameters were: age, tumor size, axillary lymph node (N), distant metastasis (M), histological grade (HG), estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), Ki-67, p53 and BCL2

Results

ILC of non-lactating women showed a larger (p = 0.009), lymph node involvement (p = 0.051) and distant metastasis (p = 0.060). They were also more proliferative tumors measured by Ki-67 (p = 0.053). Breastfeeding history did not influence the subsequent behavior of the tumor regardless of histological subtype

Conclusion

Lactation seems to influence the biological characteristics of ILC defining a subgroup with more tumor size, axillary lymph node involvement, distant metastasis and higher proliferation measured by ki-67 expression.     

Prognostic significance of p53, bcl-2 and EGFR in carcinoma of the endometrium

OBJECTIVE: To evaluate the part played by several parameters in the prognosis of patients with endometrial carcinoma. STUDY DESIGN: Eighty imprint smears from fresh endometrial tumor specimens were studied immunocytochemically for the expression of p53, bcl-2 and epidermal growth factor receptor. Also, the presence of estrogen receptor (ER) and progesterone receptor (PR) in the tumor tissue was measured. The data obtained were related to survival, and associations were sought between the parameters studied. RESULTS: Strong associations were found between advanced stage, high grade, lymph node metastases at diagnosis, nonendometrioid histology and p53 expression with poor survival. Bcl-2 expression was associated with good five-year survival. ER expression was associated marginally with good five-year survival, but PR expression was not. A strong association was found between p53 and advanced disease, stage and lymph node metastases at diagnosis. An association between EGFR positivity and survival was not found. CONCLUSION: p53 Expression of uterine tumors is an independent and strong indicator of poor prognosis. Even patients with stage I and II disease at surgery who have p53-positive tumors must be considered at high risk.     

Emerging role of p53, bcl-2 and telomerase activity in Egyptian breast cancer patients

Apoptotic cell death represents an important mechanism for the precise regulation of cell numbers, and a defense mechanism against tumor cells. Both bcl-2 and mutant p53 gene products have been involved in apoptotic pathways. On the other hand, cell proliferation capacity and tumorgenesis have been controlled by telomerase. The purpose of our study is to assess the prognostic significance of additional markers implicated in apoptosis and tumorgenesis. Fifty-one fresh tissue samples of primary breast carcinoma and 26 tissue samples of benign breast lesions were included in this study. Expression of bcl-2 in cell lysates and mutant p53 protein in nuclear fraction were measured by Oncogene Science EIA procedures. Telomerase activity was analyzed using the Telomerase-PCR-ELISA based on the TRAP (telomerase repeat amplification protocol) method. On the same specimens, steroid hormone receptors (ER and PgR) were measured in cytosol fraction using Abbott EIA assays. In addition, information regarding surgical-pathological features of the tumor was obtained. Univariate and Multivariate analysis was done to identify variables predictive of poor prognosis. Significant expression of bcl-2, mutant p53 proteins and relative telomerase activity were observed in malignant cases when compared to benign ones. Univariate analysis revealed significant association in the level of both mutant p53 and relative telomerase activity with tumor size and disease recurrence. Moreover, telomerase activity was significantly expressed in late stages than early ones. Multivariate analysis revealed that bcl-2, mutant p53, telomerase activity, PgR and age were independent prognostic factors. Among a panel of molecular genetic factors investigated, mutant p53 and relative telomerase activity were strongly associated with disease recurrence; hence they exert a significant prognostic role in breast cancer.     

Estradiol receptor levels in human breast carcinomas.

The presence or absence of a specific estradiol-binding protein receptor in the cytoplasm of primary and secondary tumour cells has been used by physicians as an important guide in deciding whether to use hormonal therapy for patients with metastatic breast cancer. This report gives the levels of estradiol receptors in the cytosol of 228 primary and secondary breast tumours, measured by a sensitive multiple-point assay in which dextran-coated charcoal separated bound form unbound estrogen. The data were analysed with a Scatchard plot. Of the 175 primary and 53 secondary tumours 53% and 32% respectively gave positive results. The mean receptor level in the primary tumours was significantly higher among older patients and increased with age. With metastatic lesions positive results were more common in lymph node samples tha in skin nodule samples.     

Fas 相关死亡结构域蛋白在乳腺癌中表达的临床病理研究

目的:探讨Fas相关死亡结构域蛋白(Fas-associated death domain protein,FADD)在乳腺癌中表达的临床病理学意义。方法:收集乳腺癌病例及相应的临床资料包括随访资料,应用免疫组织化学技术检测乳腺良性病变,有/无淋巴结转移的乳腺癌及配对淋巴结转移灶中FADD的表达,观察分析FADD表达与乳腺癌患者年龄、肿块大小、临床分期、组织学类型和分级、雌孕激素受体水平等临床病理指标间的关系。结果:免疫组化检测结果显示良性乳腺病变组中FADD的阳性表达率(85.1%,40/47)与无淋巴结转移的乳腺癌组(45.8%,38/83),伴有淋巴结转移的乳腺癌组(67.3%72/107)和淋巴结转移灶(45.8%,49/107)组织中FADD阳性表率均有显著性差异(P值分别0.001,=0.022和0.001);此外,伴有淋巴结转移的乳腺癌组中FADD阳性表达率也均与其它三组中FADD阳性表达率之间具有显著性差异(P值分别为0.003,0.001和0.022)。FADD与患者的确诊年龄(P=0.049)和淋巴结转移有显著性相关(P=0.003),与肿瘤大小、临床分期、组织学类型、组织学分级、雌孕激素受体及cerb B-2的表达情况和月经史无明显相关性(P0.05)。生存分析显示FADD阳性表达的患者较FADD阴性患者的生存期更短。结论:FADD与乳腺癌淋巴结转移和预后有关。     

Integration of estrogen and progesterone receptors with pathological and molecular prognostic factors in breast cancer patients

In this study we have examined biopsies from women with localized primary breast cancer to investigate the prognostic performance of estrogen receptors (ER) and progesterone receptors (PR) for estimating the metastatic probability of the patients, and to explore whether discrimination gets better by combining clinicopathological and other molecular parameters into a score. This prospective study involved 205 patients with a median follow-up of 5 y. Among the evaluated clinicopathological data were: patient's age; tumor size; axillary lymph node involvement; and tumor grade. The most representative tumor samples were derived to a single laboratory for immunohistochemical evaluation of the following molecular markers: ER, PR, proliferating cell nuclear antigen (PCNA), p53 protein product, erbB-2 (HER-2/neu) oncoprotein, and P170 glycoprotein (mdr1 gen product). Distant metastases (study endpoint) appeared in 19.5% (40/205) of the patients, most of these patients presented a mixture of poor, regular and good prognostic factors. Disease-free survival analysis procedures (Kaplan–Meier method) identified tumor size, axillary lymph node involvement, tumor grade, receptor status, PCNA, p53, erbB-2 and P170 as useful prognostic factors. Proportional hazard regression analysis (Cox) identified in order of importance erbB-2, tumor size, receptors status, tumor grade and PCNA as useful prognostic factors. To facilitate the evaluation of the prognostic factors, a practical and simple score system was derived. A high pathological score identified 65% of the patients that developed distant metastases, while a high molecular score was obtained in 57% of patients with metastatic disease. There was a significant improvement in the diagnosis of probability of being with distant metastases when the pathological score was combined with the molecular score, 82% of the patients with distant metastases showed an elevated combined score. Validation of this scoring system will need further larger studies (validation set as opposed to the training set used in the present study). Due to the complexity of events in cancer, the evaluation of a combination of prognostic factors should be of value to clinicians to make a more objective estimate of the prognosis of individual breast cancer patients.     

MMP-9 and MMP-2 gelatinases and TIMP-1 and TIMP-2 inhibitors in breast cancer: correlations with prognostic factors

The goal of our study was to analyse the prognostic values for some matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in breast cancer. We evaluated the activity and the expression levels of MMP-9, MMP-2, TIMP-1 and TIMP-2 in malignant versus benign fresh breast tumor extracts. For this purpose, gelatinzymography, immunoblotting and ELISA were used to analyse the activity and expression of MMPs and TIMPs. We found that MMP-9 expression level and activity are increased in malignant tumors. In addition, MMP-9/TIMP-1 and MMP-2/TIMP-2 ratio values obtained by us were significantly different in malignant tumors compared to benign tumors. We suggest that the abnormal MMP-9/TIMP-1 balance plays a role in the configuration of breast invasive carcinoma of no special type and also in tumor growth, while altered MMP-2/TIMP-2 ratio value could be associated with lymph node invasion and used as a prognostic marker in correlation with Nottingham Prognostic Index. Finally, we showed that in malignant tumors high expression of estrogen receptors is associated with enhanced activity of MMP-2 and increased bcl- 2 levels, while high expression of progesterone receptors is correlated with low TIMP-1 protein levels.     

乳腺癌中α- 晶状体B 链蛋白表达的临床病理研究

目的:探讨α-晶状体蛋白B链(Alpha-crystallin B chain,CRYAB)在乳腺癌中表达的临床病理学意义。方法:收集乳腺癌病例及相应的临床资料包括随访资料,应用IHC染色方法检测CRYAB在乳腺良性病变(BBD)、无淋巴结转移乳腺癌(NMBC)、有淋巴结转移乳腺癌(MBC)及配对淋巴结转移灶(PMLN)中的表达,分析CRYAB表达与乳腺癌临床病理指标(患者年龄、肿块大小、淋巴结转移情况、临床分期、组织学分型和分级、雌孕激素受体和c-cerb B2表达情况、绝经情况)间及生存状态的关系。结果:CRYAB在对照组BBD组、NMBC组、MBC组、PMLN组的阳性表达率分别为97.9%(46/47)、44.6%(37/83)、13.1%(14/107)、10.8%(11/107),其中BBD组和NMBC组,BBD组、NMBC组分别与MBC组、PMLN组均存在显著性差异。CRYAB表达与淋巴结转移(P0.001)、临床分期(P=0.001)、组织学分级(P=0.037)和雌孕激素受体表达情况(P0.001)有显著相关,无淋巴结转移组的阳性表达率显著高于有淋巴结转移组,临床晚期的阳性表达率低于临床早期,雌孕激素受体阳性病例的阳性表达率显著低于雌孕激素受体阴性病例。生存分析结果显示CRYAB阳性表达的患者生存期比CRYAB阴性表达的患者生存期更长(p=0.037)。结论:CRYAB与乳腺癌的转移、临床分期、生存状态、雌孕激素受体表达有关。     

p53 aberrations in low grade endometrioid carcinoma of the endometrium with nodal metastases: possible insights on pathogenesis discerned from immunohistochemistry

Background

TP53 mutations are rarely identified in low grade endometrioid carcinoma of the endometrium, and their pathogenic significance in such tumors is evidenced by the fact that TP53 aberrations have been associated with reduced recurrence-free survival in this subset of tumors. However, TP53 aberrations may not always represent a driving molecular event in a given endometrial cancer with a mutation. In this case study, the immunophenotype of a distinctive low grade endometrioid adenocarcinoma with an unusual pattern of lymph node metastases is used to explore the possible roles for underlying TP53-related molecular events in its pathogenesis.

Case presentation

A low grade endometrioid carcinoma, 9 cm in greatest dimension, with 35% invasion of the myometrial wall thickness, focal lymphovascular invasion, and metastases to 2 of 16 pelvic lymph nodes, was diagnosed in a 52-year-old woman. The endometrial tumor showed a p53-mutation (aberrant)-type immunohistochemical pattern in 40% of the tumor, but the rest of the tumor, as well as the foci of myometrial and lymphovascular invasion, were p53-wild type. Both lymph nodes with metastatic disease showed a distinct biphasic pattern, comprised of both p53-wild type and p53-aberrant areas in tumoral foci that were spatially apposed but not intermixed. Most p53-aberrant areas (at both the lymph nodes and the endometrium) showed a higher mitotic index and increased atypia as compared to the p53-wild type areas; both showed squamous differentiation. The p53-aberrant areas at both locations were also p16-diffusely positive, vimentin-positive, and estrogen/progesterone receptor-positive, whereas the p53-wild type areas showed an identical immunophenotype with the exception of being p16-mosaic positive. All components of the tumor at both the primary and metastatic sites showed loss of MSH2 and MSH6 and retained MLH/PMS2 expression.

Conclusions

The presence of p53-mutant and wild-type areas in multiple lymph nodes, coupled with the absence of a p53-aberrant immunophenotype in the myometrium-invasive or lymphovascular-invasive portions of the tumor, argues against the possibility that the TP53 mutation in this tumor is a driving event in its pathogenesis, at least regarding the metastatic process. This case illustrates how routine immunohistochemistry can provide important insights into underlying molecular events in cancers, exemplifies an uncommon co-existence of DNA mismatch repair protein deficiency and p53-aberrant immunophenotype in low-grade endometrioid carcinoma, illustrates morphologic differences between p53-aberrant and p53-wild type areas within in the same tumor, and is an exemplar of the emerging theory that lymph node metastases of endometrial cancer may be comprised of different subclones of the primary tumor.

     

Quantitative immunoprofiles of breast cancer performed by image analysis

OBJECTIVE: To determine the biopathologic profiles of breast cancer for greater knowledge of tumor natural history and clinical outcome. STUDY DESIGN: In 99 in situ (ISC) and 2718 infiltrating breast carcinomas (IC), biologic markers (estrogen receptor [ER], progesterone receptor [PR] proliferation index, cerbB-2/NEU, p53, bcl-2 and DNA ploidy) were evaluated with an image analysis system (CAS 200/486). In 105 mixed invasive cancers with size < or = 1 cm, a separate analysis of in situ (ISCm) and invasive component (ICm) was obtained. A clinical study of 836 invasive breast cancers was performed. RESULTS: Different biophenotypes were obtained: among ISCs, cribriform type exhibited biologic behavior similar to that of normal breast tissue (ER+, PR+, proliferation index [PI] low, NEU-, p53-, bcl-2+) the opposite profile was displayed by comedo type, and intermediate phenotypes were observed in noncomedo and lobular types. Comparing ISC and ISCm, PI and p53 expression had the highest levels in ISCm with respect to other groups. NEU overexpression exhibited a decreasing value from ICm to IC. Younger women (< or = 40 years) with IC demonstrated a worse biologic profile (high PI, p53+, ER- and size > 2 cm). In multivariate analysis, PI and NEU in node-negative patients, and NEU, PR and size in node-positive ones emerged as prognostic parameters. CONCLUSION: The results underline the importance of the quantitative biologic profile for defining tumor behavior and patient management.     

Clinicopathological Features and Prognosis of Metaplastic Breast Carcinoma: Experience of a Major Chinese Cancer Center

Metaplastic breast carcinoma (MBC) is a rare heterogeneous group of primary breast malignancies, with low hormone receptor expression and poor outcomes. To date, no prognostic markers for this tumor have been validated. The current study was undertaken to evaluate the clinicopathologic characteristics, the response to various therapeutic regimens and the prognosis of MBCs in a large cohort of patients from Tianjin Medical University Cancer Hospital in China. Ninety cases of MBCs diagnosed in our hospital between January 2000 and September 2014 were retrieved from the archives. In general, MBCs presented with larger size, a lower rate of lymph node metastasis, and demonstrated more frequent local recurrence/distant metastasis than 1,090 stage-matched cases of invasive carcinoma of no specific type (IDC-NST), independent of the status of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 expressions. The five-year disease-free survival (DFS) of MBC was significantly worse than IDC-NST. Using univariate analysis, lymph node metastasis, advanced clinical stage at diagnosis, high tumor proliferation rate assessed by Ki-67 labeling, and epidermal growth factor receptor (EGFR) overexpression/gene amplification were associated significantly with reduced DFS, while decreased OS was associated significantly with lymph node metastasis and EGFR overexpression/gene amplification. With multivariate analysis, lymph node status was an independent predictor for DFS, and lymph node status and EGFR overexpression/gene amplification were independent predictors for OS. Histologic subtyping and molecular subgrouping of MBCs were not significant factors in prognosis. We also found that MBCs were insensitive to neoadjuvant chemotherapy, routine chemotherapy, and radiation therapy. This study indicates that MBC is an aggressive type of breast cancer with poor prognosis, and that identification and optimization of an effective comprehensive therapeutic regimen is needed.     

Age-associated biomarker profiles of human breast cancer

To explore the hypothesis that aging not only increases breast cancer incidence but also alters breast cancer biology, we correlated patient age and diagnosis with tumor histology, stage and biomarkers independently determined from two different tumor archives: an American collection of approximately 800 paraffin-embedded and immunohistochemically analyzed primary breast cancers, and an European collection of approximately 3000 cryobanked primary breast cancers analyzed by ligand-binding and enzyme immunoassay (EIA). The prognostic biomarkers chosen for comparison represented surrogate measures of tumor: (i). proliferation, growth and genetic instability (mitotic and apoptotic indices, Ki-67/MIB-1-positivity, nuclear grade, p53-positivity), (ii). endocrine-dependence (estrogen receptor (ER), progesterone receptors (PR), pS2, Bcl2), (iii). growth factor receptor-dependence (ErbB2, EGFR/ErbB1), and (iv). angiogenic, invasive and proteolytic potential (uPA, PAI-1, Cathepsin D, VEGF). No biomarker reflecting tumor angiogenic, invasive or proteolytic potential showed a significant correlation with patient age at diagnosis. In contrast, significant inverse correlations (|r|>0.1; P< or =0.05) were observed for all measures of tumor growth and genetic instability as well as growth factor receptor overexpression (ErbB2 or EGFR positivity). Only one marker of endocrine-dependence, ER expression, showed a significant positive correlation with patient age at diagnosis. In summary, these findings support the hypothesis that breast cancer biology is significantly affected by patient age. In particular, breast tumors arising in older patients have slower growth rates, are more likely to be ER-positive, and are less likely to be p53-positive, EGFR-positive or ErbB2-positive.     

Prognostic evaluation of breast cancer in cytologic specimens

OBJECTIVE: To evaluate prognostic factors in breast cancer using cytologic samples and to determine the correlation between those factors and ploidy. STUDY DESIGN: Two hundred sixteen fine needle aspirates from patients with primary breast cancer were analyzed for expression of estrogen receptors (ERs), progesterone receptors (PRs), Ki-67 antigen, expression of p53 tumor suppressor gene and overexpression of c-erbB-2 using a standard immunochemical method. Not all subjects had all biomarker information because of the study design (c-erbB2 added later). The specimens were analyzed also for ploidy. We used the SAMBA 4000 image analysis system for quantification of the percent of cells stained positively by the different immunocytochemical stains andfor ploidy. RESULTS: A significant correlation wasfound between ER and PR and between Ki-67 and positive p53. Steroid receptor content was not significantly related to p53, Ki-67 or c-erbB2. No correlation was found between c-erbB2 and the other biomarkers. Ploidy had a significant correlation with all the biomarkers used. CONCLUSION: A reliable and rapid evaluation of markers for breast cancer can be achieved by measuring cells stained positively by immunocytochemical stains, as well as ploidy, by means of an image analysis system. ER, PR Ki-67, p53 and c-erbB2 had a significant correlation with ploidy and overall prognostic value in breast cancer.     

Allelic imbalance in primary breast carcinomas and metastatic tumors of the axillary lymph nodes

Axillary lymph node status is the most important prognostic factor in predicting disease outcome in women with breast cancer. A number of chromosomal aberrations in primary breast tumors have been correlated with lymph node status and clinical outcome, but chromosomal changes particular to metastatic lymph node tumors have not been well studied. DNA samples isolated from laser-microdissected primary breast and metastatic axillary lymph node tumors from 25 women with invasive breast cancer were amplified using 52 microsatellite markers defining 26 chromosomal regions commonly deleted in breast cancer. Levels and patterns of allelic imbalance (AI) within and between breast and lymph node tumors were assessed to identify chromosomal alterations unique to primary or metastatic tumors and to examine the timing of metastatic potential. The overall frequency of AI in primary breast tumors (0.24) was significantly greater (P < 0.001) than that in lymph node tumors (0.10), and congruent AI events were observed for < 20% of informative markers. AI at chromosomes 11q23.3 and 17p13.3 occurred significantly more frequently (P < 0.05) in primary breast tumors alone; no chromosomal regions showed a significantly higher AI frequency in lymph nodes. Higher rates of AI in primary versus metastatic lymph node tumors suggest that acquisition of metastatic potential may be an early event in carcinogenesis, occurring before significant levels of AI accumulate in the primary tumor. In addition, patterns of AI were highly discordant between tumor types, suggesting that additional genetic alterations accumulated independently in the two cell populations.     

P-gp、MMP-2、C-erbB-2在乳腺癌原发灶和转移淋巴结中的表达对比研究

目的：探讨乳腺癌侵袭转移和多药耐药之间的关系,为治疗方案的个体化提供依据。方法：采用免疫组化方法检测46例乳腺浸润性导管癌患者乳腺原发灶及相应腋淋巴结转移灶中P-gp、MMP-2、c-erbB-2的表达,结合临床表现、病理学指标,分析其相关性。结果：46例原发灶P-gp阳性表达35例（76.1%）,MMP-2阳性表达25例（54.3%）,c-erbB-2高表达18例（39.1%）;相应腋淋巴结转移灶P-gp阳性表达28例（60.9%）,MMP-2阳性表达16例（34.8%）,c-erbB-2高表达16例（34.8%）;P-gp、MMP-2蛋白表达水平与肿块大小、淋巴结转移数目均呈正相关（P〈0.05）,c-erbB-2蛋白表达水平与腋窝淋巴结转移数量呈正相关,与ER、PR表达呈负相关,P-gp阳性表达与MMP-2和c-erbB-2的表达呈正相关（P〈0.05）。结论：肿瘤原发灶与转移灶存在异质性,P-gp、MMP-2、c-erbB-2的表达与乳腺癌的多药耐药和侵袭转移有关,检测上述基因在原发灶与转移灶的表达,为乳腺癌选择个体化的化疗、内分泌治疗及分子靶向治疗提供了分子生物学依据。