The time-course of metastases from breast cancer after mastectomy and breast-conserving surgery with and without isolated local-regional recurrence.

We have examined time intervals between events in 390 metastatic breast cancer (MBC) patients whose distant failure developed within 10 years from initial surgery of Stage I/II disease. All of the patients underwent axillary dissection and mastectomy (n=295) or breast-conserving surgery (BCS, n=95), between 1983 and 1987. Distinctions have been made between distant failure with (n=79) and without (n=311) isolated local-regional recurrence (LRR). The median survival time after first relapse was significantly longer with intrabreast (30 months) and chest wall (24 months) than with distant relapse (15 months), but with axillary (17 months) or with supraclavicular (17 months) relapse survival was similar. The delay between LRR and distant metastasis was shorter with axillary (7 months) and supraclavicular (9 months) than with breast (20 months) and chest wall (12 months) recurrences. The median postmetastatic survival time by site of first relapse was significantly shorter with supraclavicular (6 months) and axillary (9 months) than with distant site relapse (15 months) but with intrabreast (12 months) or with chest wall (11 months) recurrence survival was similar. In MBC, regional recurrences are associated with a shorter interval between events than with local recurrences. The shortened intervals for patients with regional recurrence suggest that metastases existed at the time of initial surgery. The question of whether prevention of local or regional recurrence or both improves cause-specific survival after mastectomy or BCS needs to be answered in randomized studies.

Characteristics of cystic breast disease with special regard to breast cancer development.

BACKGROUND: This prospective study compares the characteristics of cystic disease of the breast (CDB) of patients who developed breast cancer (BCa) during the follow-up (1.25-4 years) period with those who did not. MATERIALS AND METHODS: K+, Na+, albumin, dehydroepiandrosterone (DHA), DHA-sulphate, oestrone, oestradiol, testosterone and progesterone levels were determined in breast cyst fluid (BCF). Patients presented data about their menstrual status, reproductive history, lactation period, date of first and the number of BCF aspirations, gynaecological interventions, use of oral contraceptives, family history of cancer, smoking habits and coffee consumption. The BCa incidence of patients was compared with the expected number of BCas in an age-matched group of 5143 women. RESULTS: Out of 147 patients 6 developed BCa. The standardized incidence rate was 6.29. There were significant differences in testosterone, oestrone and progesterone levels and also reproductive history of patients who developed BCa compared with patients without BCa. CONCLUSION: The above markers outline a subgroup of patients with the highest BCa risk.

Allopregnanolone, pregnenolone sulfate, and epitestosterone in breast cyst fluid.

The risk of breast cancer is 2 to 5 times higher in patients suffering from gross cystic disease. Breast cysts are categorized into two groups (type I and type II) according to the concentration of electrolytes in the cyst fluid. The two types also differ with respect to accumulation of steroids and steroidogenic enzyme activity. In type I cysts a higher risk of breast carcinoma could be expected. Here, we studied a possible relationship between the type of cyst and levels of epitestosterone (an endogenous antiandrogen), allopregnanolone (a product of 5alpha-reductase activity), and pregnenolone-sulfate (an activator of N-methyl-D-asparate receptors). We have found five times higher levels of epitestosterone in BCF in comparison with the circulation. Allopregnanolone levels were similar to those in plasma of women in the luteal phase of the menstrual cycle. Pregnenolone-sulfate levels in BCF were about two orders of magnitude higher when compared with the circulation. No differences were found in concentrations of the steroids studied between the types of cysts.

Modulation of oestrone sulphate formation and hydrolysis in breast cancer cells by breast cyst fluid from British and Hungarian women.

Women with gross cystic breast disease may have an increased risk of breast cancer. In this study the ability of breast cyst fluid (BCF), obtained from British or Hungarian women, to modulate oestrone sulphate (E1S) formation or hydrolysis, has been examined. For this, oestrogen receptor-positive (ER+) MCF-7 or MDA-MB-231 (ER-) breast cancer cells were employed. The formation and hydrolysis of E1S was measured using radiometric techniques. BCF from British and Hungarian women mainly inhibited E1S hydrolysis in MCF-7 cells while stimulating hydrolysis in MDA-MB-231 cells. The extent of inhibition or stimulation of E1S hydrolysis in these cells was related to the Na+/K+ ratio of the BCF. There was a significant inverse relationship between the extent to which BCF samples inhibited hydrolysis in MCF-7 cells and stimulated it in MDA-MB-231 cells. BCF stimulated E1S formation in MCF-7 cells while inhibiting formation in MDA-MB-231 cells. No difference in the ability of BCF from British or Hungarian women to inhibit or stimulate E1S hydrolysis was detected in ER+ or ER- breast cancer cells. In contrast, BCF from British women stimulated E1S formation in ER+ cells (median 82%) to a significantly greater extent (P < 0.01) than BCF from Hungarian women (median 33%). The role that E1S has in breast cancer development remains unclear. The greater stimulation of E1S formation by BCF from British women, who have a higher risk of breast cancer than Hungarian women, suggests that it may act as a storage form of oestrogen within cells that can be activated by oestrone sulphatase.

Influence of hormonal status of patients with cystic disease on the composition of cyst fluid and breast cancer risk.

The relationship between the composition of breast cyst fluid (BCF), the menstrual status and in addition some endocrine events in the history of patients (n = 131) with gross cystic breast disease was investigated. The dehydroepiandrosterone (DHA) levels in type II (K+/Na+ < 1) cysts of the follicular group were significantly higher compared to the type II cysts of the luteal or postmenopausal groups. For testosterone a significant difference existed between the type I (K+/Na+ > or = 1) follicular and type I postmenopausal groups. Estrone levels were significantly higher in type I BCF of patients in the luteal phase compared to both the follicular and postmenopausal type I cysts. Progesterone levels were lowest in the postmenopausal subgroups (both in type I and II cyst). Significant correlations were found between the number of pregnancies and the levels of DHA-sulfate and also progesterone in BCF. DHA levels were correlated with the period of lactation. The K+/Na+ ratios were the lowest in women who lactated for the longest period. The estrone was lowest in BCF of current oral contraceptive (o.c.) users while the estradiol was lowest in patients who had never used o.c. A history of previous o.c. use was associated with a significantly high mean DHA level. A significantly higher DHA and lower testosterone level were demonstrated in BCF of patients who had some previous gynecological interventions. The composition of BCF and the "life of cysts" and thus the rate of breast cancer risk may depend on hormonal status during the menstrual cycles or postmenopause and also on endocrine history of patients.

Correlation of biochemical tumor markers with conventional pathological features in primary breast cancer.

In this prospective study the correlation of pathological with biological prognostic factors and serum tumor markers has been investigated in 574 patients with primary invasive breast cancer. The p53 protein and Bax level correlated positively with tumor size, lymph node status and histological grade. The serum levels of CEA, CA 15.3, TPA-M and TK correlated with tumor extent. There was a significant difference between pre- and postmenopausal breast cancer patients in serum levels of TPA-M and cytosol levels of Bax. Whether these correlations can help in predicting the prognosis of breast cancer by providing additional information with respect to the conventional factors, will have to be investigated by several years of careful clinical follow-up.

Endocrine mechanism of action of toremifene at the level of the central nervous system in advanced breast cancer patients.

PURPOSE: To differentiate the antagonistic and agonistic effect of toremifene at the level of the hypothalamus-hypophysis axis a leutinizing hormone-releasing hormone (LHRH) test was performed during a phase II clinical trial. METHODS: In 15 postmenopausal patients with advanced breast cancer, follicle-stimulating hormone (FSH) and LH release--induced by an LHRH agonist (Suprefact injection, 0.5 mg s.c.)--was monitored during a 16-week period of toremifene treatment (60 mg/day p.o.). Prolactin, estradiol, and sex hormone-binding globulin (SHBG) levels were also measured. The functional test was carried out prior to toremifene therapy and then 4, 8, 12, and 16 weeks afterward. RESULTS: The drug sensitized the pituitary to the action of the gonadotrophins; the LHRH-induced FSH and LH release showed a considerably increasing tendency during the toremifene therapy. Estradiol levels decreased statistically significantly and SHBG levels showed a statistically significant increase. A decreased level of prolactin is the sign of an antiestrogenic effect of toremifene on the hypophysis and, as a result, provides evidence for a direct influence of toremifene upon the pituitary. An increase in LH and prolactin release in response to the LHRH test was characteristic in the responders. CONCLUSION: According to the LHRH test, the antagonistic effect of toremifene seems to be more dominant than the concomitantly existing agonistic property. Neither clinical nor endocrinological side effects could be observed at the level of the CNS during a prolonged period of toremifene administration.

Pharmacokinetics of panomifene in healthy volunteers at phase I/a study.

Panomifene (PAN) /E/-1,2,-diphenyl-1-[4-[2-(2-hydroxyethylamino)-ethoxy]-phenyl]-3, 3,3-trifluoropropene is a new original Hungarian compound and is a tamoxifen (TMX) analog. In the phase I/a study presented here the human tolerance, pharmacokinetics and endocrine effects of a single oral dose of panomifene were evaluated in healthy, post-menopausal, female volunteers. As to the dose escalation, pharmacokinetic studies were carried out at doses of 24, 48 and 96 mg in two volunteers, and 120 mg in one volunteer. To find a suitable dose or dose range, for further evaluation of the drug detailed pharmacokinetics were performed at a selected dose level (24 mg) in 10 volunteers. The pharmacokinetic study showed considerable interindividual variability of the parameters, and only a medium correlation between dose and AUC (r=0.876). At the selected dose level (24 mg p.o.) the peak concentration of the plasma was 67.7 +/- 17.4 ng/ml (Cmax(meas)), the time to peak was 3.6 +/- 1.8 h (t[max(meas)]). The mean of the terminal half-life was 70.0 +/- 23.1 h (t(1/2beta)). The area under the plasma concentration time curve (AUC) calculated by the kinetic equation (AUCcalc) was 4814 +/- 1172 and by the trapezoidal rule (AUCtrap) was 4612 +/- 1357 (ng/ml) h.

[Steroid hormone receptors in squamous cell carcinoma of the head and neck]. / Szteroidhormon-receptorok vizsgálata fej-nyak laphámrákban szenvedó betegeken.

In this study we have tried to find new prognostic markers to extend the therapeutical modalities for patients with head and neck squamous cell carcinoma. During evolution the development of the pharyngolaryngeal region differs in males and females, therefore this region can be considered as one of the target organs for sex steroids. Some of the tumours, originating from this area, contain hormone receptors that theoretically makes them susceptible for hormone therapy. Therefore the real concentration of steroid receptors is of great clinical importance. We determined the estradiol, progesterone and testosterone receptor content using biochemical method in tumour tissue of 33 male patients with head and neck squamous cell carcinoma. The receptors in the macroscopically intact mucosa in 15 of all tumour cases were also measured. The patients were followed for 18-24 month after operation and postoperative irradiation performed according to the protocol of the Head and Neck Surgery department. There were 26/33 (79%) estradiol receptor positive, 14/33 (42%) progesterone receptor positive and 18/30 (60%) testosterone receptor positive cases among the tumour samples. The healthy mucosa samples were positive in 6/15 (40%), 2/15 (13%) and 3/15 (20%) of cases, respectively. The differences in proportion of positive status between tumour and healthy mucosa was statistically significant. We established that during the control period the highest rate of the tumour-free survival was in the estradiol receptor positive, progesterone receptor negative group. Consequently the steroid receptor status of head and neck squamous cell carcinomas might help in assessing the prognosis of survival, and in possible choice for endocrine treatment, in order to complete the complex tumour therapy.

[Endocrine effect of a new anti-estrogen compound (EGIS-5650, panomifene) in healthy volunteers: phase I/a study]. / Az antisztrogén hatású új vegyület (EGIS-5650, panomifene) endokrin hatásairól egészéges önkénteseken: fázis I/a vizsgálat.

Influence of a new Hungarian antiestrogen, panomifene (PAN) was investigated on some hormone levels of 10 postmenopausal healthy women during a partially double-blind placebo controlled phase I/a study. Following a single oral administration of PAN serum estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin (PROL) levels were measured by RIA at two selected dose levels: 12 mg and 120 mg. The low dose (12 mg) results in an increased E2 level in some cases probably due to the intrinsic estrogenic (agonistic) character of the drug. The high dose (120 mg) seems to have a strong antiestrogenic (antagonistic) action. FSH and LH changed within the normal postmenopausal range at both doses, PROL slightly decreased at 12 mg dose level. During the 14-day follow up, the 120 mg PAN considerably suppressed the PROL secretion proving the antiestrogenic character of the "high" dose. PAN seems to be a safe tamoxifen analogue, the single oral dose of which does not exert any noteworthy (pathogenic) side effect on some hormone levels of healthy women.

[Hormonal and biochemical characterization of breast cyst fluid in gross cystic mastopathy]. / A nagycisztás mastopathia cisztafolyadékának hormonális és biokémiai jellemzése.

A total of 93 breast cyst fluids (BCF) obtained by needle aspiration of women suffering from gross cystic mastopathy was hormonally investigated. The mean age of the patients was 45 years (range 27-65). Estradiol (E2), progesterone (PROG), testosterone (TE), prolactin (PROL), estriol (E3), dehydroisoandrosterone and its sulfate (DHA, DHA-S) levels were investigated in the BCF and in the respective sera. Tumour marker beta-HCG and CA 15-3 as well as cations (K+, Na+) were determined, too. E2, E3, PROG, TE, PROL, DHA, DHA-S and K+ showed significant accumulation in the BCF compared to the serum values. The K+/Na+ ratio proved to be a useful tool to divide cysts into type I (> or = 1), type II (< 1 but > or = 0.1) and type III (< 0.1) subgroups. In case of type I BCF, higher E2, DHA, DHA-S and PROL levels could be detected, while PROG and TE contents proved to be the highest in type II cysts. These findings indicate that the type I BCF is a marker for "active" GCD of the breast and suggest that it may be associated with increased breast cancer risk. It is suggested therefore when macrocysts are aspirated, sex steroids, steroid hormone precursors and cations in the BCF should be examined routinely, and women with type I cysts should be controlled carefully.

[Clinical significance of steroid receptors in breast cancer]. / Az emlörák szteroid receptorainak klinikai jelentösége.

The steroid receptor determination (first of all estrogen receptor--ER--) of the breast cancer tissue has become an important factor for prognostication and treatment. Authors from the Surgical Department of the National Institute of Oncology provide a biostatistical survey of their 727 breast cancer patients. Following factors proved to have significant impact on the prognosis: positivity of ER, the quantitative value of ER, ER vs. lymph node status, ER vs. DFI, ER and the site of metastases and the hormone therapy. The progesterone receptor (PR) provides indication in case only for DFI for metastases. However, in this very respect it has a more significant value than that of ER. Multidimensional analysis has shown that the most important prognostic factors are the lymph node status, patient's age, size of the tumour and the ER value.

Influence of toremifene on the endocrine regulation in breast cancer patients.

In a combined phase I-II study, the hormonal effects of toremifene (TOR) were investigated in 30 patients. Half of the patients received continuous therapy of TOR 60 mg and half 300 mg of TOR orally daily. Serum concentrations of oestradiol (E2), progesterone (PROG), testosterone (TE), follicle stimulating hormone (FSH), luteinising hormone (LH), prolactin (PRL), human growth hormone (hGH) and sex hormone binding globulin (SHBG) were monitored prior to the treatment and at the second, sixth, eighth and twelfth weeks. The influence of TOR upon the hypothalamo-hypophyseal axis was investigated by the TRH (thyroid-stimulating hormone releasing hormone) functional test using 400 micrograms intravenous injection of TRH for stimulation of PRL secretion. The concentration of E2 decreased during the TOR therapy with 60 mg and 300 mg causing 82 and 71% decreases, respectively (non-significant). PRL was significantly (P < 0.001) suppressed. Both these effects reflect the anti-oestrogenic action of TOR. SHBG increased significantly at both doses of TOR, probably due to a direct oestrogen-like effect of TOR in the liver. TE decreased as a consequence of the elevated SHBG. The TRH-induced PRL release was suppressed by both doses of TOR. There were 17 and 27% reductions at 12 weeks in the 60 and 300 mg groups, respectively. Other hormones measured were not significantly affected by TOR. The hormonal effects of 60 and 300 mg doses of TOR did not differ significantly. Anti-oestrogenic (i.e. decrease of E2), and partially oestrogenic (i.e. increase of SHBG) properties as well as the antiprolactinic effects of TOR may have an overall beneficial effect in the clinical management of breast cancer patients.

Studies on canine mammary tumours. II. Oestradiol and progesterone receptor binding capacity and histological type.

Tissue samples taken from the mammary gland of 42 dogs (age: 6 to 12 years) were examined. Thirty-eight samples showed neoplasia: 36 were epithelial while the remaining 2 proved to be connective tissue tumours. Thirty-four % of the neoplasms were new benign tumours (most frequently adenoma and fibroadenoma) and 66% were malignant ones (mainly adenocarcinoma). The oestrogen receptor (ER) and progesterone receptor (PR) binding capacity was determined on 21 tissue samples using the method of EORTC (1980). The connective tissue tumours and non-tumourous tissues contained no sexual steroid receptor. 71.4% of all tissue samples contained receptors. 61.9% of the samples was ER+, 42.8% was PR+, 33.3% contained both receptors, 28.6% was only ER+ and 9.5% only PR+. The average ER and PR binding capacity was 120.3 (5.0-622.8) and 266.7 (92.3-475.0) fmol/mg cytosol protein, respectively. No difference in receptor positivity was demonstrable between the benign and the malignant tumours. PR negativity accompanied by ER positivity was more common in the case of benign tumours. ER binding capacity tended to be correlated with age: this correlation could be described with a hyperboloid regression curve (r = -0.5931; 0.06 > p > 0.05).

Quality control program of steroid receptor assays: an international study.

Lyophilized calf uterine cytosol standards were prepared for quality control of estrogen receptor (ER) determination, and lyophilized cytosols and tissue powders were used for quality control of progesterone receptor (PR) analysis. Two series of four samples were analyzed either for ER or PR contents, twice within one month, by 7 laboratories in 5 countries. Coefficient of variation (CV) of the between-laboratory averages assayed in a single run of ER-positive (ER+) and PR-positive (PR+) standards varied from 29.6 to 61.8% and from 32.4 to 76.2%, respectively. All laboratories, with the exception of a single value, could recognize samples of low, medium, an high ER level, as well as a negative sample. Most laboratories evaluated properly also the level of PR samples. The average between-laboratory CV values of protein determination in the relevant standards were 23%.

[The anti-estrogenic effect of 4-chloro-1,2-diphenyl-1-(4-[2-(N,N-dimethylamino)ethoxy]phenyl)1-butene (Toremifene) on the endocrine regulation in breast cancer patients]. / Az antiösztrogén hatású 4-kloro-1,2-difenil-1-(4-[2-(N,N-dimetilamino)etoxi]fenil)-1-butén (Toremifene) hatása emlörákos betegek endokrin regulációjára.

In a combined phase I-II study the hormonal effects of Toremifene were investigated in 15-15 patients at two dose levels: 60 mg and 300 mg per os, daily. Serum estradiol, progesterone, testosterone, follicle-stimulating hormone, luteinizing hormone, prolactin, human growth hormone were monitored by radioimmunoassay and sexual hormone binding globulin by immunoradiometric assay prior to treatment and at the 2nd, 8th and 12th weeks. The influence of Toremifene upon the hypothalamo-hypophyseal axis was also controlled by a tirotropin releasing hormone functional test using 400 micrograms tirotropin releasing hormone injection iv. Estradiol, progesterone, follicle-stimulating hormone, luteinizing hormone and prolactin decreased proving the antiestrogenic activity of the drug. Sexual hormone binding globulin significantly (p less than 0.002) increased by week 12 at both doses, probably due to a direct effect of Toremifene upon the liver. The increase in sexual hormone binding globulin suggests the partial estrogenic effect of the drug. The tirotropin releasing hormone induced prolactin release was also suppressed. On the basis of hormonal changes and the clinical response of patients 60 mg of Toremifene proved to be as effective as 300 mg.

Influence of luteinizing hormone-releasing hormone agonists on human mammary carcinoma cell lines and their xenografts.

The specific binding of luteinizing hormone-releasing hormone (LH-RH) agonist in estradiol-dependent MCF-7 and estradiol-independent MDA-MB-231 human breast cancer cells has been studied using [3H]Ovurelin [(D-3H-Phe6),des-Gly10-LH-RH- ethylamide]. The results of Scatchard analyses suggest the presence of a single class of receptor sites, both in cell suspensions and membrane fractions. Evaluation of these peptide receptors appears to reflect additional characteristics of biological behaviour of these human breast cancer cells. The synthetic LH-RH agonist Ovurelin [(D-Phe6),des-Gly10-LH-RH-ethylamide] can directly interfere (25-30%) with the proliferation of MDA-MB-231 human breast cancer cells in culture. The inhibitory effect of Ovurelin in vitro was negligible in the MCF-7 cell line. In the in vivo experiments the treated immunosuppressed mice bearing either MCF-7 or MDA-MB-231 xenografts responded to the high-dose LH-RH analogue Zoladex depot and Decapeptyl depot therapy. Since the MDA-MB-231 tumour was found to be ER-negative it seems possible that the regression of this xenograft results from the direct antitumor action of the LH-RH agonist.

Effect of toremifene in breast cancer patients. Preliminary communication.

Toremifene, an antiestrogenic drug administered at three dose levels (60, 120, and 300 mg/day) was investigated in 17 postmenopausal patients with advanced breast cancer previously treated with hormonal and/or cytostatic therapy. The drug proved to be well tolerated at all dose levels without any serious side effects even on prolonged administration. Neither response nor side effects have shown any dose dependency in this small group of patients.

Hormonal effects of toremifene in breast cancer patients.

The effect of toremifene treatment on the serum levels of sex steroids (estradiol, progesterone, testosterone), FSH, LH, prolactin, TSH, T3, T4 and SHBG was investigated. Basal prolactin level and the "prolactin reserve capacity" of the hypophysis was also studied by the TRH functional test. Steroid hormone receptors were detected in the patients where a tumor biopsy could be obtained. In a randomized trial patients were treated by 60 and 300 mg of toremifene per os, daily. Hormone levels were assayed prior to treatment and at the 2nd, 6th, 8th and 12th week of tormifene therapy. The hormonal effects of toremifene were the most marked at the 2nd and at the 8th week. Estradiol decreased continuously, SHBG increased slightly and the high initial value of basal prolactin level decreased. The TRH-induced prolactin release was suppressed by tormifene after an 8-week period. No clinical response-related tendency was found.