Immunohistochemical investigation of estrogen and progesterone receptors in breast tumors

Estrogen (ER) and progesterone (PR) receptor levels were assayed in 344 breast tumors. The following 4 patterns were identified: ER+ PR(+)--61%; ER+ PR- 24%; ER- PR(+)--15% and ER- PR(-)--35%. While no correlation was found between histological pattern, on the one hand, and the ER/PR ratio and age, on the other, there was one between estrogen and progesterone receptor content, on the one hand, and age, tumor size and metastatic spread to regional lymph nodes, on the other (p > 0.001).     

Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptor-positive primary breast cancer

BACKGROUND: HER-2/neu, which encodes a receptor tyrosine kinase, is amplified and overexpressed in 20%-25% of human breast cancers. Such tumors are often resistant to hormone therapy. Despite a general inverse association between HER-2/neu amplification/overexpression and estrogen receptor (ER) and/or progesterone receptor (PR) expression, a fraction of patients are both HER-2/neu- and hormone receptor (HR)-positive. The efficacy of hormone therapy in this group is currently a matter of debate. To better understand the relationship between HER-2/neu positivity and HR expression, we analyzed HER-2/neu, ER, and PR as continuous variables in breast cancer cell lines and two cohorts of primary breast cancer patients. METHODS: HER-2/neu and ER/PR expression was analyzed by enzyme-linked immunosorbent assay (ELISA) and enzyme immunoassay (EIA), respectively, in 14 human breast cancer cell lines, some of which had been transfected with the HER-2/neu gene. For the clinical study population, HER-2/neu protein levels were assessed by ELISA (cohort A, n = 665), and HER-2/neu gene copy number was determined using fluorescence in situ hybridization (cohort B, n = 894). ER/PR expression was analyzed by EIA (cohort A) or radioligand binding (cohort B). Associations between HER-2/neu and ER/PR expression were analyzed using Spearman's rho correlation and the chi-square test, and absolute levels were compared using the Mann-Whitney U test. All statistical tests were two-sided. RESULTS: HR-positive human breast cancer cell lines transfected with the HER-2/neu gene expressed statistically significantly lower levels of ER and PR than parental lines. In the clinical cohorts, levels of HER-2/neu overexpression and gene amplification were inversely correlated with ER/PR levels (Cohort A [n = 112]: for ER, r = -0.34, P<.001; for PR, r = -0.24, P =.010. Cohort B [n = 188]: for ER, r = -0.39, P<.001; for PR, r = -0.26, P<.001). Among patients with HR-positive tumors, HER-2/neu-positive tumors had statistically significantly lower ER/PR levels than HER-2/neu-negative ones (Cohort A: for ER, median = 25 fmol/mg [interquartile range [IQR] = 13-78] versus median = 38.5 fmol/mg [IQR = 17-99] and P =.031; for PR, median = 35 fmol/mg [IQR = 12-119] versus median = 88.5 fmol/mg [IQR = 22-236] and P<.001. Cohort B: for ER, median = 44 fmol/mg [IQR = 13-156] versus median = 92 fmol/mg [IQR = 35-235] and P<.001; for PR, median = 36 fmol/mg [IQR = 13-108] versus median = 84 fmol/mg [IQR = 24-250] and P<.001). Patients with higher levels of HER-2/neu overexpression or amplification had statistically significantly lower levels of ER/PR than patients with lower levels of HER-2/neu overexpression or amplification. CONCLUSION: Because absolute HR levels are strongly related to response to hormone therapy in primary and advanced breast cancer, reduced ER/PR expression may be one mechanism to explain the relative resistance of HER-2/neu-positive:HR-positive tumors to hormone therapy.     

Expression of estrogen and progesterone receptors and oncoprotein HER-2 as a marker for clinical course and outcome in endometrioid adenocarcinoma of the uterine body (immunohistologic study)

A retrospective immunohistological assay identified estrogen (ER) (72%) and progesterone (PR) (71%) receptor content in tumors from 76 patients with endometroid cancer (ER+ PR(+)--63.2%; ER- PR(-)--22.3%; ER+ PR- 9.2%; ER- PR+ -5.3%). Pattern R+ involved well differentiated cells, slight invasion of the myometrium and infrequent spreading to the regional lymph nodes, as compared with cases of unidentified ER or PR. Five-year survival in patients with ER+ PR+ tumors was 83% vs. 53% in cases without steroid hormone receptor expression (p = 0.04). HER 2 overexpression was found in 31.6% of tumors involving a decrease in total survival from 73 to 54.2% (p = 0.04). No significant correlation was established between ER and PR, on the one hand, and HER 2 expression, on the other. HER 2 overexpression leveled off the prognostic value of steroid receptor expression to a considerable degree; relapse incidence in patients with HER 2 overexpression in ER+ PR+ tumors rose 9-26.7% while five-year survival dropped 88-60% (p = 0.03). A distinct correlation between ER and PR expression (r = 0.96) was reported by D.C. Alfred et al. and verified by the H-scor procedure (R.A. Mc Clelland et al.). This procedure for steroid receptor expression determination is as the first unsophisticated, yet informative, method.     

The estrogen receptor negative-progesterone receptor positive breast carcinoma is a biological entity and not a technical artifact

The ER-/PR+ breast tumor may be the result of a false ER negative result. The aim of this study was to investigate whether there is a difference in patient and tumor characteristics of the ER-/PR+ phenotype in an Asian setting. A total of 2629 breast cancer patients were categorized on the basis of their age, ethnicity, tumor hormonal receptor phenotype, grade and histological type. There were 1230 (46.8%) ER+/PR+, 306 (11.6%) ER+/PR-, 122 (4.6%) ER-/PR+ and 972 (37%) ER-/PR-. ER-/PR+ tumors were 2.5 times more likely to be younger than 50 years at diagnosis (OR: 2.52; 95% CI: 1.72-3.67). Compared to ER+/PR+ tumors, the ER-/ PR+ phenotype was twice more likely to be associated with grade 3 tumors (OR:2.02; 95%CI: 1.00-4.10). In contrast, compared to ER-/PR- tumors, the ER-/PR+ phenotype was 90% less likely to be associated with a grade 3 tumor (OR: 0.12; 95%CI:0.05-0.26), and more likely to have invasive lobular than invasive ductal histology (OR: 3.66; 95%CI: 1.47-9.11). These results show that the ER-/PR+ phenotype occurs in a younger age group and is associated with intermediate histopathological characteristics compared to ER+/PR+ and ER-/PR- tumors. This may imply that it is a distinct entity and not a technical artifact.     

Association of Poor Prognosis Subtypes of Breast Cancer with Estrogen Receptor Alpha Methylation in Iranian Women

Breast cancer is a prevalent heterogeneous malignant disease. Gene expression profiling by DNA microarraycan classify breast tumors into five different molecular subtypes: luminal A, luminal B, HER-2, basal and normallikewhich have differing prognosis. Recently it has been shown that immunohistochemistry (IHC) markersincluding estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2(Her2), can divide tumors to main subtypes: luminal A (ER+; PR+/-; HER-2-), luminal B (ER+;PR+/-; HER-2+),basal-like (ER-;PR-;HER2-) and Her2+ (ER-; PR-; HER-2+). Some subtypes such as basal-like subtype have beencharacterized by poor prognosis and reduced overall survival. Due to the importance of the ER signaling pathwayin mammary cell proliferation; it appears that epigenetic changes in the ERα gene as a central component of thispathway, may contribute to prognostic prediction. Thus this study aimed to clarify the correlation of differentIHC-based subtypes of breast tumors with ERα methylation in Iranian breast cancer patients. For this purposeone hundred fresh breast tumors obtained by surgical resection underwent DNA extraction for assessedment oftheir ER methylation status by methylation specific PCR (MSP). These tumors were classified into main subtypesaccording to IHC markers and data were collected on pathological features of the patients. ERα methylation wasfound in 25 of 28 (89.3%) basal tumors, 21 of 24 (87.5%) Her2+ tumors, 18 of 34 (52.9%) luminal A tumors and7 of 14 (50%) luminal B tumors. A strong correlation was found between ERα methylation and poor prognosistumor subtypes (basal and Her2+) in patients (P<0.001). Our findings show that ERα methylation is correlatedwith poor prognosis subtypes of breast tumors in Iranian patients and may play an important role in pathogenesisof the more aggressive breast tumors.     

Do we need HER-2/neu testing for all patients with primary breast carcinoma?

BACKGROUND: HER-2/neu is a valuable prognostic marker in primary breast carcinoma. Controversy surrounds the correlation between HER-2/neu expression and other prognostic markers, as has been discussed in preclinical and clinical studies. The objective of the current study was to investigate the probability, calculated using parameters that are assessed routinely in clinical practice, that patients with breast carcinoma had positive HER-2/neu status. METHODS: The authors evaluated HER-2/neu status in 923 consecutive patients with breast carcinoma by immunohistochemical methods. Correlations involving HER-2/neu status, estrogen receptor (ER) and progesterone receptor (PR) status, tumor grade, patient age, lymph node involvement, and tumor size were evaluated using the Mantel-Haenszel chi-square test and the Spearman correlation. The authors created a simple scoring system (i.e., the diagnostic instrument for validation of HER-2/neu score) to define subgroups of patients with breast carcinoma and to determine the likelihood of HER-2/neu positivity. RESULTS: HER-2/neu overexpression was correlated significantly with negative ER (P = 0.0001) and PR status (P = 0.0001), Grade 3 (G3) lesions (P = 0.0001), and young age (P = 0.006). The likelihood of HER-2/neu positivity in a patient with positive ER and PR status and G1/G2 disease was approximately 6.1%. CONCLUSIONS: The authors demonstrated in a large patient series that HER-2/neu overexpression was associated with negative hormone receptor status, G3, and young age. In a subgroup of patients presenting with hormone-responsive and G1/G2 tumors, the likelihood of HER-2/neu overexpression was very small. Therefore, the assessment of HER-2/neu status in this subgroup of patients with breast carcinoma may be considered unnecessary, unless the role of HER-2/neu status in adjuvant treatment has been proven.     

不同亚型乳腺癌脑转移临床特点及生存分析

目的探讨不同亚型乳腺癌脑转移的临床特点及预后。方法回顾性分析90例乳腺癌脑转移患者的临床资料,分为雌激素受体(ER)和(或)孕激素受体(PR)阳性,人表皮生长因子受体-2(HER-2)阳性和三阴性(ER、PR及HER-2均阴性)三种亚型。 结果90例患者中,ER和(或)PR阳性51例(56.7%)、HER-2阳性12例(13.3%)、三阴性27例(30.0%),中位无病生存期(30.9月、25.4月和16.0月,P=0.001)、无脑转移生存期(36.0月、38.0月和22.0月,P=0.008)之间差异有统计学意义,但总生存期(52.0月、25.5月和36.0月,P=0.075)及确诊脑转移后的生存期(11.0月、5.5月和8.0月,P=0.829)之间的差异无统计学意义。结论三阴性乳腺癌无病生存期明显缩短,更易于早期发生脑转移,但总生存期及确诊脑转移以后的生存期无明显差别。     

HER-2/neu Status: A Neglected Marker of Prognostication and Management of Breast Cancer Patients in India

Background: Categorizing breast tumors based on the ER, PR and HER/Neu 2 receptor status is necessary in order to predict outcome and assist in management of breast cancer. Herfe we assessed this question in South Indian patients. Materials and Methods: A total of 619 formalin fixed paraffin embedded breast tumor tissues were collected from pathology archives after receipt of ethical clearance. With the help of primary and secondary conjugated antibodies, expression status of ER, PR and HER2/neu was determined. All the experimental data were assessed for correlations with histopathological features of tumors and clinical presentation of the subjects. Results: In the present study, the ages ranged from 20-87 years with a mean of 50.0±12.q years, and majority of the tumors (84%) were of infiltrating duct cell carcinoma type. Assessment of ER, PR and Her-2/neu expression showed that 46% were triple negative. Interestingly, an inverse relation between ER, PR and HER-2/neu was apparent in 41.2% (p<0.0001) of the tumors, of which 24.5% (p<0.0001) were ER and PR co-negative but HER-2 positive. Conclusions: ER and PR positive tumors are less common (i.e<30%) compared to HER-2/neu positive tumors (i.e>50%) in Indian breast cancer patients, underlining the need for effective diagnostic screening and specific therapeutic managements in order to improve the survival rate of patients in low resource countries such as India.     

Breast cancer subtypes identified by the ER, PR and HER-2 status in Thai women

Expression of estrogen-receptor (ER), progesterone-receptor (PR) and HER-2 has recently been linked with various breast cancer subtypes identified by gene microarray. This study aimed to document breast cancer subtypes based on ER, PR and HER-2 status in Thai women, where expression of these subtypes may not be similar to those evident in Western women. During 2009 to 2010, histological findings from 324 invasive ductal carcinomas (IDC) at Siriraj Hospital were studied. Various subtypes of IDC were identified according to expression of ER, PR and HER-2: luminal-A (ER+;PR+/-;HER-2-), luminal-B (ER+;PR+/-;HER-2+), HER-2 (ER-;PR- ;HER-2+) and basal-like (ER-;PR-;HER-2-). As well, associations of tumor size, tumor grade, nodal status, angiolymphatic invasion (ALI), multicentricity and multifocality with different breast cancer subtypes were studied. Of 324 IDCs, 143 (44.1%), 147 (45.4%), 15 (4.6%) and 12 (3.7%) were T1, T2, T3 and T4, respectively. Most tumors were grade 2 (54.9%) and had no nodal involvement (53.4%). According to ER, PR and HER-2 status, 192 (59.3%), 40 (12.3%), 43 (13.3%) and 49 (15.1%) tumors were luminal-A, luminal-B, HER-2 and basal-like subtypes. HER-2 subtype presented with large tumor (p=0.04, ANOVA). Luminal-A IDC was associated with single foci (p<0.01, χ2). HER-2 and basal-like subtypes were likely to have high tumor grade (p<0.01, χ2). In addition, HER-2 subtype had higher number of nodal involvement (p=0.048, χ2). In conclusion, the luminal-A subtype accounted for the majority of IDCs in Thai women. Percentages of HER-2 and basal-like IDCs were high, compared with a recent study from the USA. The HER-2 subtype was related with high nodal invasion. The findings may highlight biological differences between IDCs occurring in Asian and Western women.     

不同病理亚型乳腺癌脑转移患者预后分析

目的:了解不同病理亚型乳腺癌脑转移患者的预后特点。方法:根据肿瘤组织免疫组化ER、PR、HER-2 的表达情况将89例患者分为4 组:Luminal A型（ER+ 和/或PR+ ,HER-2-）17例、Luminal B型（ER+ 和/或PR+ ,HER-2 +）15例、HER-2 + 型（ER- ,PR- ,HER-2 +）24例和Basal-like型（ER- ,PR- ,HER-2-）33例。主要观察4 组患者分布比例、发病年龄、月经状态、病理类型、病理分级、肿瘤大小、淋巴结状态及脑转移发生距手术时间及部位等。使用SPSS15.0 统计软件进行数据分析,定量资料采用t检验,计数资料比较采用卡方检验,生存率计算采用Kaplan-Meier 法并用Log-rank 检验,P<0.05为差异有统计学意义。结果:所有患者当中Basal-like型所占比例最高（37.1%）,其次为HER-2 +（27%）,Luminal A型（19.1%）,Luminal B型最少（16.9%）。 Basal-like 型患者预后最差,其病理分级Ⅲ级的患者比例达到了73% 。在其他部位出现转移情况上,Luminal型患者表现出较高的骨转移倾向。全组患者的中位生存期为47个月,无病生存期为20个月,确诊脑转移后的生存期为9 个月。ER（-）且PR（-）较ER/PR（+）（45个月vs.52个月,P=0.006）、HER-2（+）较HER-2（-）（45个月vs.51.5 个月,P=0.04）、Basal-like亚型的患者预后较其他亚型差（33个月vs.52个月,P=0.000）。 结论:病理亚型是判断乳腺癌脑转移患者预后不同的良好指标,ER（-）且PR（-）、HER-2（+）、Basal-like亚型患者容易出现脑转移且预后较差。      

乳腺导管原位癌和乳腺导管原位癌伴微浸润的分子分型差异性研究

背景与目的：乳腺导管原位癌伴微浸润（ductal carcinoma in situ with microinvasion,DCISMI）是乳腺导管原位癌（ductal carcinoma in situ,DCIS）发展到浸润性乳腺癌（invasive breast cancer,IDC）的中间阶段,该研究旨在分析乳腺DCIS和DCIS-MI这两类早期乳腺癌不同临床病理学特征和各个分子分型间的差异。方法：本回顾性研究纳入了317例DCIS患者,其中227例（71.6%）为纯DCIS患者,90例（28.4%）为DCIS-MI患者。所有患者根据其DCIS成分而非微浸润成分的免疫组织化学检查结果分成腔面A型［雌激素受体（estrogen receptor,ER）和（或）孕激素受体（progesterone receptor,PR）阳性,人类表皮生长因子受体2（human epidermal growth factor receptor 2,HER-2）阴性］、腔面B型［ER和（或）PR阳性,HER-2阳性］、HER-2过表达型（ER和PR阴性,HER-2阳性）和基底样型（ER和PR阴性,HER-2阴性）。结果：DCIS-MI患者的肿瘤大小倾向更大（P=0.059）,病理核分级显著更高（P=0.002）。和DCIS患者相比,乳腺DCIS-MI患者中腔面A型比例较低而基底样型比例较高（P=0.001）。结论：乳腺DCIS和DCIS-MI间分子分型分布不同,临床病理特征迥异,提示DCIS-MI是DCIS发展的新阶段,有了“质”的改变,本结论有待后续更大样本量的研究进行验证。     

Comparison of ER,PR & HER-2/neu (C-erb B 2) Reactivity Pattern with Histologic Grade,Tumor Size and Lymph Node Status in Breast Cancer

Introduction: Carcinoma of the breast is the most common malignancy of women in Karachi. The currentstudy was conducted with the objective of assessing estrogen receptor (ER), progesterone receptor (PR) andHER-2/neu reactivity patterns of mammary cancers for correlation with histologic grade, tumor size and lymphnode metastasis. Materials and methods: One hundred and fifty modified mastectomy specimens received atthe section of histopathology, Aga Khan University Hospital, were selected using a non-probability samplingmethod. Results: Mean age of the patients was 48.3 years (95%CI 46.5, 50.2). The left breast was more commonlyinvolved (57%). Tumor size ranged from 0.3 to 15.0 cm; 12% were ≤2.0 and 35.3% were ≥ 5.0 cm in diameter.The predominant morphology was infiltrating ductal carcinoma (85.3%). The majority of the cases presentedas grade II (55.3%) lesions with tumor necrosis (70%) and lymph node involvement (71.3%). ER and PR werepositive in 32.7% and 25.3% cases respectively. HER-2/neu was positive (3+) in 24.7%. ER positivity increasedand HER-2/neu positivity decreased with rising age. ER and PR expression was significantly lower in HER-2/neu positive as compared with HER-2/neu negative tumors (ER 83.8% vs 69.8%; PR 91.9% vs 77.8%). In theHER-2/neu positive tumors, ER and PR expression in high grade tumors was significantly decreased comparedwith intermediate grade tumors (ER 5.6% vs 10.5; PR 0% vs 5.3%). ER expression in the HER-2/neu positive,large sized tumors was also significantly decreased compared with smaller tumors (ER 6.3% vs 11.8). Conclusions:ER and PR expression in breast cancers in the current study was found to be comparable to publishedinternational data, but the frequency of HER-2/neu expression was higher, possibly reflecting a young age atdiagnosis. Assessment of prognostic markers for the clinical management of breast cancer patients is stronglyadvocated to provide best therapeutic options.     

Age interacts with the expression of steroid and HER-2 receptors in operable invasive breast cancer

BACKGROUND: The negative association between the oestrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER-2) in breast cancer travels in both directions. ER+ tumours are less likely HER-2+ and HER-2+ tumours are less likely ER+. METHODS: We studied the age-related immunohistochemical (IHC) expression of ER, progesterone receptor (PR) and HER-2 in 2,227 tumours using age as a continuous variable. Steroid receptors were considered positive for any nuclear staining of invasive cancer cells and for HER-2, either for strong expression by IHC (score 3+) or gene amplification by fluorescence in situ hybridisation (FISH). Based on nonparametric regression, the age-related association between steroid receptors and HER-2 was presented as likelihood curves. RESULTS: The association between ER or PR and HER-2 is age-related. The age-related expression of ER and PR is HER-2 dependent. In HER-2(-) cases, the odds ratio (OR) for being ER+ was 2.594 (95% CI = 1.874-3.591) up to age 50 and age-independent thereafter; for PR-expression the OR was 2.687 (95% CI = 1.780-4.057) up to age 45 and 0.847 (95% CI = 0.761-0.942) thereafter. In HER-2+ cases, the OR was 0.806 (95% CI = 0.656-0.991) to be ER+ and 0.722 (95% CI = 0.589-0.886) to be PR+. The age-related OR for breast cancers to be HER-2+ is steroid receptor dependent. Taking together, ER+PR+HER-2+ breast cancers appear on average 5.4 years earlier than breast cancers of any other ER/PR/HER-2 phenotype (95% CI = 3.3-7.5; P < 0.0001). CONCLUSION: There is a qualitative interaction between age and expression of steroid and HER-2 receptors. Our findings suggest a strong age-related selective growth advantage for breast tumour cells belonging to the ER+PR+HER-2+ subgroup.     

HER-2,P53 and Hormonal Receptors Protein Expression as Predictive Factors in Breast Cancer Prognosis

Objective  Breast cancer is a heterogeneous disease with variable biological and clinical characteristics. We conducted a study to evaluate P53, HER-2/neu and hormonal receptor expression as predictors of prognosis in breast cancer. Methods  In a prospective study, we recruited 81 consecutive patients with primary operable breast cancer who were treated with mastectomy followed by locoregional radiotherapy or chemotherapy and studied the presence of P53, HER-2/neu and hormonal receptors (ER/PR) expression in tumor tissues by immunohistochemical staining. Associations between these markers expression and clinical outcomes, including local and regional recurrence and metastasis were evaluated. Statistical analysis was performed with the SPSS so ware. Results  The mean time of follow-up was (47.3 ± 4.6) months. Expression of P53, HER-2/neu, Estrogen receptors and progesterone receptors were observed in 31.1%, 38.5%, 31.8% and 51.7% of the patients, respectively. P53, HER-2/neu and Negative ER status were potent predictors of local-regional recurrence (P = 0.034, 0.038, 0.044, respectively). Also HER-2/neu, Negative ER and Negative PR status were strong predictors of metastasis (P = 0.001, 0.042, 0.054, respectively). Conclusion  P53 and HER-2/neu expression and also steroid receptors status (ER/PR status) have an important role in predicting the outcome of breast cancer and thus may be of value in selecting suitable therapeutic strategy and determining prognosis in these patients.     

Estrogen receptor negative/progesterone receptor positive breast cancer is not a reproducible subtype

Introduction

Estrogen receptor (ER) and progesterone receptor (PR) testing are performed in the evaluation of breast cancer. While the clinical utility of ER as a predictive biomarker to identify patients likely to benefit from hormonal therapy is well-established, the added value of PR is less well-defined. The primary goals of our study were to assess the distribution, inter-assay reproducibility, and prognostic significance of breast cancer subtypes defined by patterns of ER and PR expression.

Methods

We integrated gene expression microarray (GEM) and clinico-pathologic data from 20 published studies to determine the frequency (n = 4,111) and inter-assay reproducibility (n = 1,752) of ER/PR subtypes (ER+/PR+, ER+/PR-, ER-/PR-, ER-/PR+). To extend our findings, we utilized a cohort of patients from the Nurses’ Health Study (NHS) with ER/PR data recorded in the medical record and assessed on tissue microarrays (n = 2,011). In both datasets, we assessed the association of ER and PR expression with survival.

Results

In a genome-wide analysis, progesterone receptor was among the least variable genes in ER- breast cancer. The ER-/PR+ subtype was rare (approximately 1 to 4%) and showed no significant reproducibility (Kappa = 0.02 and 0.06, in the GEM and NHS datasets, respectively). The vast majority of patients classified as ER-/PR+ in the medical record (97% and 94%, in the GEM and NHS datasets) were re-classified by a second method. In the GEM dataset (n = 2,731), progesterone receptor mRNA expression was associated with prognosis in ER+ breast cancer (adjusted P <0.001), but not in ER- breast cancer (adjusted P = 0.21). PR protein expression did not contribute significant prognostic information to multivariate models considering ER and other standard clinico-pathologic features in the GEM or NHS datasets.

Conclusion

ER-/PR+ breast cancer is not a reproducible subtype. PR expression is not associated with prognosis in ER- breast cancer, and PR does not contribute significant independent prognostic information to multivariate models considering ER and other standard clinico-pathologic factors. Given that PR provides no clinically actionable information in ER+ breast cancer, these findings question the utility of routine PR testing in breast cancer.     

Implications of constructed biologic subtype and its relationship to locoregional recurrence following mastectomy

Introduction

We examined the prognostic value of biologic subtype on locoregional recurrence (LRR) after mastectomy in a cohort of low risk women who did not receive adjuvant radiation therapy.

Methods

A total of 819 patients with invasive breast cancer underwent mastectomy from January 2000 through December 2005. No patient received preoperative chemotherapy. Estrogen receptor (ER) receptor, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status were used to construct the following 4 subtypes: i) ER+ or PR+ and HER2- (HR+/HER2-), ii) ER+ or PR+ and HER2+ (HR+/HER2+), iii) ER- and PR- and HER2+ (HR-/HER2+)and iv) ER- and PR- and HER2- (HR-/HER2-). LRR-free survival was estimated by the Kaplan-Meier method. Cox proportional hazard models were used to evaluate the association between time-to-event outcomes and patient prognostic factors.

Results

At a median follow-up of 58 months, five-year cumulative incidence of LRR for the entire cohort was 2.5%. Subtype specific LRR rates were 1% for HR+/HER2-, 6.5% in HR+/HER2+, 2% for HR-/HER2+ and 10.9% for HR-/HER2- (P < 0.01). In HER-2+ patients (irrespective of ER/PR status), trastuzumab therapy was not associated with LRR-free survival. On multivariate analysis, one to three positive lymph nodes (HR 4.75 (confidence interval (CI) 1.75 to 12.88, P < 0.01), ?? 4 positive lymph nodes (HR23.4 (CI 4.64 to 117.94, P < 0.01), HR+/HER2+ (HR 4.26 (CI 1.05 to 17.33), P = 0.04), and HR-/HER2- phenotype (HR 13.87 (CI 4.96 to 38.80), P < 0.01) were associated with shorter LRR-free survival whereas age > 50 at diagnosis (HR 0.31 (CI 0.12 to 0.80), P = 0.02) was associated with improved LRR-free survival. Among the HR-/HER2- subtypes, five-year LRR incidence was 23.4% in patients with positive lymph nodes compared to 7.8% for lymph node negative patients (P = 0.01), although this association did not reach significance when the analysis was limited to HR-/HER2- women with only one to three positive lymph nodes (15.6% versus 7.8%, P = 0.11).

Conclusions

Constructed subtype is a prognostic factor for LRR after mastectomy among low risk women not receiving adjuvant radiation therapy, although rates of LRR remain low across subtypes. Patients with node positive, HR-/HER2- type tumors were more likely to experience LRR following mastectomy alone. Prospective studies to further investigate the potential benefit of adjuvant radiation therapy in these women are warranted.     

Clinical outcome of adjuvant endocrine treatment according to PR and HER-2 status in early breast cancer.

Patients with estrogen receptor (ER)+/progesterone receptor (PR)- and/or HER-2 overexpressing breast carcinomas may derive lower benefit from endocrine treatment. We examined retrospectively data from 972 breast cancer patients who received tamoxifen (725), tamoxifen + Gn-RH analogs (127) and aromatase inhibitors (120) as adjuvant treatments. ER+/PR- versus ER+/PR+ tumours were characterised by larger size (P = 0.001), higher tumour grade (P = 0.001), higher Ki-67 expression (P = 0.001) and lower mean ER (P = 0.000) and HER-2 expression (P = 0.000). At univariate analysis, tumour grading [hazard ratio (HR) = 4.0; 95% confidence interval (CI) = 1.4-11.1; P = 0.007], nodal status (HR = 3.4; 95% CI 1.2-5.7; P = 0.000), tumour diameter (HR = 2.9; 95% CI 1.7-4.7; P = 0.000) lack of PR expression (HR = 2.1; 95% CI 1.3-3.4; P = 0.002) and HER-2 overexpression (HR = 1.9; 95% CI 1.0-3.5; P = 0.03), as well as Ki 67 expression (HR = 1.7; 95% CI 1.0-2.7; P = 0.04) were associated with shorter disease-free survival (DFS). At the multivariate analysis, nodal status (HR = 3.6; 95% CI 1.9-6.8; P = 0.0001), lack of PR expression (HR = 2.3; 95% CI 1.3-4.0; P = 0.003) and tumour diameter (HR = 2.1; 95% CI 1.1-3.8; P = 0.018) retained their prognostic significance, whereas HER-2 overexpression was associated with a trend towards shorter DFS that was of borderline statistical significance (HR = 2.0; 95 % CI 1.0-3.9; P = 0.05). Our data suggest that lack of PR expression and HER-2 overexpression are both associated with aggressive tumour features, but the prognostic information of PR status on the risk of recurrence in endocrine-treated breast cancer patients is stronger.     

The expression of progesterone receptors coincides with an arrest of DNA synthesis in human breast cancer

Two main models to account for the heterogeneous expression of estrogen receptors (ER) and progesterone receptors (PR) in human breast cancer have been proposed: the clonal model and the stem cell model. The authors previously provided evidence supporting the stem cell model since it was found that most of the proliferating cells in ER-positive (ER+) human breast cancer lack ER and that the ER-negative (ER-) and ER+ subpopulations are interrelated. The authors have analyzed in eighteen ER+/PR+ primary breast tumors the simultaneous expression of ER or PR (by immunohistochemistry) and DNA synthesis (by autoradiography) after 30 minutes of 3H-thymidine incorporation. The authors demonstrated that: (1) the average numbers of ER+ and PR+ cells were similar (36.8 +/- 10.7% and 39.3 +/- 17.6%, respectively); (2) The thymidine-labeling indexes of the ER+, ER-, PR+, and PR- subpopulations were 0.53 +/- 0.69%, 0.74 +/- 0.49%, 0.21 +/- 0.21 and 0.94 +/- 0.54%, respectively; and (3) 75.2% of the DNA-synthesizing cells were ER-, and 88.8% of them were PR-. The authors conclude that the cellular subpopulations expressing ER and PR were not identical, and the expression of PR was associated with a lower rate of cellular proliferation than was ER expression.     

Elevated serum Her-2/neu level predicts decreased response to hormone therapy in metastatic breast cancer.

PURPOSE: To determine the effect of elevation of serum HER-2/neu on response to hormone therapy. PATIENTS AND METHODS: Seven hundred nineteen metastatic patients with estrogen receptor-positive (ER(+)), progesterone receptor-positive, or both or ER status unknown breast cancer were randomized in three independent clinical trials to receive second-line hormone therapy with either megestrol acetate or an aromatase inhibitor (fadrozole or letrozole). An automated enzyme-linked immunosorbent assay specific for the extracellular domain of the HER-2/neu (c-erbB-2) oncoprotein product was used to detect serum levels. RESULTS: Two hundred nineteen patients (30%) had elevated serum HER-2/neu protein levels, using the mean + 2 SD (15 ng/mL) from the serum of healthy women as an upper limit. Response to treatment was available for 711 patients. The response rate (complete responses plus partial responses plus stable disease) to endocrine therapy was 45% in 494 patients with non-elevated and 23% in 217 patients with elevated serum HER-2/neu levels (P <.0001). Median duration of treatment response (using the time to progression [TTP] variable for patients who responded) was shorter in the group with elevated serum HER-2/neu levels (11.7 months) compared with the patient group with non-elevated levels (17.4 months). TTP, time to treatment failure, and median survival (17.2 months v 29.6 months) were also significantly shorter in the patients with elevated serum HER-2/neu levels (P <.0001). CONCLUSION: Patients with ER(+) and serum HER-2/neu-positive metastatic breast cancer are less likely to respond to hormone treatment and have a shorter duration of response than ER(+) and serum HER-2/neu-negative patients. Their survival duration is also shorter.     

HER-2, P53 and hormonal receptors protein expression as predictive factors in breast cancer prognosis

OBJECTIVE Breast cancer is a heterogeneous disease with variable biological and clinical characteristics. We conducted a study to evaluate P53, HER-2/neu and hormonal receptor expression as predictors of prognosis in breast cancer.
METHODS In a prospective study, we recruited 81 consecutive patients with primary operable breast cancer who were treated with mastectomy followed by locoregional radiotherapy or chemotherapy and studied the presence of P53, HER-2/neu and hormonal receptors （ER/PR） expression in tumor tissues by immunohistochemical staining. Associations between these markers expression and clinical outcomes, including local and regional recurrence and metastasis were evaluated. Statistical analysis was performed with the SPSS software.
RESULTS The mean time of follow-up was （47.3 ± 4.6） months. Expression of P53, HER-2/neu, Estrogen receptors and progesterone receptors were observed in 31.1%, 38.5%, 31.8% and 51.7% of the patients, respectively. P53, HER-2/neu and Negative ER status were potent predictors of local-regional recurrence （P = 0.034, 0.038, 0.044, respectively）. Also HER-2/neu, Negative ER and Negative PR status were strong predictors of metastasis （P = 0.001, 0.042, 0.054, respectively）. CONCLUSION P53 and HER-2/neu expression and also steroid receptors status （ER/PR status） have an important role in predicting the outcome of breast cancer and thus may be of value in selecting suitable therapeutic strategy and determining prognosis in these patients.