Jean-Claude Heuson

Significance of quantitative assessment of estrogen receptors for endocrine therapy in advanced breast cancer

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.

Six-year results of a multimodality treatment strategy for locally advanced breast cancer

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 >9 years. This aggressive multidisciplinary treatment approach is associated with a projected 30% long‐term survival (10 years), excellent local control, but substantial toxicity.

EFFECTS OF AMINOGLUTETHIMIDE ON ADRENAL STEROID SECRETION

Effects of various doses of aminoglutethimide (AG) alone upon adrenal steroidogenesis were studied in normal postmenopausal women, whereas the effects of combined treatment with aminoglutethimide in variable doses together with 40 mg of hydrocortisone were studied in postmenopausal women with advanced mammary concer and compared to effects of treatment with cortisol alone. Despite the well known inhibitory effect of AG on cortisol biosynthesis, plasma cortisol levels were unaffected by AG in doses of 150–1000 mg/d, probably due to a compensatory increase in ACTH in subjects with an intact pituitary‐adrenal axis. The aromatase system appeared to be very sensitive to inhibition by AG, a clearcut inhibition being shown at doses as low as 150 mg/d. Evaluated from the ratio of plasma oestrone (E1) to plasma androstenedione (AN), treatment with AG at a dose of 150 mg/d appeared to reduce the aromatase activity to 33% of the basal value; 250 mg/d resulted in a reduction to 20% and 1 g/d to 5% of basal values. Whereas AG at 150 mg/d did not appear to affect 11β‐hydroxylase, the latter was clearly inhibited by 250 mg/d and even more so by 1000 mg/d, as indicated by the increase in plasma 11‐desoxycortisol and 17‐OH progesterone (17‐OHP) levels. Due to the increase of the latter, their biosynthetic precursor, AN and to a lesser degree testosterone (TS) levels increased significantly during AG treatment at a dose of 250 or 1000 mg/d. Δ5 steroid levels remained practically unchanged, probably because 11‐(as well as the 21‐) hydroxylation concerns essentially the Δ4 pathway. During combined treatment with 500–1000 mg/d of AG and cortisol 40 mg/d, AN and TS were significantly higher than during treatment with cortisol alone, suggesting that cortisol had not completely blocked ACTH secretion. E1 and E2 levels were however lower than during treatment with cortisol alone, a consequence of the inhibition of the aromatase activity. Although at a dose of

Physiological and pharmacological effects of estrogens in breast cancer

n Focus here is on the mechanism of action of both estrogens and antiestrogens at the tumor cell levels in breast cancer. The interactions of estrogens and their antagonists are emphasized and analyzed in terms of current and potential clinical applications to breast cancer treatment. This review deals with these interrelationships at the molecular levels, not just with general aspects of endocrine interrelationships. The article is divided into 8 main parts: 1) an introduction, which reviews historical understanding of receptor technology and significances; 2) main properties of estrogens and estrogen receptors; 3) the influence of estrogens and antiestrogens on growth of experimental mammary tumor systems; 4) the suppression of or administration of estrogens for treatment of advanced human breast cancer; 5) estrogen receptivity of mammary tumors; 6) progress in treatment of advanced breast cancer derived from studies on the mode of action of estrogens; 7) the prognostic significance of estrogens and estrogenic receptivity (the estriol theory); and 8) concluding remarks on the future paths of receptor research.n

Effects of a gonadotropin-releasing hormone (GnRH) analogue (A-43818) on7,12-dimethylbenz(a)anthracene-induced rat mammary tumors. Histological and endocrine studies

Abstract The effect of A- 43818 [D-leu 6 (des-gly-NH 10 2 , pro-ethylamide 9 )]-gonadotropin releasing hormone (GnRH) was investigated on rats bearing 7,12 -dimethylbenz(a)anthracene (DMBA)-induced mammary tumors. Tumor growth was significantly inhibited by the s.c. administration of 10 μ g A- 43818 , twice daily, for six weeks. A dose of 25 μ g seemed less effective. Controls and experimental groups were subjected to radioimmunoassays (RIA) of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH) and prolactin (PRL), and to histological examination of pituitaries and ovaries. Treatment with A- 43818 resulted in atrophy of pituitary lactotropes and decreased prolactin concentration in plasma. Plasma LH levels were enhanced whereas FSH levels remained unchanged. The endocrine mechanisms of inhibition of tumor growth are discussed in the light of the well-known hormone dependance of DMBA-induced mammary tumors.

Estrogen receptors interaction with Estracyt and degradation products, a biochemical study on a potential agent in the treatment of breast cancer

SummaryEstracyt is a nitrogen mustard derivative of estradiol-17-phosphate and thereby a candidate for the treatment of breast carcinoma. Binding of Estracyt to estrogen receptors of rat uterine cytosol was studied by competitive inhibition of the binding of3H-estradiol-17 β. Rapid degradation of the drug into higher binding affinity compounds precluded an accurate assessment of its binding affinity but the highest estimate yielded values 10,000 and 100 times lower than that of estradiol-17 β and U 11, 100 A, respectively. Binding of Estracyt and its degradation products was reversible and did not alter the receptors. The affinity of dephosphorylated Estracyt was apparently 2 to 3 times higher than that of Estracyt. Its stability was also higher than that of Estracyt and estradiol-17-phosphate, although limited degradation occurred. Degradation of Estracyt occurred to a limited extent in rat serum but to a very marked degree in rat liver cytoplasmic preparations. Dephosphorylated Estracyt remained stable in these preparations.These data suggest that Estracyt administration results in flooding the organism with compounds having high affinity for the estrogen receptors and resultant saturation of their binding sites. Therefore, it is unlikely that the drug might exert significant therapeutic effects in breast cancer, based on a receptor-related mechanism. Dephosphorylated Estracyt appears more promising in this regard.

Cisplatin plus vindesine in advanced breast cancer: a phase II trial of the EORTC breast cancer coooperative group

This phase II clinical trial was conducted in a series of patients with advanced breast cancer, refractory to conventional chemotherapy. The therapeutic regimen consisted of a combination of cisplatin 100 mg/m2, given as a 24-hr infusion on day 1 and vindesine (VDS) 2 mg/m2, i.v. bolus on days 1 and 8. VDS injection was omitted on day 8 in patients with poor bone marrow reserves (prior extensive irradiation). Courses were repeated at 4-week intervals until documented disease progression. Among 46 evaluable patients, there were two complete and seven partial remissions for an overall response rate of 20%. These responses lasted for a median of 21 weeks (range 8-89 weeks). Remission rates according to the predominant metastatic site were as follows: soft tissue, 3/8 (38%); bone, 0/6 (0%); viscera, 6/32 (19%). Transient myelosuppression and gastrointestinal intolerance were almost universal. Renal function impairment and neurologic manifestations were frequently encountered but these adverse reactions were generally mild. Significant antineoplastic activity in far-advanced and heavily pretreated patients warrants further evaluation of this regimen at an earlier stage of the disease.

N-(Phosphonacetyl)-l-aspartate (PALA) in advanced breast cancer: a phase II trial of the EORTC breast cancer cooperative group

Twenty-nine evaluable patients with extensively pretreated breast cancer received PALA, a new pyrimidine antimetabolite. The drug was given by intravenous infusion over 60 min, at a daily dose of 2.5 g/m2 for 2 consecutive days. Courses were repeated at 2-week intervals and doses were escalated to toxicity. Two objective partial remissions were observed, lasting for 3 and 4.5 months respectively. Toxic effects were dose-related and consisted mainly of mucocutaneous manifestations, i.e., skin rashes, stomatitis, diarrhea, conjunctivitis and corneal ulcerations. Evidence of antitumor potential in far-advanced disease and lack of myelosuppression point to the need for additional trials of PALA in a more favorable selection of patients with breast cancer.

Estrogen Receptor Variations after Systemic Treatment in Breast Cancer

The importance of the determination of estrogen receptor concentration (ER) for the prognosis and treatment of breast cancer has been demonstrated by several authors. Many factors have been investigated for their possible correlation with the ER status of breast cancer cells; these include age, menopausal status, histopathologic features, and site and type of metastasis. During the course of disease, patients receive several treatments. Whether and how ER status could be affected by therapy is a very important problem for the therapeutic management of these patients. This study reports some data regarding effects of systemic treatment on ER in patients with breast cancer; these data were collected at the Jules Bordet Institute in Bruxelles.

Estrogen Receptors and Distribution of Prognostic Factors in Primary Breast Cancer

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.