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European guidelines for quality assurance in the surgical management of mammographically detected lesions.

After modified radical mastectomy, 490 primary breast cancer patients were followed for a median of 75 months. Bloom grade was measured in 340 patients and ER status in 341. Follow-up of these patients has yielded the following results: (a) The value of traditional indices has been reaffirmed. (Cox's multivariate analysis identified, in order of decreasing importance, the number of invaded lymph nodes, the initial tumor size and the histological grade. Other variables were found to be of lesser importance and were correlated with the three main indices.) (b) The value of ER status disappeared after more than 3 years of follow-up. (c) ER positive patients fared better after recurrence. This was interpreted as being a consequence of their responsiveness to hormonal treatment.

The authors studied the relationships existing between various cytomorphonuclear parameters recorded on 25 primary breast cancers and their estrogen receptor (ER) content. Cell image analyses of Feulgen-stained imprint smears, allowing determination of morphologic, densitometric, as well as textural parameters, were assessed by using the SAMBA 200 system (TITN, France). The ER levels were measured by the conventional dextran-coated charcoal assay. The authors then divided the 25 cancers into three categories: (1) "ER-negative or poorly positive tumors," i.e., those having less than 50 fmol ER/mg protein; (2) "ER-positive tumors," i.e., those containing between 50 and 150 fmol ER/mg protein; and (3) "ER highly positive tumors," i.e., those having more than 150 fmol ER/mg protein. The authors' results show that ER-negative or poorly positive breast cancers possess cells with bigger nuclei and higher DNA content, related to higher proliferation index than ER-rich tumors. Furthermore, the chromatin pattern of cells from ER-negative or poorly positive breast cancers is significantly more condensed than the thinly textured chromatin of ER highly positive tumors. Cell image analysis of Feulgen-stained imprints is proposed as an additional tool for grading malignancy.

The predictive significance of quantitative assessment of estrogen receptors in tumor tissue was analyzed in women with advanced breast carcinoma. Receptor concentration was measured by the 3H-estradiol binding capacity of the cytosol fraction of biopsies taken before initiation of the treatment. The E. O. R. T. C. criteria for the assessment of the patients' response were used. In a total of 34 assessments, 25 biopsies contained receptors; the remaining ones were negative. Objective remission to various endocrine therapies was recorded in only eight of the receptor-positive patients. Responses occurred along the whole scale of receptor concentrations with an apparent crowding in the region of the higher values. Linear logistic regression analysis revealed that among 12 variables of known prognostic value, receptor concentration was the most significant in relation to therapeutic response. Other significant variables were bone involvement and age. Computations yielded formulas that are presented in graph form and provide an estimate of the probability of a given patient to respond to endocrine treatments. On the other hand, the results suggest that all patients are possibly hormone dependent, although to variable degrees. The latter concept has very definite therapeutic implications.

Oestrogen receptors were found in 156 (73%) out of 214 primary breast cancers and in 98 (58%) out of 168 metastatic deposits. These proportions reached 82% and 70% respectively in the second half of the study. Receptors were not found in samples of normal breast tissue but small amounts were present in tissue from some hyperplastic lesions and in male gynaecomastia. Receptor concentrations in the malignant samples were evenly distributed over a wide range of values, suggesting that even "negative" tumours might contain trace amounts undetectable by the method used. Each tumour was characterized by a given level of receptor concentration. In most cases the amounts found in the invaded axillary nodes and their corresponding primary tumours were the same. We suggest that quantitative rather than qualitative assessment should provide an appropriate criterion for studies of biochemical and clinical correlations.

Samples from 77 primary and 65 metastatic human breast cancers were assayed for specific cytoplasmic estrogen receptors. Cytosol preparations were incubated with increasing amounts of 3 H-estradiol- 17 β. The unbound radioactivity was removed by charcoal-coated dextran. Saturable high affinity binding sites were detected in 56% of the primary and 37% of the metastatic tumors. The binding constants of these receptor sites for estradiol were quite variable; most ranged from 1·0 to 20 × 10 −10 M, but some were larger (up to 108 × 10 −10 M). The concentrations of binding sites were distributed within a continuous range from 5 to 1330 femtomoles per mg protein. This wide range was not ascribable only to variations in amounts of contaminating serum proteins. Receptors were detected in only 8% of cytosol preparations containing less than 2 mg protein per ml; in contrast they were detected in 53% of cases with higher protein concentration. This indicates that at low protein concentration, false negative results are likely to occur. Detectable amounts of receptors were not found in sera or samples from normal mammary gland, nipple, areola, skin and non-invaded lymph nodes. The reliability of a simplified procedure based on isotopic dilution of the labelled estradiol, to be used with very small tumor tissue samples, was studied. It compared quite well with the other one except in case of very low concentrations of receptor. No relationship was found between the occurrence of receptor and the age of the patient or the histological type of the tumor. There was also no relationship between the occurrence of receptors in the primary tumor and presence or absence of metastatic axillary lymph nodes. However, when present, the latter had the same characteristics with respect to the receptor as the corresponding primary, with only one exception. In cases of metastatic tumors, no correlation was observed with the free interval.

IN THE European Journal of Cancer & Clinical Oncology, Umberto Veronesi published what he cautiously calls ‘long term’ results of his already well-known Q.U.A.R.T. versus Halsted study [l]. I, among many others, find those results to be highly significant and definitive. One must now pose the question: where do we go from here? It is perhaps important to remember where we come from. One century ago Halsted described his radical mastectomy (1894), the perfect surgical answer to what was known of breast cancer at that time: an aggressive form of tumor progressing centrifugally mostly along known lymphatic pathways. The generalization of this radical surgical practice resulted in a spectacular increase in cure rate and a decrease in local recurrences [2]. The answer to the remaining failures was ‘more is better’ until the early sixties. As young surgeons, we were disappointed by the results of one of the first large international randomized trials comparing the standard Halsted procedure to the en-bloc superradical mastectomy including the internal mammary nodes. No improvement was noted, the limited advantage of the largest procedure in a small subset of patients was negatively compensated by increased morbidity and mortality [3]. As young oncologists, we began to learn even more. Cancer of the breast was no longer considered a malignant process with a predictable behavior. The most important lesson was the knowledge that the metastatic process starts very early and remains mute for a variable and possibly very

The interest of estrogen receptor assays has been pointed out by numerous authors [1], especially with reference to the determination of potential responders to endocrine therapy among generalized breast cancer patients. The relationship between the estrogen receptor level in breast primaries and other prognostic factors remains a matter of controversy and is the subject of the following article, which is based on a series of 490 previously unreported cases.

Between 1976 and 1982, 59 patients with locally advanced breast cancer were treated with preoperative supervoltage radiotherapy, adjuvant preoperative and postoperative hormonochemotherapy, and modified radical mastectomy. Systemic treatment, which was started simultaneously with radiotherapy, consisted of a combination of daily oral tamoxifen and a monthly alternation of Doxorubicin + vincristine and cyclophosphamide + methotrexate + 5-fluorouracil (CMF). One of each cycle was given preoperatively at half dosage and five of each were repeated postoperatively at full dosage. All patients became operable. Results of pathologic examination of the operative specimen, available in 51 patients, showed complete disappearance of tumor tissue in breast areas in eight patients, of which three still had positive axillary nodes. After a median follow-up time of 6 years locoregional failure was observed in 12 patients (20%) but in only three (5%) did it occur before distant failure. The actuarial median survival of the entire patient population is close to 4 years. Seven patients are alive without recurrence at greater than 9 years. This aggressive multidisciplinary treatment approach is associated with a projected 30% long-term survival (10 years), excellent local control, but substantial toxicity.

Since Jensen’s initial work in 1971 [1], many reports have confirmed the utility of estrogen receptor assays for predicting the results of endocrine treatments in advanced breast cancer (review article [2]). These assays, which can be performed either on the primary tumor or on metastases, are deemed to provide the clinician with a tool for measuring the degree of hormone dependence of the tumor. Accordingly, they could be used to select the most appropriate treatment either as palliation in advanced disease or as a prophylaxis against recurrence in stage II cases. We intend to review briefly the currently active protocols in the EORTC Breast Cancer Cooperative Group. We will focus in more detail on those which include endocrine therapy. The possible role of receptor assays in the design of these trials will be analyzed.