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The relationship between DNA distribution pattern and estrogen receptor (ER) content was investigated in primary mammary carcinomas from 56 female patients. The data showed that mammary carcinomas in which the DNA amounts of the tumor cells do not deviate conspicuously from diploid or tetraploid DNA values of normal mammary epithelium are characterized by high levels of ER. On the other hand, mammary carcinomas containing a sizable number of cells with DNA amounts in the normal DNA synthesis region or with high degrees of aneuploidy are distinguished by low or even unmeasurable ER levels. These results strongly indicate a correlation between nuclear DNA distribution patterns and ER levels in primary breast carcinomas.

Immediately after mastectomy, estrogen receptor concentration was measured in fine needle aspirates and in histologic tissue specimens from 13 human breast carcinomas. Fine needle aspirates were shown to contain enough material for receptor analysis when the sensitive method of isoelectric focusing in slabs of polyacrylamide gel was used for receptor determination. Aspirations with two different needles (outer diameter 0.7 and 1.4 mm) from each tumor yielded highly correlated receptor values (r = 0.97, p less than 0.0001). There was also a highly significant correlation (r = 0.91, p less than 0.0001) between the receptor content in needle aspirates and in tissue specimens from the same tumor.

Histological specimens from 80 invasive breast carcinomas comprising typical cases of 16 ductal, nine papillary, 14 comedo, 13 colloid (mucous), 15 lobular, and 13 medullary carcinomas were examined with respect to nuclear DNA and estrogen receptor content. In agreement with previous studies, ductal carcinomas were found to exhibit different types of nuclear DNA distribution patterns, i.e., tumors with DNA values in the normal diploid or tetraploid regions indicative of good prognosis (euploid tumors) or those with values exceeding the normal tetraploid region indicative of poor prognosis (aneuploid tumors). The majority of the papillary and colloid tumors were euploid, while comedocarcinomas in general had aneuploid profiles. These findings are in agreement with expected survival within these patient groups. In lobular breast carcinomas, the correlation between the DNA distribution patterns and expected patient survival was less obvious; and in medullary carcinomas where the vast majority of the tumors showed aneuploid DNA profiles, the correlation to expected patient survival was low. Thus, lobular carcinoma in general seems to have a worse prognosis than is expected from nuclear DNA analysis, whereas medullary carcinomas in general seem to carry a better prognosis than indicated from DNA measurements. In agreement with earlier reports there was a good correlation between nuclear DNA content of the tumor cells and cytosol estrogen receptor values, i.e., euploid tumors in general exhibited relatively high receptor levels, whereas aneuploid tumors had low or unmeasurable estrogen receptor levels.

This report provides a histological review of 264 female primary breast cancers analyzed for estrogen receptor protein (ER). We also describe 5 cases of male breast cancer all of which bound estradiol specifically. Generally the ER concentrations were lower in the tumors of premenopausal women than in those of postmenopausal women. Three types of cancer with specific morphological features were shown to have ER concentrations that differed significantly from the other types of cancer. Medullary and comedo carcinoma had very low and papillary carcinoma very high levels of ER. No obvious trend in ER concentration was found in unspecified ductal carcinoma, colloid carcinoma, nor in lobular carcinoma. A positive correlation was demonstrated between ER content and degree of differentiation in ductal carcinoma. Cancer with lymphoid infiltration generally showed low ER levels.

Isoelectric focusing in polyacrylamide gel combined with limited proteolysis is a simple and specific method for quantitation of estradiol receptors in breast cancer tissue. At least eight different samples can be analyzed simultaneously on one gel, and the whole procedure, including sample preparation, takes less than 7 hr. In comparison with sucrose gradient centrifugation, isoelectric focusing is more sensitive, possibly due to the short time (1.5 to 2 hr) needed for the analysis. Furthermore, only one incubation with tritium-labeled estradiol is needed for an analysis, which means that a smaller amount of tumor tissue is needed than for most other methods. This fact allows analysis of the estrogen receptor content in tumor material obtained from fine-needle biopsy.

At the time of treatment in 1977 for primary breast cancer of all stages, the tumors of 270 women were examined for estrogen-receptor (ER) content by isoelectric focusing on polyacrylamide gel. The procedures for the initial and follow-up examinations were standardized. Postoperative adjuvant radiotherapy or chemotherapy was given to pre- and postmenopausal women aged up to 70 years with nodal involvement. Adjuvant tamoxifen treatment (20 mg twice daily for 2 years) was given to one-half of the postmenopausal patients aged 70 years or less, selected at random, and irrespective of any other adjuvant therapy. These forms of treatment appeared not to introduce bias into the results of the study. There was no correlation between the ER content and tumor spread. Symptom-free survival during the follow-up period was best for the patients with tumors with a high ER content, poorer for the patients with tumors of intermediate ER content and least favorable for patients with tumors having low ER content. (Ranges for high, intermediate and low levels: 2.18-9.08, 0.13-2.17 and 0-0.12 fmoles/microgram DNA). The differences between the survival curves were significant. For the 120 operable patients with nodal involvement there were also significant differences in recurrence-free survival. The premenopausal patients in this group likewise showed a significant difference in survival with respect to ER content. For the operable patients with nodal involvement and poorly differentiated tumors there was also a difference in the survival rate depending on the ER content. In this study the ER content of breast cancer was shown to be a quantitative rather than a qualitative entity. The study confirms the independent prognostic importance of the ER content and points to its potential value as a stratification criterion in adjuvant therapy trials.