Assessment of hormone receptor status in breast cancer

The aim of the present paper was to investigate the most adequate method for the assessment of hormone receptor status in breast cancer in routine clinical settings. Subjects were 486 patients with primary breast cancer who underwent surgery and postoperative tamoxifen monotherapy in 1982-1993. Using representative sections of the primary lesion in each patient, estrogen receptors (ER) were immunohistochemically stained. Patients were divided into ER-positive and ER-negative groups using various methods, and then overall and 5 year recurrence-free survival rates were compared. The results of ER status, which are diagnosed on entire cancer area and invasive cancer area, matched in 98% of cases. When assessing prognosis based on the proportion of positive cells, a significant difference in 5 year recurrence-free survival was seen between ER-positive and ER-negative patients for a cut-off of 10%, and in overall and 5 year survival for a cut-off of 33%. Based on the proportion and the intensity of positive cells (Allred score), a significant difference was seen in overall and 5 year survival for a cut-off in total scores between 4 and 5 points. When assessing hormone receptors of breast cancer in routine clinical settings, it is sufficient to determine the proportion of positive cells in the entire cancer area.     

11q13 is a susceptibility locus for hormone receptor positive breast cancer

A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P ≤ 3 × 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 × 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype.     

Estrogen receptor beta is expressed in human colorectal adenocarcinoma

Estrogen receptor beta (ER-beta) has recently been detected in a human colon cancer cell line. The aim of this work was to determine whether ER-beta is expressed in human colorectal carcinoma (CRC) tissue and the extent of this expression. ER-beta expression in CRC was investigated by immunohistochemical staining of sections of formalin-fixed, paraffin-embedded tissue from 55 CRC. The percent of positive cells was recorded. ER-beta immunoreactivity was always present in normal epithelium and adenomas in the same sections of some CRC and was always nuclear. In CRC, nuclear ER-beta immunoreactivity was detected in >10% of the cancer cells in 67% of the cases and was almost always associated with cytoplasmic immunoreactivity. There were no statistically significant differences between the ER-beta-positive and -negative groups in regard to depth of invasion, nodal metastases, or survival, regardless of the cut-off value used. We conclude that (1) a significant number of CRCs are positive for ER-beta. (2) estrogen may play an important role in the proliferation of normal colonic epithelium, and (3) there is differential localization of ER-beta immunoreactivity between normal colon, adenomas, and CRCs. Whether different ER-beta isoforms are differentially expressed in CRCs, and whether human CRCs respond to treatment with antiestrogens, is the subject of studies currently in progress.     

Obesity is associated with a poorer prognosis in women with hormone receptor positive breast cancer

Objective

Whether moderate to severe obesity (body mass index (BMI) ≥ 30 to <40 kg/m²) contributes to breast cancer recurrence and mortality remains uncertain.

Subjects and methods

1199 women, recruited within 12 months of their diagnosis of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−) invasive breast cancer completed an enrolment questionnaire and an annual follow-up questionnaire every 12 months for another 5 years. The impact of obesity on time to either local or distant recurrence or new breast cancer, or death due to breast cancer was determined by Cox regression. Women in the most extreme categories of BMI (<18.5 and ≥40) were excluded from the analysis.

Results

Of the 1155 included women, mean age, 58.4 ± 11.6 years, 53.8% had Stage 1 disease and 88.9% received oral adjuvant endocrine therapy (OAET) within 2 years of diagnosis. The likelihood of an event was significantly associated with moderate to severe obesity (HR = 1.71, 95%CI, 1.12–2.62, p = 0.014), disease beyond Stage 1 (HR = 2.87, 95% CI 1.73–4.75, p < 0.001), OAET (HR = 0.26, 95%CI 0.14–0.46, p < 0.001), mastectomy (HR = 3.28, 95%CI 1.98–5.44, p < 0.001) and radiotherapy (HR = 2.12, 95%CI 1.24–3.63, p = 0.006). For Stage 1 disease, only moderate to severe obesity (HR 3.23, 95%CI 1.48–7.03, p = 0.003) and OAET use (HR 0.41, 95%CI 0.17–0.98, p = 0.046) were significantly associated with an event.

Conclusion

Moderate to severe obesity is associated with a poorer invasive breast cancer prognosis; this is also true for women with Stage 1 disease, and is independent of age and treatment.     

Immunohistochemical expression of gonadotropin releasing hormone receptor in human breast carcinoma

Gonadotropin releasing hormone (GnRH) analogs can cause regression of hormone-dependent breast carcinomas via the specific GnRH receptor (GnRH-R). In an attempt to obtain a better understanding of GnRH actions in human breast carcinoma, the expression of GnRH-R was examined immunohistochemically in 58 invasive ductal carcinomas and correlated with various clinicopathological parameters. GnRH-R was immunolocalized in the cytoplasm of carcinoma cells in 37 of 58 invasive ductal carcinoma cases (64%). Immunoreactivity for GnRH-R was also detected focally in the cytoplasm of morphologically normal glandular epithelia adjacent to the carcinoma. A significant correlation was observed between the immunohistochemical expression of GnRH-R and estrogen receptor labeling index (LI; P = 0.030) or progesterone receptor LI (P = 0.0074). There was a significant inverse correlation between GnRH-R immunoreactivity and Ki-67 LI (P = 0.012). No significant correlations were detected between GnRH-R and other clinicopathological parameters, including patient age, menopausal status, stage, tumor size, lymph node status, histological grade and prognosis. This study indicates that GnRH-R is widely distributed in human breast carcinoma cells and regulates GnRH actions locally. Breast carcinomas positive for GnRH-R maintain some hormonal regulatory mechanisms, and GnRH actions may lead to a low proliferative rate in human breast carcinoma.     

Vimentin is preferentially expressed in human breast carcinomas with low estrogen receptor and high Ki-67 growth fraction.

Vimentin expression, growth fractions (GF), and estrogen receptor (ER) levels were determined for 90 untreated primary breast carcinomas. Coexpression of keratin and vimentin was found in approximately 20% of the tumors regardless of menopausal status. Vimentin was expressed preferentially in tumor cells of high-grade ductal breast carcinomas (15 of 28 histologic grade 3 vs. 0 of 40 grades 1 and 2). Vimentin expression was found preferentially in tumors with high GF (greater than 15% Ki-67 positive by immunoperoxidase staining) and low ER levels (less than 60 fmols/mg protein by a monoclonal enzyme immunoassay). Sixty-eight percent of tumors in this group were vimentin positive and 88% of all vimentin-positive tumors fell into this category. More than 50% of the tumor cells coexpressed vimentin and keratin. Thus, vimentin expression may be helpful in identifying a substantial subset of ER-independent breast carcinomas with poor prognostic indicators.     

Usefulness of liquid-based cytology in hormone receptor analysis of breast cancer specimens

Immunohistochemical (IHC) analysis of the hormone receptor (HR) in breast cancer cytology is an important issue nowadays. Several studies have shown discrepancy in the HR status between the primary tumor and metastases. Cytology can be used for patients with metastatic disease. Although cytological assessment of HR is an excellent method, it has not been routinely used because of the difficulty in consistently preparing multiple good quality slides. Liquid-based cytology (LBC) preparation is considered as the key to resolving the aforementioned problem; however, few studies have reported the HR assessment in breast cancer using LBC. Therefore, the HR status of LBC slides from 82 breast cancers was compared with that of the corresponding surgical specimens. The HR assay in both the LBC slides and surgical specimens was conducted by IHC using an autostainer. For the IHC staining, the protocol recommended by the manufacturer for paraffin-embedded sections was used for both the cytology and histology specimens. The HR results of the cytology agreed with those of the histology in 80 of the 82 cases (accuracy rate, 98%) for estrogen receptor, and in 78 of the 82 cases (accuracy rate, 95%) for progesterone receptor. The overall accuracy of the HR status on the cytology and the histology was 99% in 81 of the 82 cases. In conclusion, in HR analysis of breast cancers, LBC followed by IHC using an autostainer was useful for the standard processing of cytological specimens and showed a good correlation with the results of analysis on the histology specimens.     

Place of hormone receptor determination in the therapeutic strategy of breast cancer

Up to the discovery of hormonal receptors it was somewhat uncertain to prescribe hormonotherapy for the treatment of a breast cancer. The presence of estrogen receptors (ER) and progesterone receptors (PR) allows the estimation of the probability of hormone-dependence. The response to endocrine therapy will be expected with a rate of: 80% of the tumors PR +; 30% of the tumors ER+ but PR-; 10% of the tumors ER - and PR -. The response to chemotherapy is no accurately correlated with the concentration of receptors. The planning of therapy will be founded on the following principles. ER -: less favourable prognosis and unlikely response to endocrine therapy, therefore chemotherapy if the other prognostic factors are bad. ER +: endocrine therapy is required, especially if PR +. The role of chemotherapy ought to be discussed with respect to the other prognostic factors. All these factors are reviewed and a decision-tree of the treatment of advanced breast cancers is put forward. In short, it is obvious that the receptors assays have to be carried out as for as possible.     

Growth hormone is present in the human retina and vitreous fluid

Growth factors have been found in vitreous fluid, in which they regulate retinal function and provide markers of ocular dysfunction. Since growth hormone (GH) has recently been discovered in the eyes of rodents and embryonic chicks and found to be neuroprotective for retinal ganglion cells, the possible presence of GH in the human retina and vitreous fluid has been assessed. GH-immunoreactivity in the retina and vitreous fluid of cadavers and in the vitreous fluid of patients with ocular dysfunction was determined by Western blotting. GH-immunoreactivity, identical in size (22 kDa) to recombinant pituitary GH was found in proteins extracted from the retina and in the vitreous fluid of patients with ocular disease (proliferative diabetic retinopathy, epiretinal membrane and vascular hemorrhage) and individuals with no history of ocular disease. GH-immunoreactivity was also detected in large, discrete cells in the retinal ganglion cell layer, in which GH staining was mainly within the nuclear compartment. The novel presence of GH in the human retina and vitreous fluid suggests GH may have roles in visual function and be involved in the pathogenesis of ocular disease.     

Oestrogen receptor values and histological grade in human breast cancer

Histological grading of 126 oestrogen receptor positive and 81 oestrogen receptor negative breast carcinomas, using the WHO system, showed that some tumours in all grades had high receptor values, others low. There was no correlation between the receptor values and histological grade. It is suggested that factors other than the degree of dedifferentiation of the tumour may be responsible for the consistent tendency for receptor negative tumours to be placed in a high histological grade.     

Androgen receptor is frequently expressed in HER2-positive, ER/PR-negative breast cancers

The estrogen receptor (ER)/progesterone receptor (PR)-negative breast carcinomas (BCs) encompass three molecular subtypes: one with human epidermal growth factor receptor 2 (HER) overexpression, one normal like, and the triple negative. The androgen receptor (AR) is expressed in 70–90% of invasive BCs. The aim of our study is to detect the expression of AR in a series of ER/PR-negative BCs to ascertain if there is clinical significance in relation to BC molecular subtypes. A immunohistochemical study for all receptors and cytokeratin expression was performed in 232 cases of ER/PR-negative BCs. According to cytokeratin expression, BCs were classified into two groups: luminal-type BCs (44.2%) and basal-like-type BCs (55.8%). According to the expression of HER2, 59.3% were triple-negative BCs (when ER, PR, and HER2 were negative) and 40.7% were HER2-positive BCs. AR expression was observed in 128 tumors (56.6%). One hundred and ten cases (48.8%) had >10% and 18 (7.8%) had <10% of positively stained cells. AR immunoreactivity was found in 31.2% basal-like BCs, while in the luminal group 71.1% of cases were positive, showing highly significant correlation (p < 10⁻⁸). Regarding HER2 status, 76.7% of HER2-positive BC cases were AR positive compared with only 30.4% of triple-negative BC types, showing a strong statistically significant correlation. In conclusion, we show that AR is frequently expressed in ER/PR-negative BCs and that expression of HER2 and AR is highly correlated (p < 0.005). Our results point out the role of AR and HER2 in the pathogenesis of BCs and suggest the potential role of AR in clinical management of ER/PR-negative BCs.