Maintenance of DNA content and erbB-2 alterations in intraductal and invasive phases of mammary cancer

Summary Ductal carcinomain situ (intraductal carcinoma) of the breast is a commonly recognized and curable clinical entity. Patients with intraductal carcinoma are at risk to develop invasive breast cancer presumably due to a transition from the noninvasive to the invasive phase of growth. Primary breast malignancies commonly display bothin situ and invasive phases of growth in the same tumor. In the current study, DNA content and alterations in the erbB-2 (HER-2/neu) oncogene product were examined simultaneously in both growth phases of primary breast cancers by image analysis. DNA content in the intraductal and invasive components of primary breast cancers were virtually identical (r = 0.979, p < 0.001). Quantitative image analysis was used to measure erbB-2 expression and categories of expression were related to copy number of the erbB-2 gene. Expression of erbB-2 was similar in both growth phases and implies identity of the erbB-2 genotype. The identity of DNA content suggests that the noninvasive and invasive phases within a single breast cancer are highly related. It is likely that erbB-2 gene number remains the same during progression from intraductal to invasive disease.     

HER-2/neu overexpression and in vitro chemosensitivity to CMF and FEC in primary breast cancer

Available clinical and experimental data on the effect of HER-2/neu overexpression on chemosensitivity are controversial. It was the purpose of this in vitro study to define the association between HER-2/neu overexpression and the sensitivity to the chemotherapeutic drug combinations of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) and 5-fluorouracil, epirubicin and cyclophosphamide (FEC) of breast cancer cells derived from 140 chemotherapy-naïve patients at the time of primary surgery. Both drug combinations were tested at six different concentrations ranging from 6.25–200% peak plasma concentration (PPC). Immunohistochemical detection of HER-2/neu overexpression was performed with the HER-2/neu antibodies, CB11, TAB250 and AO485, in the same tumor specimens. Immunoreactions were determined as negative (0/1+), weakly positive (2+) and strongly positive (3+). However, the antibodies varied in their degrees of sensitivity. Breast cancer samples with strong (3+) HER-2/neu overexpression demonstrated 90% growth inhibition (IC₉₀) at significantly lower PPC values, using the CB11 (p=0.048), TAB250 (p=0.007) and AO485 (p0.01) antibodies, and showed 50% growth inhibition (IC₅₀) at significantly lower PPC values, using the CB11 antibody (p=0.01) compared to their counterparts with lower levels of HER-2/neu expression. When analyzing the group of patients with intermediate and strong HER-2/neu overexpression (2+ and 3+), an association between HER-2/neu overexpression and increased chemosensitivity was seen with the TAB250 (p=0.044) and AO485 (p=0.032) antibodies, but not with the CB11 antibody (p=0.8) at the IC₉₀ level. Differences in chemosensitivity between samples with strong HER-2/neu overexpression and those with lower levels were then analyzed separately for CMF and FEC. Both regimens achieved 90% tumor growth inhibition at lower PPC values in samples with strong HER-2/neu overexpression (3+) compared to their counterparts with lower expression levels (AO485 p=0.011 for CMF, and p=0.09 for FEC). Cumulative concentration-response plots of tumors responding in vitro with 90% tumor cell inhibition showed a stronger dose dependence for both CMF and FEC among tumor samples with strong HER-2/neu overexpression compared to those with lower levels of expression. In conclusion, the data show that HER-2/neu overexpression was not associated with in vitro drug resistance to CMF or FEC. In contrast, tumors with strong HER-2/neu overexpression demonstrated increased dose-dependent in vitro sensitivity to both the FEC and CMF regimens.     

HER-2/Neu overexpression does not predict response to neoadjuvant chemotherapy or prognosticate survival in patients with locally advanced breast cancer

Data about the prognostic and predictive value of HER-2/neu overexpression in patients with locally advanced breast cancer (LABC) treated with primary chemotherapy is limited. Therefore, this retrospective study was performed to examine this issue. Fifty-four consecutive patients with LABC were prospectively managed using a uniform multimodality approach. Response to neoadjuvant chemotherapy and survival were examined against HER-2/neu overexpression as determined by an immunohistochemistry method on formalin-fixed, paraffin-embedded samples of breast cancer using the commercially available, United States Food and Drug Administration-approved kit HercepTest (Dako Corp, Carpinteria, CA). The number of patients in each Hercep Test immunostaining group were as follows; 0 in 12 patients (22%), 1+ in 8 (15%), 2+ in 12 (22%), and 3+ in 22 (41%). None of the clinical variables was significantly associated with HER-2/neu expression. After primary therapy, 22% of patients attained clinical complete response and an additional 70% achieved clinical partial response with an overall response rate of 92% (95% confidence interval: 100% to 79%). There was no significant correlation between clinical response and HercepTest positivity (p=0.85). Of 52 patients with complete pathological data, there was no significant difference in HercepTest status between those who attained complete pathological response (46%) and those who did not (38%) (p=0.74). Moreover, there was no significant difference in disease-free survival (75% vs 84%, [p=0.26]) or overall survival (81% vs 84% [p=0.31]) between those who overexpressed HER-2/neu and those with negative HercepTest, respectively. In patients with LABC, HER-2/neu overexpression determined using HercepTest assay and according to the manufacturer’s approved guidelines failed to demonstrate a predictive or a prognostic role.     

Evaluation of HER-2/NEU protein expression in breast cancer by immunohistochemistry: an interlaboratory study assessing the reproducibility of HER-2/NEU testing

This study investigated the degree of interlaboratory agreement when HER-2/neu was evaluated by immunohistochemistry (IHC) on archival primary breast cancer samples. IHC for HER-2/neu was performed on the same archival tissue sections from 394 invasive primary breast cancers in two different laboratories. Both laboratories used the primary antibody NCL-CB11; however, different methods of immunostaining (antigen retrieval procedure and manual processing or no antigen retrieval and autostainer processing) as well as different scoring systems were used. Fluorescence in situ hybridization (FISH), considered as the correlation method for HER-2/neu status determination, was performed using the PathVysion kit and compared to the IHC results. Forty-eight of 394 analyzed tumors (12.2%) were scored as HER-2/neu positive in one laboratory, and 109 (27.7%) in the other laboratory where antigen retrieval was performed. Complete concordance in categorization of HER-2/neu status between the two laboratories was achieved in 333 of 394 cases (84.5%). FISH performed in 248 formalin-fixed samples revealed HER-2/neu gene amplification in 55/248 (22.2%). Concordance of FISH and IHC was found in 211/248 cases (85.1%) and 220/248 cases (88.7%) when the CB11 antibody was used without and with antigen retrieval, respectively. Both IHC methods generated similar rates of false results, but with different positive predictive values. Our data demonstrate that HER-2/neu evaluation by IHC is not a reproducible technique if there is no standardization of the procedure.     

HER-2/neu amplification testing in breast cancer by Multiplex Ligation-dependent Probe Amplification: influence of manual- and laser microdissection

Background  

Accurate assessment of HER-2/neu status is crucial for proper prognostic information and to offer direct appropriate treatment for breast cancer patients. Next to immunohistochemistry (IHC) to evaluate HER2 protein overexpression, a second line gene amplification test is generally deemed necessary for cases with equivocal protein expression. Recently, a new PCR based test, called Multiplex Ligation-dependent Probe Amplification (MLPA), was introduced as a simple and quick method to assess HER-2/neu gene amplification status in invasive breast cancer. MLPA was previously shown to correlate well with IHC and in situ hybridization (ISH), but a low tumor percentage in the tissue tested could negatively affect the accuracy of MLPA results.     

Significance of p53, Bcl-2, and HER-2/<Emphasis Type="Italic">neu</Emphasis> protein expression in Omani Arab females with breast cancer

Recial disparity in the presentation of breast cancer and the outcome of its treatment is well established. However, the causes remain unexplained. The scarcity of reports about the prognostic significance of p53, bcl-2, and HER-2/neu in Arab females with breast cancer has been the impetus to this study. We evaluated the prognostic significance of altered expression of p53, bcl-2,HER-2/neu in Omani Arab females with non-metastatic breast cancer with correlation to other established prognostic factors. We have retrospectively analyzed the immunohistochemical expression of p53, HER-2/neu and bcl-2 in paraffin embedded blocks of 72 females diagnosed with invasive breast cancer between 1992 and 2002. The expression of the above proteins was correlated with other prognostic factors and univariate and multivariate analysis was carried out for all prognostic factors. Overexpression of p53 significantly correlated with younger age (<40), pre-menopausal status, poor differentiation with inverse correlation with bcl-2 expression. Expression of bcl-2 immunopostivity significantly correlated to low histological grade and positive estrogen and progesterone receptor status. On univariate and multivariate p53 overexpression and lack of bcl-2 immunostaining resulted in worse survival outcome, but notHer-2/neu overexpression. Expression patterns of p53 and bcl-2 are independent predictors of survival in Omani Arab population which may help to stratify these patients into different risk groups.     

Survival after bilateral breast cancer: results from a population-based study

Background Controversy exists on the impact of bilaterality of breast cancer on survival. We used population-based data to compare survival of women with unilateral versus bilateral breast cancer. Patients and methods At the Geneva cancer registry, we identified all 7,912 women diagnosed with invasive breast cancer between 1970 and 2002. Breast cancers were categorized as unilateral, synchronous bilateral (contralateral tumour diagnosed within six months after the first tumour) and metachronous bilateral (contralateral tumour diagnosed over six months after the first tumour). With multivariate modelling we compared characteristics and survival between women with unilateral and bilateral disease. Results Patients with synchronous bilateral tumours (n = 155, 2.0%) had more often lobular histology and less frequently stage I disease than women with unilateral disease. Women with metachronous breast cancer (n = 219, 2.8%) received less often chemotherapy or hormone therapy for their first tumours. Ten-year disease-specific survival was similar (66%) after unilateral and metachronous bilateral breast cancer, but worse after synchronous bilateral cancer (51%). After adjustment, breast cancer mortality risks were not significantly increased for women with either synchronous or metachronous bilateral disease (Hazard ratios 1.1 (0.8–1.5) and 0.8 (0.5–1.4), respectively). Conclusion This large population-based study indicates that bilaterality of breast cancer is not associated with impaired survival.     

Evaluation of tumor markers (HER-2/neu oncoprotein,CEA, and CA 15.3) in patients with locoregional breast cancer: prognostic value

Tumor markers were studied in the sera of 883 untreated patients with primary breast cancer diagnosed between 1989 and 2007. Abnormal human epidermal growth factor receptor 2 (HER-2)/neu levels (>15 ng/mL) were found in 9.5%, carcinoembryonic antigen (CEA) in 15.9%, and cancer antigen (CA) 15.3 in 19.7% of the patients. One or more tumor markers were abnormal in 305 (34.5%) of the 883 studied patients. Significantly higher serum HER-2/neu levels were found in patients with tissue overexpression of this oncoprotein (p < 0.0001). CEA, CA 15.3, and HER-2/neu (only in those patients with tissue overexpression) serum levels were related with tumor stage (tumor size and nodal involvement) and steroid receptors (higher values in estrogen receptor-negative (ER−) tumors). Univariate analysis showed that HER-2/neu serum levels were prognostic factors in disease-free survival (DFS) and overall survival (OS) only in patients with tissue overexpression. Multivariate analysis in 834 patients show that nodal involvement, tumor size, ER, CEA, and adjuvant treatment were independent prognostic factors in DFS and OS. When only patients with HER-2/neu overexpression in tissue were studied, tumor size, nodal involvement, and tumor markers (one or another positive) were independent prognostic factors for both DFS and OS. HER-2/neu serum levels were also an independent prognostic factor, with CEA, ER, and nodes in 106 patients treated with neoadjuvant treatment. In summary, serum HER-2/neu, CEA, and CA 15.3 are useful tools in the prognostic evaluation of patients with primary breast cancer.     

Detection of genetic instability at <Emphasis Type="Italic">HER-2/neu</Emphasis> and <Emphasis Type="Italic">p53</Emphasis> loci in breast cancer cells sing Comet–FISH

Summary A proportion of breast cancers acquire genetic alterations at 17q11.2–q12 (HER-2/neu), 20q13.2 (ZNF217 gene) and 17p13.1 (p53). We describe a unique technique (Comet–FISH) in which we documented relative genetic instability at p53 and HER-2/neu gene loci within a panel of malignant breast cancer cell lines (MCF-7; MDA-MB-468 and CRL-2336). Furthermore, Comet–FISH data were consistent with preferential repair of the p53 locus following gentoxic insult and suggest that this assay may be quite useful for the study of genetic instability.     

EGFR与HER-2在不同分子类型乳腺癌中的表达及其相关性分析

目的：探讨EGFR和HER-2在不同分子类型乳腺癌组织中的表达及其相关性。方法：回顾性分析2015年1月—2020年3月在邯郸市中心医院行手术治疗的乳腺癌患者资料650例(其中浸润性导管癌600例，浸润性小叶癌50例)及乳腺纤维腺瘤30例，应用免疫组织化学(IHC)方法对手术切除标本进行EGFR和HER-2蛋白表达检测，采用χ²检验及Spearman相关分析对数据进行统计学分析。结果：EGFR在乳腺浸润性导管癌中表达阳性率为48.7%，显著高于浸润性小叶癌(24.0%)及纤维腺瘤(16.7%)(P<0.01)。HER-2在乳腺浸润性导管癌中表达阳性率为27.8%，显著高于浸润性小叶癌(8.0%)及纤维腺瘤(6.7%)(P=0.002)。乳腺浸润性导管癌与浸润性小叶癌中，EGFR阳性率与HER-2评分等级呈正相关(r=1.000，P<0.05)，且EGFR阳性率与HER-2阳性表达呈正相关(r=1.000，P<0.05)。EGFR阳性率在HER-2过表达型与三阴型乳腺癌组织中显著高于Luminal A型和Luminal B型，且Luminal B中HER-2阳性显著高于HER-2阴性亚型(P<0.001)。结论：EGFR、HER-2阳性率在乳腺浸润性导管癌显著升高，且EGFR阳性率与HER-2的评分等级及阳性表达率均呈正相关，EGFR在HER-2过表达型与三阴型乳腺癌组织中显著升高，为进一步研究HER-2阳性乳腺癌及三阴型乳腺癌的靶向药物治疗提供线索及理论依据。     

Clinical significance and prognostic value of serum sHER-2/neu levels in patients with solid tumors

The purpose of this study was to determine HER-2/neu in the serum of patients with solid tumors and to investigate its potential usefulness in predicting the clinical course of the disease. At the same time, we compared the ability of serum HER-2/neu, CA15.3, CA12-5, CA19-9, carcino embryonic antigen (CEA), and α-feto-protein (AFP) in breast, colorectal, and lung cancer patients. Forty, thirty-six, and twenty-three patients with lung, colon and breast cancer were included in this study, respectively. Serum levels of HER-2/neu, CA15.3, CA12-5, CA19-9, CEA, and AFP were measured. Her-2 neu levels were significantly higher in the breast cancer groups than colorectal and lung cancer and controls groups (P < 0.01). There is no significant difference when compared with others groups (P > 0.05). There was a positive correlation between the HER-2/neu and CA15-3 values in breast cancer groups. We found 0.75(0.59–0.90) for Her-2/neu from the area under the curve (AUC). P-value for breast cancer is 0.003, and we discovered that 9 ng/ml was the best inersection point. In this situation, we calculated that sensitivity was 65.2%, specificity was 100%, positive predictive value was 100%, negative predictive value 75.8%, and accuracy was 83.4%. These findings indicate that serum HER2/neu levels are clinically valuable in monitoring metastatic breast cancer and non-small cell lung cancer patients. Prognosis of breast cancer provides an additional value over the commonly used CA15-3 test. Measurements of levels of serum HER-2/neu provide prognostic and predictive information to the clinician and can especially be used for monitoring metastatic breast cancer patients. Further clinical validation is needed to confirm these findings.     

Expression of Tight Junction Protein Claudin-4 in Basal-Like Breast Carcinomas

Claudins (CLDN) are tight junction proteins which contribute to the paracellular transport and ionic permeability of various epithelia. In recent years they came into focus for their suggested role in carcinogenesis and possible role in cancer therapy. According to our previous studies, in breast tissue CLDN4 is also related to the level of cellular differentiation. Thirty-eight estrogen (ER) and progesterone receptor (PgR) negative, HER2/neu negative, but cytokeratin 5/6 positive basal-like—mainly grade 3—breast carcinomas were compared with twenty-one grade 1, twenty-five grade 2 and twenty grade 3 non-basal-like invasive breast carcinomas, in respect to their CLDN4 expression. The immunohistochemical reactions were evaluated both semiquantitatively and by morphometrical analysis. Statistically significant difference (p = 0.001) was observable regarding CLDN4 expression in the basal-like group as compared to grade 1 and 2 cancers. Further, CLDN4 expression was significantly higher (p = 0.017) in the basal-like compared with the non-basal-like grade 3 carcinomas. Our results suggest that basal-like carcinomas are a subset of breast cancer with high level of CLDN4 protein expression. The finding is in accordance with our former observation that CLDN4 is indeed related to cellular differentiation. This observation may be seen as a further proof that basal-like carcinomas represent a separable group amongst grade 3 breast carcinomas. Janina Kulka and Attila Marcell Szász have contributed equally to this work.     

C-erbB-2 overexpression and survival in early onset breast cancer

Young breast cancer patients have a decreased survival rate and it has been demonstrated that young age is an independent predictor of adverse prognosis. Overexpression of c-erbB-2 protein (also known as HER-2/neu) has been shown to be a prognostic indicator in breast cancer in general and especially among patients with axillary nodal metastases. The present study was initiated to determine the prognostic significance of c-erbB-2 protein overexpression in early onset breast cancer.A population consisting of 110 young breast cancer patients, 36-year-old at diagnosis, was analyzed with immunohistochemical staining for c-erbB-2 protein.Thirty patients (27%) were found to overexpress the c-erbB-2 protein. C-erbB-2 positivity was significantly associated with poor survival when all patients were included in the analysis (P=0.002) and for patients with axillary nodal metastases (P=0.0007). No such association was found for node-negative patients. Furthermore, the difference in prognosis in relation to c-erbB-2 among node-positive patients was maintained, when these were stratified in groups treated or not treated with adjuvant chemotherapy.The study indicates that overexpression of c-erbB-2 protein is a strong prognostic factor in young breast cancer patients with axillary nodal metastases. Moreover, the adverse prognosis associated with c-erbB-2 overexpression in node-positive patients was observed whether or not the patients had received adjuvant chemotherapy.     

Contribution of XPD (Lys751Gln) and XRCC1 (Arg399Gln) Polymorphisms in Familial and Sporadic Breast Cancer Predisposition and Survival: An Indian Report

The etiology of a significant proportion of familial breast cancers is still poorly understood, with known high penetrance gene mutations accounting for only a small proportion of the cases. The increased risk of breast cancer for the majority of women with a family history likely reflects shared minor low penetrant genetic factors. In the present case-control study undertaken to examine the influence of DNA damage repair gene polymorphisms in familial and sporadic breast cancer susceptibility, 219 Sporadic and 140 familial breast cancer patients and 367 controls were genotyped using PCRRFLP. Odds Ratios (ORs) and 95% Confidence Intervals (95%CIs) were calculated by unconditional logistic regression adjusted to age. Variant genotypes XRCC1 Arg/Gln or Gln/Gln and XPD Lys/Gln or Gln/Gln increased both familial and sporadic breast cancer susceptibility. However, when the intra group risk was compared, the risk due to the XPD polymorphic genotypes Lys/Gln or Gln/Gln was significantly lower among familial breast cancer patients compared to sporadic breast cancer patients [OR = 0.61; 95%CI = 0.39–0.94; p value = 0.024) whereas the risk implied by XRCC1 variant genotype was not significantly different between the familial and nonfamilial groups of breast cancer patients [OR = 0.97; 95%CI = 0.63–1.49; p value = 0.882]. Both these variant genotypes were not associated with the disease characteristics or survival of either familial or sporadic breast cancer patients. This study represents an addition to previous published work on GSTs from the same study population and substantiates the hypothesis that the impact of the low penetrance gene polymorphisms differ by family history of the disease.     

Increased N-myc downstream-regulated gene 1 expression is associated with breast atypia-to-carcinoma progression

N-myc downstream-regulated gene-1 (NDRG1) has been identified as a protein involved in the differentiation of epithelial cells. As a newly metastasis suppressor gene, whether it contributes to carcinogenesis of breast cancer is still unknown. This study aimed to clarify the possible role of NDRG1 for breast cancer carcinogenesis, and further to investigate its clinicopathological significance in invasive breast cancer. We examined the expression of NDRG1 in normal epithelium of breast (n = 35), usual ductal hyperplasia (n = 22), atypical ductal hyperplasia (n = 33), atypical lobular hyperplasia (n = 8), ductal carcinoma in situ (n = 16), lobular carcinoma in situ (n = 6), invasive ductal carcinoma (n = 50), and invasive lobular carcinoma (n = 45) by immunohistochemistry and analyzed the correlation between NDRG expression and clinicopathological features of invasive breast cancer. Western blot analysis was carried out to investigate the expression of NDRG1 in 20 invasive ductal breast cancer and the paired non-tumor portion of the same case. NDRG1 expression in invasive breast cancer (70/95, 73.7%) was higher than that in noninvasive breast lesions (29/85, 34.1%; p < 0.05) which was higher than that in normal breast epithelium (5/35, 14.3%; p < 0.05). Statistical analysis revealed a significant correlation between NDRG1 expression with tumor stage in invasive breast cancer, and its expression in invasive ductal carcinoma is significantly higher than invasive lobular carcinoma (p < 0.05). It was not associated with age, menopausal status, tumor size, and lymph node metastasis. NDRG1 protein levels were significantly higher in invasive ductal breast cancer compared to the paired non-tumor portion of the same case by Western blot analysis (p < 0.05). Increased NDRG-1 expression is associated with breast atypia-to-carcinoma progression. NDRG1 expression might participate in the carcinogenesis and progression of invasive breast cancer. These findings provide further evidence that NDRG1 may serve as an important biomarker for invasive breast cancer.     

Validation of a differential PCR and an ELISA procedure in studying HER-2/neu status in breast cancer

HER-2/neu oncogene status and total cellular p185^HER-2 content were simultaneously analyzed in 415 invasive breast-cancer specimens by differential PCR and ELISA respectively. Mathematical analysis of the data led us to establish a cut-off value of 1.7 for the ratio between the intensity of the HER-2/neu gene band and the reference gene band, to consider the HER-2/neu gene amplified, and of 260 fmol/mg protein, to consider p185^HER-2 over-expressed. Of the 415 tumors studied, 15% showed a diverse degree of HER-2/neu gene amplification. Of these tumors, 87% showed over-expression of the p185^HER-2. Of the remaining 352 specimens that did not display HER-2/neu gene amplification, 97% showed no p185^HER-2 over-expression (p < 0.0001). In 40 selected samples with a p185^HER-2 level lower than 260 fmol/mg protein, the degree of p185^HER-2 phosphorylation was very low or undetectable. Conversely, 38 of 46 selected tumors with a p185^HER-2 level higher than 260 fmol/mg protein exhibited a considerable degree of p185^HER-2 phosphorylation (p < 0.0001). Our data suggest that: (i) differential PCR and ELISA, which are relatively simple procedures, give similar information on HER-2/neu status in breast cancer; and (ii) given the large series analyzed, the cutoff values established can be considered as safe values for determining whether, in a given tumor, the HER-2/neu oncogene is amplified or p185^HER-2 is over-expressed. © 1996 Wiley-Liss, Inc.     

Phosphorylation of Ser<Superscript>78</Superscript> of Hsp27 correlated with HER-2/<Emphasis Type="Italic">neu</Emphasis> status and lymph node positivity in breast cancer

Background  

Abnormal amplification/expression of HER-2/neu oncogene has been causally linked with tumorigenesis and metastasis in breast cancer and associated with shortened overall survival of patients. Recently, heat shock protein 27 (Hsp27) was reported to be highly expressed in HER-2/neu positive tumors and cell lines. However, putative functional links between phosphorylation of Hsp27 with HER-2/neu status and other clinicopathological features remain to be elucidated.     

Association of Expression of Kruppel-Like Factor 4 and Kruppel-Like Factor 5 with the Clinical Manifestations of Breast Cancer

Kruppel-like factors (KLFs) are import modulators of cell proliferation, differentiation, and transformation and have recently been considered possible prognostic factors in breast cancer. In this study, we investigated the correlation between KLF4 and KLF5 expression and the clinical manifestations of breast cancer by immunohistochemical analysis. We observed increased KLF4 and KLF5 expression in tumor cells (invasive and in situ carcinomas), consistent KLF4 and KLF5 expression in in situ and invasive carcinomas, significant associations between KLF4 expression and tumor grade (p = 0.033), size (p = 0.035) and stage (p = 0.006), and an association between KLF5 expression and tumor grade (p = 0.033). Interestingly, we observed a relationship between increasing age and KLF4 expression (p = 0.007), with a tendency towards greater expression in tumor cells in patients over 50 years old. Moreover, KLF5 nuclear localization was restricted to non-tumor breast ducts and lobules; however, loss of nuclear expression of KLF5 in in situ and invasive carcinomas was observed. Although the mechanism of the loss of KLF5 nuclear expression is not clear, this phenomenon may imply a possible tumor-suppressor-like role for KLF5 in breast cancer tumorigenesis. The expression of KLF4 and KLF5 in breast cancer patients in Taiwan is similar to that in Western countries, except for the uncertainty surrounding its prognostic significance. Further clarification of the underlying mechanisms of KLF4 and KLF5 expression and their correlations with breast cancer outcomes is necessary.     

Influence of Neoadjuvant Chemotherapy on HER2/neu Status in Invasive Breast Cancer

IntroductionReliably estimating HER2/neu expression in breast cancer is important for predicting patient prognosis and optimizing adjuvant therapeutic strategies. In this retrospective cohort study, effects of NAC on HER2/neu status in invasive breast cancer were evaluated, and the related factors were analyzed.Patients and MethodsOne hundred thirty-one patients with primary breast cancer were treated with anthracycline- and/or taxane-based NAC. HER2/neu status was evaluated by IHC on core needle biopsies of primary tumors before NAC and surgical resection specimens of post-NAC residual breast cancers or tumor-positive axillary lymph nodes. Thirty-two pairs of specimens with discordant HER2/neu IHC scores were analyzed by fluorescence in situ hybridization (FISH).ResultsA significant difference in HER2/neu status by IHC between core needle biopsies and surgical resection specimens in patients receiving NAC was observed. After NAC, 23.4% (29 of 124) of tumors showed downregulated HER2/neu expression by IHC. Alterations of HER2/neu IHC scores did not significantly correlate with tumor subtype, pathologic response to NAC, adjuvant regimen, or time interval from the last chemotherapy to surgery. HER2/neu protein overexpression level was associated with favorable pathologic response to anthracycline and taxane-based chemotherapy. However, tumors with altered HER2/neu IHC scores after NAC revealed stable HER2/neu gene amplification/nonamplification by FISH analysis.ConclusionNeoadjuvant chemotherapy for breast carcinoma resulted in the HER2/neu status alteration by IHC, but they have stable gene amplification status by FISH. HER2/neu protein overexpression indicated greater sensitivity to neoadjuvant anthracycline- and taxane-based chemotherapy. Thus, retesting HER2/neu IHC status in residual tumors after NAC should be considered in order to optimize adjuvant systemic therapy.     

HER-2/<Emphasis Type="Italic">neu</Emphasis> expression in primary and metastatic breast cancer

Introduction Trastuzumab is a highly effective therapy for the treatment of HER-2/neu positive breast cancer. To maximize benefit and minimize unnecessary toxicity, patient selection is essential. Currently HER-2/neu analysis is routinely performed only for primary invasive breast cancers, and trastuzumab therapy is recommended based on primary analysis only. Methods Using immunohistochemistry, we performed a retrospective study comparing HER-2/neu expression in original primary to subsequent metastatic breast cancers. Results Tumors from 382 patients with metastatic breast cancer were studied. In 254 cases (66%) both primary and metastatic lesions were concordant. In 90 cases the primary lesion was HER-2/neu positive with the metastatic lesion negative; whereas, in 37 cases the primary lesion was HER-2/neu negative and the metastatic lesion positive. Primary HER-2/neu immunostaining was associated with a negative predictive value of 35.7%. Although all four groups were similar at diagnosis, survival differences were noted with the best survival experienced by patients with initial primary lesions HER-2/neu negative and subsequent metastatic lesions positive. Patients with hormone receptor and HER-2/neu positive primary lesions who received tamoxifen were more likely to have HER-2/neu positive metastasis. Conclusions The significant discordance between HER-2/neu expression in primary and metastatic tumors suggests that determination of HER-2/neu status in metastatic disease should be attempted.