Estrogen and progesterone receptors in breast cancer patients. Epidemiologic characteristics and survival differences

Risk factors commonly associated with breast cancer were studied in relation to: (1) tumor estrogen receptor (ER) or progesterone receptor (PR) status and (2) the presence of tumor hormone receptors in relation to subsequent survival. For 171 Israeli women diagnosed with breast cancer in 1976 to 1979, tumor hormone receptor status (positive if greater than 20 fmol receptors/mg protein; negative if less than or equal to 20 fmol/mg) and survival as of April 1984 were ascertained. There were 77 ER- versus 94 ER+ and (for 134 PR analyses) 69 PR- versus 65 PR+. Although ER status and PR status were found to be highly positively related, the epidemiologic features of women with an ER+ tumor were different from those with a PR+ tumor. Age tended to be associated positively with both ER+ and PR+. Being postmenopausal, older at menopause or at first birth, nulliparous, having more years of schooling, and a higher body mass index for older women or a lower body mass index for younger women were correlated positively with ER and negatively with PR. Among women with Stage III or IV tumors at diagnosis significant differences existed: restricted mean survival for follow-up time was 47.2 months for ER-, 73.8 months for ER+, 45.8 months for PR-, and 61.9 months for PR+. The combined hormone effects on survival at Stages III to IV showed a similar trend: restricted mean survival of 38.4 months for ER-PR-, intermediate survival with one positive hormone receptor status, and 74.6 months for ER+PR+.     

Estrogen and progesterone receptors as prognostic factors in breast cancer

The relation between estrogen receptors (ER) and/or progesterone receptors (PgR) and some clinical factors such as tumor size, axillary node involvement, histological tumor grade, and disease-free interval (DFI) in 500 patients with operable (TNM stage I-III) breast cancer was studied. ER-positive (ER+) tumors were commoner in older patients, whereas PgR-positive (PgR+) tumors were similarly distributed within the age groups. The concentration of ER+ protein also increased with age in contrast to PgR+ protein concentration. However, receptor status was not associated with menopausal status independently of age. Axillary node involvement influenced neither ER nor PgR status, but there was a statistically significant relation between tumor size and positivity of ER or PgR. There was no association between histologic tumor grade and either steroid receptor phenotype. DFI was longer in patients with ER+ than those with ER- tumors, independently of axillary nodal status. The positivity of PgR in patients with ER+ tumors contributed to an even longer DFI, suggesting that the combination of ER/PgR is a better indicator of DFI than ER or PgR alone.     

Estrogen receptors,progesterone receptors,and cell proliferation in human breast cancer

Summary The breast is a target organ for estrogens and progesterone. These hormones control several functions of the normal and abnormal mammary epithelium including cell proliferation. Most of the actions of estrogens and progesterone are mediated via specific steroid receptors, and one would expect that proliferating cells should contain estrogen receptors (ER) and/or progesterone receptors (PR). However, the correlation between receptor expression and cell proliferation is still controversial. In the present study we have examined 29 human breast cancer samples; in 17 of them we evaluated the simultaneous ER and PR localization with that of proliferating cell nuclear antigen (PCNA) and silver-stained nucleolar organizer regions (AgNORs) in a cell-by-cell study. We found that in almost 50% of the tumor biopsies examined, the cells expressing ER were significantly associated with elevated cell proliferation. In another group (38%) there were not significant differences between ER expression and cell proliferation. In only one of the samples (6%) the cells expressing ER showed lower cell proliferation. The study also revealed that in 44% of the tumors the PR expressing cells were associated with elevated cell proliferation. In a second group the PR expression was not significantly associated with cell proliferation (33% of the cases). Finally, in 22% of the samples the cells carrying PR showed lower cell proliferation. We also detected lower ER immunoreactivity in 30% of the breast cancer biopsies with one of the monoclonal antibodies against ER (antibody 1D5 directed against the A/B domain). This group of tumors was PR-negative (or very weakly positive) and had high proliferation. The presence of tumors with abnormal ER proteins and displaying ER/PR significantly associated with elevated cell proliferation could have implications in human breast cancer treatment.     

Estrogen and progesterone receptors in gastric cancer

Cancerous tissue from 86 patients with primary gastric cancer were examined for the presence of receptors for estrogen (ER) and progesterone (PgR). ER and PgR were present in 8 (15.4%) and 5 (9.6%), respectively, of 52 male patients, 9 (26.6%) and 7 (20.6%), respectively, of 34 female patients, a total of 17 (19.8%) and 12 (14.0%), respectively. One male patient (1.9%) and 4 female patients (11.8%) had both ER and PgR, and 40 male (76.9%) and 22 female patients (64.7%) showed no ER or PgR. The binding activity ranged from 6 to 200 fmol/mg protein for estradiol and from 5 to 58 fmol/mg protein for progesterone. ER- and/or PgR-positive cases were characterized grossly as Borrmann type 4, and microscopically as diffuse type with scirrhous growth pattern. The presence of ER and/or PgR in some gastric cancers indicates the possibility that sex hormonal factors are involved in these tumors.     

Estrogen and progesterone receptors in ovarian cancer

To determine whether steroid hormone receptor expression is clinically relevant in ovarian cancer, cytoplasmic and nuclear estrogen (ER) and progesterone (PR) receptor levels have been measured and their concentration calculated by Scatchard analysis. Of 89 samples from patients with non-pretreated epithelial ovarian cancer, 33% were ER-positive, PR-positive (ER+PR+) and 40% ER-negative, PR-negative (ER-PR-); 20% were ER+PR-, and 7% ER-PR+. There was no correlation between receptor status and patient age, menopausal status, or tumor grade, although serous tumors were more likely to be ER+. The incidence of PR+ tumors was highest in early disease and decreased with increasing International Federation of Gynecology and Obstetrics (FIGO) stage. Survival of patients with advanced disease (FIGO Stages IIC, III, or IV) was significantly prolonged by optimal initial cytoreductive surgery (P = 0.002), platinum therapy (P = 0.003), and tumor expression of PR (P = 0.009). On multivariate analysis, PR positivity was still associated with improved survival, although this did not retain statistical significance (P = 0.09).     

Estrogen and progesterone receptors in the normal female breast

We have studied estrogen receptor (ER) and progesterone receptor (PR) in normal breast by immunocytochemistry using tissue biopsies and fine needle aspirates (FNA) and, in the case of ER, by enzyme immunoassay. For ER we found a high degree of reproducibility for biopsies taken from the upper outer quadrant: FNA, r = 0.56 (P less than 0.002); tissue section immunocytochemistry, r = 0.89 (P less than 0.0001); and enzyme immunoassay, r = 0.76 (P less than 0.0001). For PR, FNA (r = 0.56, P less than 0.002) and tissue section (r = 0.97, P less than 0.0001) were also found to be reproducible techniques. Using enzyme immunoassay, we were able to measure ER accurately in normal breast tissue. In 59 samples we found a range of 0-37 fmol/mg cytosol protein (mean, 4 fmol/mg). In an age-matched group of 126 women with breast cancer, we found a significantly higher ER [range, 0-139 fmol/mg; mean, 37 fmol/mg (P less than 0.001)]. We then analyzed the ER and PR content of FNAs obtained from the upper outer quadrant of the normal breast in 143 normal women. We found that in only 23 of 143 samples (16%) were greater than or equal to 50% epithelial cells stained. There was a relationship between ER and PR (P = 0.03) and a higher ER content in European women than in non-European women (P less than 0.03). The PR content was related to high body mass index (P less than 0.02) and family history of breast cancer (P = 0.04). Samples tended to be more frequently ER positive by FNA if taken in the follicular phase of the menstrual cycle. We conclude that, although the levels of ER and PR are low in normal breast, they can be accurately measured. There is significant variation of ER and PR with several clinical parameters.     

Estrogen and progesterone receptors in breast carcinoma and in nonmalignant breast tissue

Since 1983 we have studied the relationship, in the same patient, between receptor status in breast carcinoma and in nonmalignant breast tissue. Fifty patients have been evaluated to date. The total unoccupied cytosol estrogen and progesterone receptors were determined by a dextran-coated charcoal method. In nonmalignant breast tissue we found a measurable receptor concentration above the sensitivity of the method in 62% of cases for estrogen receptors and in 44% of cases for progesterone receptors. No relationships were found between the receptor level of each tumor and that of the corresponding benign tissue. The data suggest that the levels of the receptors in the tumor and in the nonmalignant tissue are totally independent.     

Estrogen, progesterone, and androgen receptors in breast cancer in the Japanese: brief communication

Estrogen, progesterone, and androgen receptors (ER, PgR, and AR, respectively) were determined by dextran-coated charcoal assay analyzed with Scatchard plots in cytosols from 81 Japanese patients with breast cancer. For the estimations of PgR and AR, the following compounds were used: a synthetic progestin, [3H]R5020 (17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione), not bound by corticosteroid-binding globulin; and a synthetic androgen, [3H]R1881 (17beta-hydroxy-17-methylestra-4,9,11-trien-3-one), not bound by human sex steroid plasma-binding protein. Forty-two of 81 of the cancers revealed measurable amounts of ER (greater than 2 fmoles/mg cytosol protein), whereas the rates of measurable amounts of PgR (greater than 5) and AR (greater than 5) were 27% (18/67) and 36% (17/47), respectively. PgR were found in 45% of cancer patients with ER, but in only 9% of the cancer patients without ER. AR were found in 50% of the cancer patients with ER, but in only 22% of the cancer patients without ER. These results are consistent with those reported by Western investigators.     

Estrogen receptors in bilateral breast cancer

Estrogen receptor status, tumor histology, and the interval between the development of tumors were assessed in 99 patients with bilateral breast cancer. Tumors were first grouped into those simultaneously detected in both breasts or within 12 months of each other (synchronous bilateral breast cancer, of which there were 64) and second, those detected within more than 12 months of each other (asynchronous bilateral breast cancer, of which there were 35). Nineteen percent of all tumors were lobular carcinomas. Overall, the rate of receptor discordance between the two tumors was not significantly different from that previously reported between biopsies of primary tumor and metastases in patients with unilateral breast cancer. Synchronous receptor-positive tumors occurred significantly more frequently than expected, suggesting that the development of the two tumors was influenced by a common mechanism. In patients with asynchronous bilateral breast cancer there was a significantly longer interval between tumors if both were receptor-positive compared with concordant receptor-negative tumors and tumors with discordant receptor status. There was a significant discordance in the receptor status of asynchronous tumors when the histology also differed, indicating that the tumors in this group were likely to be separate primary tumors.     

Estrogen and progesterone receptor isoforms: clinical significance in breast cancer

The identification and exploitation of biomarkers that may predict response to anti-cancer treatments has the capacity to revolutionize the way that patients with cancer are treated. In breast cancer, the estrogen receptor (ER) and the progesterone receptor (PgR) are known to have a significant predictive value in determining sensitivity to endocrine therapies. Tumor expression of ER or PgR is known to affect clinical outcome and this information is often used to determine a patient's optimal treatment regimen. However, the measurement of ER and PgR alone is more complex than originally thought and the impact of the recently identified isoforms of ER (ERα and ERβ) and PgR (PgRA and PgRB), as well as several variant and mutant forms, upon the choice of treatment remains unclear. Therefore, ER and PgR expression alone are unlikely to determine a patient's optimal treatment regimen, particularly when the amount of ‘cross-talk’ between different pathways, such as the epidermal growth factor receptor pathway, is considered. In order to account for the complex cell-signaling environment that occurs in breast cancer, multifactorial techniques are needed to analyze tumor biomarker expression. The recent advances in genomic- or proteomic-based approaches has enabled molecular portraits of breast cancers to be painted, allowing biomarkers of response and prognosis to be identified and characterized more accurately than before. In the future, patients could be treated according to the molecular portrait of their tumor biomarker expression, maximizing the therapeutic benefit that each patient receives. This revised version was published online in August 2006 with corrections to the Cover Date.     

Steroid hormone receptors and survival in breast cancer patients

Estrogen receptor (ER) levels were measured in 280 breast cancer patients (mean age 54.5 years). Progesterone receptor (PR) levels were assayed in 101 of them. 61.4% of cases were at stages I and IIa. No significant difference in 2-year survival was established between ER-negative and ER-positive patients (96.7 and 96.0%, respectively). Two-year survival rate and recurrence--free survival for PR-positive cases were significantly higher than those for PR-negative ones (p greater than 0.05).     

Estrogen and progesterone receptors in breast cancer: correlation with clinical and pathological features and with prognosis.

Estrogen and progesterone receptor status was reviewed in 405 patients from prior adjuvant breast cancer trials at the University of Verona. Only 233 patients were actually examined with respect to hormone status and outcome. No relationship between hormone receptor status and most of the commonly followed prognostic signs, i.e. tumor size, nodal status, and age, was found. Overall survival was correlated with hormone receptor positivity for patients with more than 4 positive axillary nodes. Disease-free survival was correlated only with PgR positivity, in premenopausal and in T1 groups.     

Role of progesterone receptors in breast cancer

It has been demonstrated that progesterone receptors (PRs) are at least as valuable as estrogen receptors (ERs) for predicting outcome in breast cancer patients. Retrospective analysis indicates that the presence of PRs may be the second most critical factor, after the number of positive nodes, in predicting disease-free survival, with a correlation between length of survival and number of tumor PRs. The presence of PRs has been shown to be of value for predicting response in both early and advanced breast cancer patients. In studies of assay consistency, major discordance rates were minimal in simultaneous assays, but extremely high in sequential assays of tumors that were PR-positive in initial assay. The responsible factor was interim endocrine therapy, and it was subsequently determined that the prognosis was worse for those patients whose tumors lost PR between assays.     

Estrogen and progesterone receptor profile patterns in primary breast cancer

Summary Estrogen (ER) and progesterone receptor (PgR) analyses have been performed in 884 primary, malignant human breast tumor biopsies. Receptor contents were evaluated with respect to age and menopausal status. The frequency of ER + tumors was found to be significantly higher in postmenopausal than in pre/perimenopausal women. Age rather than menopausal status was found to be associated with this difference. The significant association with age was found in the post- but not the pre/perimenopausal women.The frequency of PgR + tumors was found to be significantly lower in the postmenopausal than in the pre/perimenopausal women. Neither age nor menopausal status alone could account for this difference, which appears to be due to a compound effect of the two factors.The distribution of receptor profile patterns is described according to menopausal status. The patterns differ significantly in pre- and postmenopausal women. PgR dominates in the premenopausal tumor while ER dominates in the postmenopausal tumor. This difference is apparent within the subgroup of ER + PgR + patients as well.The current tenets for prediction of recurrent disease utilizing steroid hormone receptor determinations are discussed for the group of ER + PgR + patients.sponsored by The Danish Cancer Society     

Estrogen and progesterone receptors in human breast cancer. Correlation with histologic subtype and degree of differentiation

Microscopic review of 490 consecutive human breast biopsy and mastectomy specimens were correlated with estrogen and progesterone receptor content of the tissue, by subtype and degree of differentiation. Of the 4 grades of differentiation, the less differentiated Grade III and IV tumors showed significantly lower levels of estrogen and progesterone receptors in infiltrating ductal and lobular carcinoma (P less than 0.001). In contrast, patients with medullary carcinoma had the lowest tissue levels of estrogen and progesterone receptors with approximately 80% of the cases with less than 10 fmol/mg protein. Patients with mucinous carcinoma had the highest percentages of positive estrogen and progesterone receptor levels (75% and 87%, respectively). Sixty-three percent of the patients with Grade IV infiltrating ductal carcinoma were younger than 53 years of age (P less than 0.001). Patients younger than 53 years of age with Grade II and III infiltrating ductal carcinoma also had significantly lower levels of estrogen receptors, but not of progesterone receptors, than those patients older than 53 years of age (P less than 0.001). Nineteen of 20 "normal" breast tissue specimens were negative (less than 3 fmol/mg protein) for estrogen and progesterone receptors. About 50% of 17 tissue specimens from benign breast lesions (fibroadenoma, fibrocystic disease, sclerosing adenosis) showed positive estrogen (greater than 10 fmol/mg protein) or progesterone receptor values. In two patients with gynecomastia, no estrogen or progesterone receptors were detectable.     

Estrogen and estrogen receptors of breast cancer.

Human breast cancer can be divided into a group that contains specific receptor sites for estrogen and a group without such specific estrogen-binding sites. The presence of specific estrogen receptors in some tumors indicating hormonal dependency has been shown to be of predictive value for endocrine treatment. This would greatly improve therapeutic planning for patients with breast cancer. Tumor tissue from 52 patients was investigated for content of both cytosol estrogen and estrogen receptor. In addition, the total tumor estrogen was also determined in 14 of these tumors. The results of this investigation show two distinct groups: one group containing both estrogen receptor and estrogen and a second group with no receptor but with measurable amount of estrogen. Tumors with estrogen receptors have higher tissue levels of estrogen than tumors without specific estrogen receptor. Even in the absence of estrogen recptor, however, most tumor tissue examined contained a measurable amount of estrogen.     

Estrogen receptors in male breast cancer: clinical and pathologic correlations

Breast cancer tissue from 12 male patients was evaluated for the presence of estrogen receptors (ER), and at least 10 of 12 were found to be high in ER (ER+). A combination of previously published cases and our own experience indicates that 80% of patients (37/47) have ER+ tumors. This incidence of ER positivity in men is greater than that in women with breast cancer. Clinical responses to hormonal therapy have been observed in the ER+ patients but not in one ER--patient. Measurement of ER may be clinically important in men with breast cancer.     

Estrogen receptor quantitative measures and breast cancer survival

Purpose

While the estrogen receptor (ER) is the single most widely used biomarker to evaluate breast cancer outcomes, aspects of ER marker biology remain poorly understood. We sought to determine whether quantitative measures of ER, such as protein expression and intensity, were associated with survival, or with survival disparities experienced by Hispanic women.

Methods

A case-cohort study included a 15% random sample of invasive breast cancer cases diagnosed from 1997 to 2009 in six New Mexico counties and all deaths due to breast cancer-related causes. Pathology reports and tissue microarrays served as sources of ER information. Analyses were restricted to women with ≥1% ER immunohistochemical staining. Hazard ratios (HR) and 95% confidence intervals (CI) for breast cancer death were estimated using Cox proportional hazards models.

Results

Included women represented 4336 ER+ breast cancer cases and 448 deaths. Median follow-up was 93 months. ER percent expression was not associated with breast cancer survival after adjustment for standard prognostic factors (p trend = 0.76). ER intensity remained a strong and independent risk factor for breast cancer survival in multivariate analyses: Women whose tumors expressed ER at intensity = 2 (HR 0.6; 95% CI 0.4–1.0) or 3 (HR 0.5; 95% CI 0.2–0.9) had a reduced risk of breast cancer mortality, compared to ER intensity = 1 (p trend = 0.02). Neither ER protein expression nor intensity influenced Hispanic survival disparities.

Conclusions

Estrogen receptor percent positive staining is not independently related to breast cancer survival after adjustment for other survival-related factors. ER intensity, in contrast, demonstrates promise for prognostic utility.