Oestrogen and progesterone receptor status in bone biopsy specimens from patients with breast cancer

Of 16 breast cancer patients with histologically proven, tumour-infiltrating biopsy specimens most had low ER and PR values; the ER and PR contents varied between 0 and 135 and 0 and 44 fmol/mg protein, respectively. With the conventional clinical threshold of 10 fmol/mg protein, 8 specimens (50%) were ER-PR-, 4 (25%) ER-PR+, 3 (19%) ER+PR+ and 1 (6%) ER+PR-. ER levels were significantly lower in the tumoral bone lesion compared with the primary tumour. For 15 patients with negative biopsies and without endocrine treatment, ER and PR concentrations were quantifiable (2 fmol/mg protein or more) in 9 (60%) and 11 cases (73%), respectively. 8 of 9 patients over 55 (89%) were ER+ (2 fmol/mg protein or more). Conversely, for patients under 55, 1 of 6 (17%) was ER+ (P < 0.001). Results for PR were similar. These data strongly suggest that steroid receptors are present in healthy bone tissue.     

Influence of the menstrual cycle on the concentrations of estrogen and progesterone receptors in primary breast cancer biopsies

Summary There is controversy in the literature regarding the effects of endogenous hormones on estrogen receptors (ER) and progesterone receptors (PR) in young women with breast cancer.We studied 117 young women with primary breast cancer and assessed their breast biopsies for ER and PR. The women had a record of their last menstrual period prior to breast biopsy. The menstrual cycle was divided into four phases — early proliferative (days 1–7), late proliferative (days 8–15), early secretory (days 16–22), and late secretory (days 23–30). There were lower levels of both ER and PR in biopsies excised during the early secretory phase than in other phases of the cycle; early proliferative phase receptor positive medians of ER = 77 fmol/mg protein and PR = 467 fmol/mg protein fell to ER = 28 fmol/mg and PR = 128 fmol/mg protein in the early secretory phase.     

Hormone receptors in male breast carcinoma

It is well established that approximately 60% of female breast cancers contain estrogen receptors (ER+). The hormonal receptor status of male breast cancers remains relatively unknown. Tumor tissue from 14 patients has been reviewed at the University of Oregon Health Sciences Center. Specimens of all 14 patients were ER+ with a range of 5.5 to 374 fmol/mg protein. Eight of 12 patients had tumors which also contained progesterone receptors (PR+) with a range of 42 to 1852 fmol/mg protein. Nine patients were treated by modified radical mastectomy, two by radical mastectomy, one by simple mastectomy, and two by biopsies only. Twelve patients remain free of disease with a mean follow-up of less than 2 years. The two patients who developed metastases both responded to endocrine ablation by orchiectomy and subsequent adrenalectomy. These data suggest that male breast cancer is highly endocrine sensitive and that endocrine ablation can play an integral part in those men unfortunate enough to develop disseminated disease.     

Quantitative comparison of estradiol and progesterone receptor contents of primary and metastatic human breast tumors in relation to response to endocrine treatment

Summary Cytosol receptors for estradiol (RE) and progesterone (RP) in breast tumors from women attending one clinic have been analyzed. The analysis involved a single concentration of [³H] ligand and low speed centrifugation of homogenates. Analysis of tumors immediately before the start of first endocrine treatment indicated a poor response rate in patients with tumor RE <20 fmol/mg protein. A cut-off value of 20 fmol/mg protein gave the best discrimination between responders and nonresponders in both pre- and postmenopausal patients. An appreciable number of responses (17%) was seen with RP negative tumors (<5 fmol/mg protein) and analysis of this receptor alone is not recommended. Combined analysis of RE and RP indicated good response rates for RE+ RP+ (64%) and RE – RP+ (67%) tumors and a low response rate for RE– RP– (9%) tumors. Responses also occurred in patients with RE+ RP– tumors (30%). The influence of cut-off value and menopausal status on clinical usefulness of combined RE and RP analysis is discussed.Data are also presented on the clinical value of receptor analyses on primary tumors in predicting the endocrine sensitivity of subsequent metastatic disease.Receptor results for tumors obtained at different times from the same patient are presented and discussed. Receptor phenotype of some tumors does change with time and this is influenced by receptor amount, histological appearance, and intervening treatment.     

Primary systemic therapy for operable breast cancer.

Eighty-eight patients presenting with operable breast cancer of 4 cm or greater in diameter (T2, T3, N0, N1, M0) have received primary systemic therapy. Response was assessed following 12 weeks of systemic therapy by linear regression analysis of changes in tumour volume. Definitive locoregional surgery (mastectomy n = 82, wide local excision n = 6) was performed on completion of systemic therapy (3-6 months). Response was observed in 24 (39%) of the 61 patients who received endocrine therapy; all 24 had tumours with an oestrogen receptor (ER) concentration of greater than or equal to 20 fmol mb-1 cytosol protein. Cytotoxic therapy was reserved for patients with tumours of ER concentration less than 20 fmol mg-1 cytosol protein (n = 27) or when endocrine therapy had failed (n = 20). Response was observed in 34 patients (72%). The overall survival rate at 3 years was 86%, with 81% remaining free from local relapse. We propose that the treatment policy outlined in this paper should now be tested against orthodox management by controlled randomised trial.     

Heterogeneity of O(6)-alkylguanine-DNA alkyltransferase activity in colorectal cancer: implications for treatment

OBJECTIVES: MGMT (O(6)-alkylguanine-DNA alkyltransferase) reverses the carcinogenic, mutagenic and cytotoxic effects of alkylating agents. Measurement of MGMT activity in tumours might thus be of use in selecting those patients with colorectal cancer who may be sensitive to adjuvant alkylating agent therapy. The aim of this study was to assess whether measurement of MGMT activity in a single tumour biopsy is representative of the whole tumour. METHODS: Multiple symmetrically spaced biopsies were taken from colorectal cancers obtained from 9 patients. MGMT activity was then measured in cell-free extracts by quantifying the transfer of [(3)H]methyl group from calf thymus DNA methylated in vitro with N-nitroso-N-[(3)H]-methylurea to the MGMT protein. RESULTS: MGMT activity was detected in all tumour samples with the activity ranging between 3.6 and 36.2 fmol/microg DNA and 202-1,986 fmol/mg protein. Heterogeneity in MGMT activity (ratio of maximum/minimum MGMT levels per tumour) varied between 1.3 and 5.4. CONCLUSIONS: Measurement of MGMT activity in a single biopsy is not necessarily indicative of the level throughout the tumour. The response of colorectal cancers to alkylating agent treatment is likely to be non-uniform both within the tumour and between patients.     

Does the oestrogen receptor concentration of a breast cancer change during systemic therapy?

The effect of systemic therapy on tumour oestrogen receptor (ER) concentration has been studied in 88 patients with large, operable, primary tumours (total 89) of the breast. In 26 patients, tumour was not available for study on one occasion (usually post-treatment). Forty-five patients were treated initially by endocrine therapy but, of these, 13 who had failed to respond went on to receive chemotherapy also. Seventeen patients with low concentrations of ER (less than 20 fmol mg-1 protein) were treated directly by chemotherapy. Patients underwent an incisional biopsy for confirmation of diagnosis and determination of pre-treatment ER by radioligand binding assay, followed by systemic therapy for 3 months (or 6 months for both endocrine and cytotoxic therapies). Response was assessed clinically and mammographically before mastectomy. ER concentration was then determined in the post-treatment tumour specimen. No significant change in ER concentration was seen in any treatment group except when the patients had received tamoxifen; there, receptor concentration fell to very low levels, presumably due to interference with the assay. There was no relationship between tumour response to systemic treatment and change in ER concentration. It is concluded that changes in ER concentration are unlikely to play a major role in the early response of breast tumours to systemic therapy.     

Variations in steroid receptor status with disease stage in breast cancer

Oestrogen and progesterone receptor (ER and PgR) distribution in three clinical subgroups of 421 breast carcinomas was analysed. The groups comprised (1) early breast cancer (T1-2a, N0M0; n = 64); (2) untreated advanced fungating cancer (n = 27) and (3) advanced cancer relapsing after endocrine therapy (n = 29). Receptor distribution in each of the subgroups was compared to that of the total population. The advanced fungating group contained no ER--ve/PgR--ve tumours and the distribution was also significantly different from the total population (P less than 0.001 by Chi-squared test). The proportion of tumours in the total population that contained greater than 40 fmol/mg ER was 187/421 (44.4%). There was no significant difference between the early breast cancer group and the total population (P greater than 0.9). However, the proportion of tumours containing ER greater than 40 fmol/mg in the advanced fungating cancer group (16/27, 59.3%) was significantly higher than in the total population (P less than 0.01). This difference may be partially explained by the older age at presentation in this group. In the relapsed after endocrine therapy group only four of 29 (13.8%) contained ER greater than 40 fmol/mg which was significantly different from the total (P less than 0.001). There was a higher proportion of early breast cancers containing PgR greater than 40 fmol/mg than in the total population (P less than 0.001). There was no significant difference between PgR distribution in the advanced fungating and relapsed groups compared to the total population. The data suggest that patients presenting with advanced fungating cancer are more likely to respond to endocrine therapy than the population as a whole, and that in breast cancer that has relapsed following endocrine therapy receptor levels decrease with progression of the disease.     

Breast cancer during follow-up and progression – A population based cohort on new cancers and changed biology

BackgroundEmerging data indicate an important role for biopsies of clinically/radiologically defined breast cancer ‘recurrences’. The present study investigates tumour related events (relapses, other malignancies, benign conditions) after a primary breast cancer diagnosis.Patients and methodsThe cohort includes 2102 women, representing all patients, with primary invasive breast cancer during 2000–2011 in the county of Värmland, Sweden. A comparative analysis of oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and proliferation (Ki67) between the primary tumour and the relapse was performed and related to outcome.ResultsWith a mean follow-up time of 4.8 years, 1060 out of 2102 patients have had a biopsy taken after the initial breast cancer diagnosis demonstrating 177 recurrences, 93 other malignancies (colorectal, lung, skin), 40 cancer in situ (skin, breast) and 857 benign lesions. Approximately 70% (177 out of 245) of all cases of relapsed breast cancer underwent a biopsy during this time period. For patients with recurrences, ER (n = 127), PR (n = 101), HER2 (n = 73) and Ki67 (n = 55) status in both primary tumour and the corresponding relapse were determined. The discordance of receptor status was 14.2%, 39.6%, 9.6% and 36.3%, respectively. Loss of ER or PR in the relapse resulted in a significant increased risk of death (hazard ratio (HR) 3.62; 95% confidence interval (CI), 1.65–7.94) and (HR 2.34; 95% CI, 1.01–5.47) compared with patients with stable ER or PR positive tumours. The proportion of patients losing ER was bigger in the group treated with endocrine therapy alone or in combination with chemotherapy, 16.7% and 13.3%, respectively, compared with the group treated with chemotherapy alone or that which received no treatment 4.3% and 7.7%, respectively.ConclusionDiscordance of biomarkers between the primary tumour and the corresponding relapse was seen in 10–40% of the patients, adjuvant therapies seem to drive clonal selections. Patients with tumours losing ER or PR during progression have worse survival compared with patients with retained receptor expression.     

Relationship between c-erbB-2 protein product expression and response to endocrine therapy in advanced breast cancer.

Of 221 patients with breast cancer of known epidermal growth factor receptor (EGFR) and oestrogen receptor (ER) status, 99 had developed recurrences during the period of follow-up (range 3-60 months, median 24 months). Of these, 72 received endocrine therapy as first-line treatment for relapse. Immunohistochemical assessment of c-erbB-2 protein product expression was made using paraffin-embedded tumour tissue from 65 of these 72 patients. Including patients whose disease remained stable for more than 6 months with those showing an objective response (CR or PR for more than 3 months), only one (7%) of 14 c-erbB-2 positive tumours responded to endocrine manipulation compared with 19 (37%) of 51 c-erbB-2 negative tumours (P less than 0.05). Coexpression of c-erbB-2 reduced the response rate of ER positive patients from 48% to 20% and of ER negative cases from 27% to 0% (P less than 0.01). EGFR and c-erbB-2 protein appeared to have additive effects in reducing the likelihood of response, and none of eight patients with EGFR positive, c-erbB-2 positive tumours derived benefit from endocrine therapy. The results of this study suggest that c-erbB-2 protein overexpression, a marker of poor prognosis in breast cancer, is associated with a lack of response to endocrine therapy on relapse, and particularly in combination with EGFR may be useful in directing therapeutic choices.     

Correlation of lactogenic receptor concentration in human breast cancer with estrogen receptor concentration

The presence of receptors for lactogenic hormones in human breast cancer tissue has been documented previously, but the relationship between the expression of these receptors and estrogen receptor (ER) status has not been adequately studied. In this report, the specificity of 125I-human growth hormone (HGH) binding in both cultured human breast cancer cell lines and tumor biopsies was studied to establish that HGH was a suitable ligand for investigating lactogenic receptor concentration in these tissues. In addition, the relationship between specific binding of 125I-HGH and ER concentration in human breast cancer was investigated. Specific 125I-HGH binding to 14 breast cancer cell lines in long term culture and to membrane preparations (microsomal and plasma membrane fractions) from 31 breast cancer biopsy specimens was examined. Human prolactin and HGH were approximately equipotent in inhibiting binding of 125I-HGH to both cultured breast cancer cell lines and to membrane preparations from breast cancer biopsy specimens. Competitive inhibition experiments using lactogenic and somatogenic hormones established that the specificity of 125I-HGH binding to breast cancer biopsy material was similar to that of cultured breast cancer cell lines and similar to that reported for subprimate lactogenic receptors. Saturable, high-affinity (Ka = 0.53 to 2.33 nM-1), low-capacity (330 to 6560 sites/cell) growth hormone binding sites were found on each of the ER-positive cell lines, whereas no specific 125I-HGH binding to ER-negative cell monolayers was detected. When all cell lines were considered, a significant linear correlation (r = 0.745, p less than 0.001) between ER and lactogenic receptor concentrations was found. Significant specific 125I-HGH binding, greater than 1% of the total radioactivity added, was detected in 20 of 31 (65%) breast tumor biopsy specimens. The mean affinity and capacity of the lactogenic receptor as measured in 8 separate membrane preparations were Ka = 0.52 +/- 0.09 (S.E.) nM-1 and 255 +/- 85 fmol/mg protein. Membrane preparations from ER-negative tumors (less than 3 fmol ER/mg cytosol protein) bound significantly less 125I-HGH than did membrane preparations from ER-positive tumor biopsies (1.22 +/- 0.44 versus 3.21 +/- 0.56%, p less than 0.05). A significant linear correlation between specifically bound 125I-HGH and ER concentration (r = 0.412, p less than 0.02) was demonstrated in the 31 breast cancer biopsy specimens studied.(ABSTRACT TRUNCATED AT 400 WORDS)     

Response to endocrine manipulation and oestrogen receptor concentration in large operable primary breast cancer

Forty-three patients with large (greater than or equal to 4 cm) but operable carcinoma of the breast have been treated by endocrine manipulation before definitive local surgery. This has allowed the study of the relationship between response to therapy and pretreatment oestrogen receptor (ER) concentration, as measured by a dextran-coated charcoal adsorption method. Premenopausal patients (17) were treated by surgical (4) or medical (13) oophorectomy. Post-menopausal patients (26) received either tamoxifen (10) or an aromatase inhibitor (16). Response was assessed from statistical analysis of the changes in tumour size. On completion of 12 weeks of endocrine therapy, there was significant regression of tumour size in 18 of the 43 patients. All 18 patients had tumours with ER concentrations of greater than or equal to 20 fmol mg-1 cytosol protein. Conversely all patients except one progressing on treatment had tumours with ER concentrations of less than 20 fmol mg-1 cytosol protein. This relationship applied for both premenopausal and post-menopausal patients. The overall response rate of patients with tumours of ER concentration greater than or equal to 20 fmol mg-1 cytosol protein was 60%.     

Epidermal growth factor receptor-negative tumors are predominantly confined to the subgroup of estradiol receptor-positive human primary breast cancers

A total of 725 human primary breast tumor biopsy samples were analyzed for epidermal growth factor receptor (EGFR) content, using a multiple-point EGFR assay standardized in accordance with the recommendations of the European Organization for Research and Treatment of Cancer Receptor Study Group. After the establishment of a lower cell membrane protein threshold of 0.2 mg of membrane protein per ml of assay buffer, the results of 27% (194 samples) of the EGFR determinations were excluded from the study because of insufficient assay membrane protein content. Of the remaining 531 breast tumor biopsy samples, 57% (302 samples) were shown to be EGFR positive by Scatchard analysis, with a median value of 40 fmol/mg of membrane protein. Of the breast tumor biopsy samples, 72% (380 samples) were estrogen receptor (ER) positive, and 65% (344 samples) were progesterone receptor (PgR) positive. EGFR positivity was found in 46% (173 of 380) of ER-positive and in 85% (129 of 151) of ER-negative breast tumor biopsy samples (P less than 0.0001), as well as in 49% (168 of 344) of PgR-positive and in 72% (134 of 186) of PgR-negative breast tumor biopsy samples (P less than 0.0001). Mean EGFR levels in ER-positive breast tumor biopsy samples were lower than they were in ER-negative ones, 40 +/- 31 (SD) against 72 +/- 55 fmol/mg of membrane protein (P less than 0.0001). Similarly, mean EGFR levels in PgR-positive breast tumor biopsy samples were lower than they were in PgR-negative ones, 41 +/- 29 against 70 +/- 56 fmol/mg of membrane protein (P less than 0.0001). Both EGFR positivity and EGFR levels decreased with increasing steroid hormone receptor levels. A multivariate analysis showed only ER to be independently associated with EGFR.     

Gamma linolenic acid with tamoxifen as primary therapy in breast cancer

Gamma linolenic acid (GLA) has been proposed as a valuable new cancer therapy having selective anti-tumour properties with negligible systemic toxicity. Proposed mechanisms of action include modulation of steroid hormone receptors. We have investigated the effects of GLA with primary hormone therapy in an endocrine-sensitive cancer. Thirty-eight breast cancer patients (20 elderly Stage I-II, 14 locally advanced, 4 metastatic) took 8 capsules of oral GLA/day (total = 2.8 g) in addition to tamoxifen 20 mg od (T+GLA). Quality and duration of response were compared with matched controls receiving tamoxifen 20 mg od alone (n = 47). Serial tumour biopsies were taken to assess changes in oestrogen receptor (ER) and bcl-2 expression during treatment. GLA was well tolerated with no major side effects. T+GLA cases achieved a significantly faster clinical response (objective response vs. static disease) than tamoxifen controls, evident by 6 weeks on treatment (p = 0.010). There was significant reduction in ER expression in both treatment arms with T+GLA objective responders sustaining greater ER fall than tamoxifen counterparts (6-week biopsy p = 0.026; 6-month biopsy p = 0.019). We propose GLA as a useful adjunct to primary tamoxifen in endocrine-sensitive breast cancer. The effects of GLA on ER function and the apparent enhancement of tamoxifen-induced ER down-regulation by GLA require further investigation.     

A case of advanced breast cancer with multiple organ metastases successfully treated by tamoxifen]

A 66-year-old postmenopausal woman presented in June 1991 with a giant ulcerated left breast tumor. She had discovered the tumor two years previously, but had never visited any medical institution. She was diagnosed as advanced breast cancer with multiple lung metastases, bone metastasis, and both supraclavicular lymph node metastases by physical examination, fine needle aspiration cytology, chest X-P, and bone scintigraphy. Incisional biopsy, performed to confirm the histological type of breast cancer and to evaluate estrogen and progesterone receptor (ER and PgR) status, revealed solid-tubular carcinoma. Both ER and PgR were highly positive at 322.6 and 228.0 fmol/mg protein, respectively. Therefore, endocrine therapy was chosen to treat this advanced breast cancer patient, although she had multiple organ metastases. Twenty mg of Tamoxifen a day was administered per os. After treatment with tamoxifen, the size of ulceration started to decreased and the dyspnea caused by multiple lung metastases was reduced. Eight weeks after, she showed partial response (PR) determined from the size of the ulceration and chest X-P. She has been maintaining PR for more than 9 months. Thus, Tamoxifen was shown to be very effective for this case of advanced breast cancer with multiple organ metastases.     

Predictive value of tumor estrogen and progesterone receptor levels in postmenopausal women with advanced breast cancer treated with toremifene

The predictive value of estrogen receptor (ER) concentrations was evaluated in a group of 113 postmenopausal patients with estrogen-receptor-positive (ER greater than 7 fmol/mg protein) advanced breast cancer. In 103 patients, tumors were also sampled for progesterone receptor (PgR) determination. All patients were treated with toremifene, a novel antiestrogen, 60 mg daily. The median ER in 51 responders was 78 fmol/mg protein, and in 62 nonresponders, 51 fmol/mg protein; the median PgR levels were 40 and 37 fmol/mg protein, respectively. The response rate in patients with ER less than 50 fmol/mg protein was 38%, and 51% in the group with ER greater than 50 fmol/mg protein (not significant [NS]). The response rate in patients with PgR less than 10 fmol/mg protein was 42%, and in patients with greater than 10 fmol/mg protein, 44%. The duration of response in patients with ER greater than 50 fmol/mg protein was significantly longer than with lower ER levels (P = 0.002). PgR was not associated with the duration of response. In Cox's multiple regression analysis, ER was an independent prognostic factor (P = 0.005) for response duration. Thus, the ER concentration of tumor tissue predicts the duration of response but not the response rate to toremifene in patients with advanced breast cancer. The PgR status does not predict the response rate or the duration of response.     

Variability of steroid receptors in multiple biopsies of breast cancer: Effect of systemic therapy

Summary Estrogen receptor (ER) was measured on two or more specimens taken from each of 53 patients with carcinoma of the breast (18 also had progesterone receptor analyzed). Among the 35 patients who had no interval therapy, 27 patients had repeated tests within one month, and only two had reversal of ER results. Among the eight patients who had ER tests 9–36 months apart, four of five ER + lesions (7 + fmol/mg cytosol protein) had ER – metastasis. Among the 18 patients who received systemic therapy, three of ten ER + became ER –, while two of ten ER – became ER +. Our data and reports in the literature are summarized, showing that about 20% of receptor studies among multiple samples are different even when patients received no interval therapy. In asynchronous studies, it is more likely to have ER positive change to negative than vice versa (31% vs 12%). Interval chemotherapy or endocrine therapy tends to increase the occurrence of ER negative relapse among patients with ER positive tumors.     

Correlation of breast tumour aromatase activity and response to aromatase inhibition with aminoglutethimide

Tumour aromatase, oestrogen (E) and progesterone (P) receptor (R) measurements were carried out in biopsies from 29 patients with advanced or recurrent breast cancer. Patients were then treated with aminoglutethimide according to one of two dosage regimens: (a) aminoglutethimide 1000 mg/day + hydrocortisone 20 mg/day, and (b) aminoglutethimide 250 mg/day. Tumour aromatase values varied from 0.05 to 2.07 pmol ER produced/mg protein/h and ER and PR values from less than 1 to 249 and less than 1 to 132 fmol of steroid bound/mg protein, respectively. There was no correlation between aromatase values and either ER or PR and also no correlation between ER and PR and response to aminoglutethimide. Tumour aromatase values did however correlate with response to treatment. Mean aromatase levels for responders (1.18 +/- 0.64 pmol E produced/mg protein/h) were significantly higher than those of non-responders (0.34 +/- 0.27) (t = 5.20, DF 27; p less than 0.005). Ten out of fourteen patients with aromatase values greater than 0.5 pmol ER produced/mg protein/h responded, whereas 0 out of 15 patients with tumour aromatase values less than this responded. Responses were seen at both dosages of aminoglutethimide. It is concluded that tumour aromatisation will be a useful measurement in predicting response to aromatase inhibitors.     

Estrogen and progesterone receptors in melanoma metastases with special reference to analytical methods and prognosis

Fifty-one tumor biopsies from 33 patients with metastatic melanoma were assessed for estrogen receptor (ER) content, and 46 of these for progesterone receptor (PgR) content in the cytoplasm. ER posivity (above 0.2 fmol/mg protein), as measured with isoelectric focusing on polyacrylamide gels, was found in 23 (70%) of the patients (range 0.2 - 14 fmol/mg protein). With a reference limit of 2 fmol ER/mg protein, 12 patients were positive (36%). PgR was analysed with the dextran coated charcoal technique and no sample demonstrated any positivity with certainty. The ER content was related to clinical prognostic factors without any significant correlation independent of reference limit used. A correlation to survival can not be excluded with ER values above 2 fmol/mg. Pertinent data are given regarding the technique used in comparison with others.     

Simultaneous estimation of epidermal growth factor receptors and steroid receptors in a series of 136 resectable primary breast tumors

Human breast cancer cell lines, as well as human breast cancer biopsies, possess specific high-affinity epidermal growth factor receptors (EGF-r). However, reports on the presence of EGF-r in human breast cancer biopsies are still controversial, especially concerning the relationship between EGF-r and other biological variables whose prognostic relevance is well known, such as the estrogen (ER) and progesterone (PgR) receptors. In the present study, the EGF-r content was estimated in a series of 136 unselected breast cancer primaries along with cytoplasmic (ERc) and nuclear (ERn) ER and cytoplasmic PgR. EGF-binding activity consisted of a single class of high-affinity binding sites (Kd = 0.55 nM) and ranged from 0 to 275 fmol/mg protein. We observed a strong inverse association between EGF-r and ERc (p less than 0.001); in fact, about two thirds of the tumors were ERc-positive/EGF-r-negative or ERc-negative/EGF-r-positive. The same type of association was found between EGF-r and either ERn or PgR. Kendall's rank correlation test confirmed that the EGF-r concentrations were correlated with the levels of ERc (tau = -0.291, p less than 0.0001), ERn (tau = -0.27, p less than 0.0005) and PgR (tau = -0.162, p less than 0.01). The EGF-r content was significantly higher (p less than 0.0001) in the ERc-negative tumors (72.6 +/- 54.4 fmol/mg protein) as compared to the ERc-positive ones (33.0 +/- 37.4 fmol/mg protein). Similarly, the subset of PgR-positive tumors was characterized by lower EGF-r mean concentrations when compared to PgR-negative cases (35.4 +/- 54.4 vs. 63.8 +/- 54.4 fmol/mg protein). These results confirm the previously described inverse relationship between EGF-r and steroid receptors. Moreover, they suggest the existence of an interaction between steroid hormones and EGF and support the need for further studies to better understand their respective roles in modulating breast cancer growth.