CORRELATION OF STEROID HORMONE RECEPTORS AND CLINICAL PATHOLOGICAL FEATURES WITH PROGNOSIS OF HUMAN BREAST CANCER

Clinical, pathological features and steroid hormone receptors (SR) including receptors of estrogen (ER), progesterone (PR) and androgen (AR) were observed in 58 cases of breast carcinoma, and related to patient 5- year survival rate through stratification and multivariatc analysis. The results showed that histologic tumor type and grading, lymphnode status, ER value and patient age took more important role in patient survival, and SR, especially, conferred survival advantage in advanced cases with tumor size larger than 2 cm, node involved, or TNM Stage Ⅱ-Ⅲ.     

Tumour steroid hormone synthesis and estrogen receptor status in breast cancer patients

Summary The capacity of breast cancer to synthesise active androgens and estrogens has been related to estrogen receptor (ER) status in 79 postmenopausal patients with breast cancer. Although there was no quantitative relationship between levels of ER and steroid metabolism in ER positive tumours, there was (a) a positive correlation between estrogen synthesis and ER positivity and (b) increased androgen synthesis and ER negativity. This may imply an inherent difference in the handling of hormones in ER positive and negative tumours. Address for reprints: R.C. Mason, University Department of Clinical Surgery, Royal Infirmary, Edinburgh EH39YW, United Kingdom.     

Steroid hormone receptors and prognosis in breast cancer

Summary The importance of steroid receptors for the prognosis of mammary carcinoma has been evaluated by investigating the course of disease in 163 patients for a median follow up time of 66 months after mastectomy. Multivariate analysis including estrogen receptor (ER), progesterone receptor (PgR), the presence of 8S and 4S ER together or 4S ER only, and the lymph node status revealed only the latter to have significant (p<0.001) predictive potency. Lymph node positive (N-pos) patients had a 3.3 (1.7–6.2) fold risk of death and 2.8 (1.7–4.7) fold risk of recurrence relative to node negative (N-neg) patients.When we compared overall survival (OAS) and disease-free survival (DFS) in the various receptorpositive groups with the groups that displayed neither ER nor PgR, significant differences in prognosis were only seen in N-neg patients. PgR did not turn out to be a better prognostic factor than ER, nor was the 8S ER a sing of increased OAS and DFS compared to total ER. However, the number of patients in this group was too small to allow a definite statement.     

Rates for breast cancer characteristics by estrogen and progesterone receptor status in the major racial/ethnic groups

It has been reported that age-specific breast cancer rates vary by estrogen receptor and progesterone receptor status. We report breast cancer rates for age-at-diagnosis, stage-at-diagnosis, histological grade and type by estrogen (ER) and progesterone (PgR) receptor status in six major racial/ethnic groups. The average annual age-adjusted rates for breast cancers with estrogen receptor positive (ER⁺), ER^–, progesterone receptor positive (PgR⁺), PgR^–, ER⁺PgR⁺, ER⁺PgR^–, ER^–PgR⁺ and ER^–PgR^– are determined from 123,732 breast cancers with known ER status, diagnosed from 1992 to 1998 from 11 Surveillance, Epidemiology, and End Results (SEER) cancer registries. For each racial/ethnic group, their ER⁺ (ER⁺PgR⁺ and ER⁺PgR^–) age-specific rates increased with age (but at a slower pace after ages 50–54) while their ER^– (ER^– PgR⁺ and ER^–PgR^–) age-specific rates did not increase after ages 50–54. The rank orders of the rates among the racial/ethnic groups varied by ER/PgR status. The stage I rates were greater than the stage II rates for the ER/PgR groups except for ER^– and ER^–PgR^– cancers. The grade 2 (moderately differentiated) rates were greater than the grades 3 and 4 (poorly differentiated and undifferentiated cancers) rates for ER⁺ cancers, but not for ER^– cancers. These results suggest that although breast cancer is a disease with enormous heterogeneity, the multiple types of breast cancer can be separated into distinct subgroups by their ER status, and perhaps by their ER/PgR status, and their cancer characteristics may be important in understanding the multiple nature of breast cancer.     

Pre-morbid body-mass-index in breast cancer: Reversed effect on survival in hormone receptor negative patients

Summary The present study consists of 1,238 women with unilateral breast cancer treated with modified radical mastectomy living in the geographic area of Haukeland Hospital. Their weight and height had been measured years before presentation of the disease. Age-adjusted Quetelet's index (weight/height²) showed that obese women had a 49% higher risk of dying from breast cancer than lean ones. The relative risk decreased slightly when adjusted for tumour diameter, lymph node status, and mean nuclear area of the tumour cells. The prognostic effect of Quetelet's index was examined according to the estrogen and/or progesterone receptor status of the tumour. In patients with a hormone receptor positive tumour, obese women had a risk that was more than three times higher than lean ones. In patients with hormone receptor negative tumour, the effect of obesity was reversed, lean patients having a risk that was more than six times higher than obese ones, even after adjustment for lymph node status, tumour diameter, and mean nuclear area. Quetelet's index, while being a prognostic variable in its own right, thus acts differently in patients with hormone receptor positive and negative tumours.     

Polymorphisms in genes of the steroid receptor superfamily modify postmenopausal breast cancer risk associated with menopausal hormone therapy

Menopausal hormone therapy (HT) is associated with increased breast cancer risk among postmenopausal women. Nuclear receptors are involved in steroid hormone‐ and xenobiotic‐mediated signal transduction playing a crucial role in regulating gene expression. Therefore, variations within these genes may influence HT‐associated breast cancer risk. We investigated 3,149 postmenopausal breast cancer patients and 5,489 controls from 2 German population‐based case‐control studies. Thirty‐three polymorphisms selected on the basis of known or putative functional relevance located in ESR1, ESR2, PGR, PXR and AR were genotyped. Conditional logistic regression was used to assess multiplicative statistical interaction between polymorphisms and duration of estrogen–progestagen therapy and of estrogen monotherapy with regard to breast cancer risk assuming log‐additive and codominant modes of inheritance. We observed an increased risk for women carrying short AR_(CAG) alleles of <22 repeats associated with combined estrogen–progestagen therapy compared with those with long alleles (≥22 repeats) (p_interaction = 0.03). Additionally, risk associated with combination therapy use was significantly modified by 2 PXR polymorphisms with reduction of risk effects in carriers of the minor PXR_rs6785049_G and PXR_rs1054191_A alleles (p_interaction = 0.04 and 0.05, respectively). Variants in both ESR1 and ESR2 modified risk associated with estrogen monotherapy use. Higher risk were observed in homozygotes for the major ESR1_rs910416_T allele (p_interaction < 0.01) and in homozygotes for the minor ESR2_rs1271572_T, major ESR2_rs4986938_G and minor ESR2_rs928554_G alleles (p_interaction = 0.02, 0.05, 0.02, respectively). Risk effect modification by ESR1_rs910416 and AR_(CAG)n polymorphisms remained significant after correction for multiple testing. We conclude that genetic variants in nuclear receptor genes may modify HT‐associated postmenopausal breast cancer risk.     

Estrogen receptor negative and progesterone receptor positive primary breast cancer: Pathological characteristics and clinical outcome

The expression of estrogen (ER) and progesterone (PgR) receptors was analyzed in a retrospective series of 3000 patients who had operable primary breast cancer. Patients were stratified according to ER and PgR status and the study was focused on the two groups (ER–PgR+ and ER–PgR–) of patients whose tumors contained low levels of ER (< 15 fmol/mg protein), regarding potential response to endocrine therapy. The comparison of clinical or histological characteristics between ER–PgR+ and ER–PgR– patients was analyzed as well as the disease-related death and survival. The mean follow-up was 86.3 months. Among the 529 ER–patients, 62 were PgR+ (12%), whereas 467 were PgR– (88%). The ER–PgR+ and ER–PgR– populations represented 2% and 15.6% of the overall population, respectively. In ER– tumors, the PgR status was significantly related to: age, menopausal status, tumor size, SBR grade, and histological type, but not to the type of surgical treatment or to lymph node involvement. ER–PgR+ tumors had smaller size (64% T1 vs 43%) (p=0.004) and were more frequently grade I (28% vs 12%) than ER–PgR– ones (p < 0.001). In addition, the patients with ER–PgR+ tumors were significantly younger (49.4 years vs 58.4 years; p < 0.0001), and were more frequently premenopausal (76% vs 36%; p < 0.001). The disease-free interval and the metastasis-free survival tended to be worse for ER–PgR– than for ER–PgR+ patients, but the difference was not statistically significant at 10 years. However, a small but significant difference in overall survival, in favor of the PgR+ group, was observed between the two groups during the first 5 years (p=0.03).We conclude that in combination with ER, PgR status defines a group of patients with clinical and biological specificity, which could be considered for specific endocrine therapy.     

Epidermal growth factor receptor in breast cancer: Storage conditions affecting measurement,and relationship to steroid receptors

Summary This study investigates the effect of freezing and storage of tissue and subcellular fractions on the measurement of epidermal growth factor receptors (EGF-r); compares competition binding and single saturating dose assays (SSD) for quantitating EGF-r levels; investigates several tissues as potential quality control; and examines the relationship between EGF-r and hormone receptor expression in human breast cancers.Mouse and calf uterine cell membranes were preferred sources of quality control tissue with similar levels of high affinity EGF-r to human breast cancer tissue (<150–200 fmol/mg membrane protein). Studies using pooled mouse uterine tissues indicated a loss of 40% in EGF-r activity following a single –20°C freeze/thaw cycle, while a breast cancer tissue showed a 75% loss, independent of storage temperature (liquid nitrogen, –70°C, –20°C). A single freeze/thaw cycle of mouse uterine broken cell pellets (nuclei plus membrane fraction) again indicated a loss of EGF-r irrespective of storage temperature (43% loss at –70°C, 52% loss at –20°C). In most cases irrespective of the tissue type or tissue fraction being stored, the length of storage had little impact on the extent of the loss in activity. A second freeze/thaw cycle of intact tissue, or freezing of broken cell pellets from a previously-frozen tissue, led to a further major or total loss of the remaining EGF-r. Overall these results are commensurate with the published effects of freezing and storage on estrogen receptor measurement. In addition, our studies suggest that the most suitable procedure for assaying frozen breast cancer specimens for EGF-r levels in conjunction with steroid receptor quantitation is to prepare and assay both cytosol and membrane fractions for their respective receptor content without further storage. A concordance of 86% was found in 44 breast cancers assayed for EGF-r by saturation analysis and SSD. Statistically significant inverse relationships were found between EGF-r and estrogen and progesterone receptor levels in a study of approximately 350 breast cancer patients. No association was found with tumor stage or diameter, axillary node involvement, or patient age.     

Electrocautery: Effects on steroid receptors in human breast cancer

The determination of steroid receptors in human breast cancers has assumed increasing importance over the past several decades. Improper handling of the specimens could affect results obtained. This study details the effects excessive levels of heat that occur with the use of electrocautery can have on steroid receptor quantities and localization. Twelve resected primary and metastatic human breast cancers were analyzed for cytoplasmic and nuclear receptors by biochemical analysis. In addition, steroid binding was determined by direct fluorescent histochemical techniques. To a portion of each resected specimen a Bovie^c was applied to simulate electrocautery resection. Analysis of the different portions of the same tumor revealed that there was a decrease in measurable cytoplasmic receptor in all cauterized specimens and a concomitant increase in the nuclear receptor. A similar shift in steroid binding was noted in all the specimens analyzed by fluorescent histochemical techniques. The results of this study show that the application of excessive heat to human breast cancers will lead to false negative biochemical steroid receptor determination by shifting the receptors intranuclear.     

Seasonal variation in breast cancer detection: Correlation with tumour progesterone receptor status

Summary A significant circannual variation of the month in which patients detect the first sign or symptom of tumour has been defined in 1413 patients with breast cancer. The months of highest detection were in the late springearly summer, and lowest detection was in late autumn-early winter. Analysis of subgroups indicates that this cyclic trend was most significant in younger women with small or moderate-sized tumours containing steroid hormone receptors, particularly progesterone receptors. It seems likely that this variation is related to the effect of cyclic hormonal changes on tumour growth, possibly mediated through the pineal.     

DNA ploidy,S-phase,and steroid receptors in more than 127,000 breast cancer patients

Summary Several potential prognostic factors are available today for patients with breast cancer, and many more are being identified and studied. To evaluate the clinical utility of these factors, it will be necessary to measure them on a large number of patients, and then follow these patients so that multivariate survival analyses can be performed.The Oncology Research Network was established in 1986 by the University of Texas Health Science Center at San Antonio and Nichols Institute Reference Laboratories in order to evaluate the clinical utility of new prognostic factors for patients with primary breast cancer. The first generation of prognostic factors included steroid receptors, along with DNA ploidy and S-phase fraction determined by flow cytometry. Currently, laboratory results have been obtained from more than 127,000 patients, and follow-up information is available on a subset of more than 25,000 of these patients.S-phase fraction was related to the ploidy status of the tumor. An increased incidence of aneuploidy and higher S-phase fractions were found in estrogen and progesterone receptor negative tumors, tumors from patients with positive axillary lymph nodes, tumors greater than 2 cm in diameter, and patients younger than 35 years of age. Preliminary survival analyses suggest that S-phase fraction and DNA ploidy, in combination with other prognostic factors, are powerful predictors of early disease relapse.The Oncology Research Network provides an important resource for examining the clinical significance of new laboratory assays and for expediting improvements in existing laboratory techniques.We regret to report that Dr. William L. McGuire died on March 25, 1992, after this work was largely completed     

FSIP1 is correlated with estrogen receptor status and poor prognosis

Fibrous sheath interacting protein 1 (FSIP1) is frequently activated in a variety of tumors including breast cancer. However, the clinical significance of FSIP1 in hormone receptor (HR)-positive breast cancer is unclear. We analyzed the expression and clinical significance of FSIP1 in human breast cancer databases. A comprehensive analysis of 1094 gene expression profiles of breast cancer in The Cancer Genome Atlas revealed that FSIP1 overexpression correlated with decreased overall survival in HR-positive breast cancer patients. We also showed that knockdown of FSIP1 in T47D and BT474 cell lines resulted in decreased cell proliferation and migration in vitro. Furthermore, we retrospectively examined the expression and prognostic value of FSIP1 in 129 breast cancer patients to examine the expression of FSIP1 by the immunohistochemical method and got the similar results that high expression of FSIP1 predicts poor prognosis. Therefore, FSIP1 has a crucial role in HR-positive breast cancer and represents an attractive therapeutic target for HR-positive breast cancer.     

Breast cancer prognosis in relation to family history of breast and ovarian cancer

We linked four nationwide Swedish population-based registries to identify first-degree family history of breast and ovarian cancer among breast cancer cases diagnosed between 1991 and 1998 and followed them until death, emigration or end of follow-up in December 1998. The median follow-up was 36 months. Using Cox proportional hazards models, the hazard ratio of death (HR) due to breast cancer was estimated. Women with a family history of breast or ovarian cancer (n=2175, 12.7%) had a nonsignificantly better prognosis than women without any family history, HR 0.86 (95% CI 0.71-1.05); this appeared unrelated to age at diagnosis either in the index case or in relative(s) with breast and/or ovarian cancer. Our study shows that prognostic outlook is not worse among breast cancer patients with family history.     

Socioeconomic status and breast cancer incidence in California for different race/ethnic groups

Objective: The majority of research on breast cancer risk and socioeconomic status (SES) has been conducted for blacks and whites. This study evaluates the relationship between SES and breast cancer incidence in California for four race/ethnic groups. Methods: Principal component analysis was used to create an SES index using 1990 Census data. Untracted cases were randomly allocated to census block groups within their county of residence. A total of 97,227 female breast cancer cases diagnosed in California between 1988 and 1992 were evaluated. Incidence rates and rate ratios (RRs) were estimated and a ² test for trend across SES levels was performed. Results: SES was positively related to breast cancer incidence, and this effect was stronger for Hispanics and Asian/others than for whites and blacks. Adjusting by SES did not eliminate the differences in breast cancer rates among race/ethnic groups. RR differences between the race/ethnic groups were greatest in the lowest SES category and attenuated with increasing SES. An increasing trend over SES was statistically significant for all race/ethnic groups. Including randomly allocated cases affected RR estimates for white women only. Conclusions: Our results are consistent with similar findings for the Los Angeles area but differ from previous results for the San Francisco Bay area.     

Effect of soybean on breast cancer according to receptor status: a case-control study in Japan

The possible association of high soy food consumption with low incidence of breast cancer in Asian countries has been widely investigated, but findings from epidemiologic studies have been inconsistent. Breast cancers defined by receptor status, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) may have distinct etiologic factors. Here, we conducted a case-control study to clarify associations between intake of soybean products and breast cancer risk according to receptor status. A total of 678 breast cancer cases and 3,390 age- and menopausal status-matched noncancer controls were included. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated using conditional logistic models adjusted for potential confounders. On analysis according to receptor status, we observed a significantly reduced risk of ER-positive (ER+) (top tertile OR = 0.74; 95% CI, 0.58-0.94; trend p = 0.01) and HER2-negative (HER2-) tumors (top tertile OR = 0.78; 95% CI, 0.61-0.99; trend p = 0.04). Further, when the 3 receptors were jointly examined, a reduced risk was observed only in patients with ER+/PR+/HER2- tumor (top tertile OR = 0.73; 95% CI, 0.54-0.97; trend p = 0.03). These findings indicate that the protective effect of soy against breast cancer risk differs by receptor status.     

Estrogen and progesterone receptors: Correlation of response rates,site and timing of receptor analysis

Summary 156 patients with advanced breast cancer of known estrogen receptor (ER) and progesterone receptor (PgR) status treated by endocrine therapy were studied. Regarding values for ER and PgR 5 fmole/mg cytosol protein as positive, patients were divided into 4 phenotypic subgroups: ER⁺PgR⁺ (43%), ER⁺PgR^– (26%), ER^–PgR⁺ (8%), and ER^–PgR^– (23%). In patients with tumor phenotype ER⁺PgR⁺, responses were seen in 20/30 (67%) assessable initial treatments when receptor assays were performed on tumor recurrence or on primary tumor immediately before endocrine therapy, and in only 11/32 (34%) assessable initial treatments when receptor analysis was performed on primary tumor and there was intervening local therapy before endocrine therapy was started for tumor recurrence (P<0.05).Responses to first endocrine therapy for each tumor phenotype were ER⁺PgR⁺ 50%, ER⁺PgR^– 27%, ER^–PgR⁺ 27%, and ER^–PgR^– 6%. Four of 16 (25%) patients with ER⁺PgR⁺ tumors responded to subsequent secondary endocrine therapy, but such responses were not observed in 20 patients with other tumor phenotypes.Duration of response was similar for each phenotype, but patients with ER^–PgR^– tumors had a significantly shorter survival from time of initial endocrine treatment than patients of any other phenotype.These results suggest that repeat steroid receptor assays on accessible tumor immediately before endocrine therapy may result in improved predictability. Address for reprints: Dr R.D. Rubens, Imperial Cancer Research Fund, Breast Cancer Unit, Guy's Hospital, London SE1 9RT, United Kingdom.     

Age-specific association of steroid hormone pathway gene polymorphisms with breast cancer risk

BACKGROUND: Breast cancer (BC) is a complex disease, and the incidence rates for BC increase with age. Both environmental factors and genetics have an impact on the risk of BC. Although the effects of environmental factors may vary with age, it has been assumed generally that the penetrance of single nucleotide polymorphisms (SNPs) is constant throughout life. In the current study, the results demonstrated that certain SNPs exhibit BC risk associations that vary considerably with age. METHODS: SNPs in 12 steroid hormone pathway genes were investigated for associations with BC risk in white women who were enrolled in an age-matched, case-control (1:2 for cases and controls, respectively) study that consisted of a discovery set (n = 5000 women) and an independent validation set (n = 1583 women). RESULTS: Significant age-related trends were identified and confirmed for SNPs in 4 genes associated with BC risk. The cytosine/cytosine (C/C) genotype of cytochrome P450 XIB2 (CYP11B2) was associated with decreased risk at younger ages (ages 30-44 years) but an increased risk at older ages (ages 55-69 years). The homozygous cytosine-guanine (CG/CG) genotype of uridine phosphorylase glycosyltransferase 1A7 (UGT1A7) was associated with increased risk at younger ages but decreased risk at older ages. Associations in cytochrome P450 19 (CYP19) and progesterone receptor (PGR) were confined to middle age (ages 45-54 years). CONCLUSIONS: The identification of age-specific genetic associations may have profound implications for future etiologic studies of BC and for the use of SNP genotyping to accurately predict the risk of BC in women.     

甲状腺激素及其受体与乳腺癌的关系

乳腺是激素依赖性器官,多种激素对其均有影响。许多研究表明,甲状腺激素与乳腺癌具有密切关系,它可以直接调控乳腺细胞的生长分化,也能通过类雌激素样作用影响乳腺癌的发生发展。而甲状腺激素受体的异常表达亦与乳腺癌发病相关。