[Oncoendocrinology: interim results and new challenges].

Over the few past years there have been passed many significant and positive changes in various fields of oncology due to both the use of achievements, stimulated by previous generations, and the progress of modern technology. This largely concerns endocrinology of malignant tumors, which is reflected in this article on the basis of the experience of the N.N.Petrov Research Institute of Oncology gained during recent times. Above all it is about the features of tumors of hormone-dependent tissues, hormonal and metabolic shifts, associated with them, and the ways of their correction based on the principles of personalized medicine.

[Ovarian cysts and hyperestrogenia as a result of treatment with tamoxifen in breast cancer patients of reproductive age].

There is considered one of the side effects of tamoxifen - the formation of ovarian cysts associated by also excessive production of estradiol. Data on likely mechanism of development of hyperestrogenia and its possible influence on anti-tumor effect of tamoxifen are presented.

[Evaluation of ovarian status in women who received anti-tumor therapy in childhood and adolescence].

The paper presents the results of a study of the ovarian reserve in young women who received treatment for malignant tumors in childhood and adolescence and are in complete clinical remission. The function of the reproductive system was evaluated by serum concentrations of gonadotropins, estradiol, anti-Müllerian hormone (AMH) and inhibin B. The results were compared to the treatment, patients' age at the beginning of therapy and at the time of the examination. AMH level in serum was the most informative indicator of ovarian reserve in patients treated for malignant tumors.

[Microviscosity of erythrocyte membranes in breast cancer patients: connection with the receptor phenotype of the tumor].

The state of the viscosity of erythrocyte membranes in breast cancer patients (68--in menopause and 32--with menstrual cycle) was studied in comparison with the content of steroid hormone receptors in the tumor tissue and the age of patients. It is showed that the less hormone dependence of the tumor the higher viscosity of erythrocyte membranes that manifested by a decrease in the coefficient of eximerization (CE) of pyrene in the protein/lipid and in particular, lipid/lipid membrane layers. Increasing CE of pyrene in lipid/lipid layer of erythrocyte membranes above 1.7 units, reflecting a decline in their microviscosity, could be considered as an additional extra-tumor criterion for identification of the tumor as of hormone dependent type.

[Family diabetes and its consequences in cancer patients].

Preliminary data are confirmed on the more rare prevalence of family history of diabetes mellitus (DM) in cancer patients, mainly females, with diabetes in comparison with diabetics without cancer pathology. Familial diabetes does not worsen additionally tumor characteristics against the same in patients with non-familial diabetes. More than that, familial diabetes in diabetics with breast cancer goes together with lesser size of tumor and demonstrates an inclination to the rarer distant metastases in breast and endometrial cancer patients. The signs of systemic DNA damage (evaluated, in particular, on the basis of 8-OH-dG serum levels) are pronounced in postmenopausal diabetic cancer patients with familial diabetes in lesser degree than in non-familial variant of DM. In toto, this allows to consider family history of DM in patients with type-2 diabetes as a particular factor of tumor growth containment, which mechanisms and causes, warrant further studies.

[Hormonal-metabolic pattern of postmenopausal females with new onset of diabetes mellitus type 2: the role of cancer and hereditary predisposition to diabetes].

85 females were studied, 35 females had new onset of diabetes (DM2) and in 50 women DM2 was associated with recently diagnosed cancer (C+DM2). Group C+DM2 was characterized by higher levels ofbody mass index, insulinemia, estradiolemia, interleukin 6 in serum, and glyoxalase I activity in mononuclears. At the same time patients in C+DM2 group who had familial predisposition to DM2 were characterized by lower body mass index, body fat content, waist circumference, insulinemia, serum interleukin 6, viscosity of erythrocyte membranes and percent of comets in mononuclears in comparison with patients without familial predisposition to DM2. These trends were mostly opposite to the data of subgroups comparison (with or without relatives with DM2) in females with DM2 without cancer. The conclusion is made that the hereditary load with DM2 is differently realized in diabetics with higher or lower predisprosition to cancer that deserves further study.

[Decrease of testosterone level in blood of breast cancer patients of reproductive age after neoadjuvant chemotherapy].

Of examined 37 breast cancer patients (average age 42,3 +/- 1,2 years) 25 had not had any specific therapy by the date of investigation and the rest 12 had received in average 5,3 +/- 0,6 cycles of neoadjuvant chemotherapy mainly TAC and FAC. It was revealed that such kind of treatment conformed to valid decrease of both testosterone level and ratio value [(testosterone concentration/follicle stimulating hormone concentration, FSH) x 100] in blood serum. Testosterone level in blood of patients in fact decreased to similar values both in amenorrhea induced by adjuvant chemotherapy and saving menorrhea. This is a confirmation that maintenance of menorrhea does not mean intactness of ovarian function (ovarian reserve) and indicates that evaluation of testosteronemia in these circumstance at least does not give in estimation of estradiol and FSH's content in blood. Further attention could be paid to study testosteronemia before and after neoadjuvant chemotherapy as a potential additional prognostic factor of efficacy of this treatment for breast cancer patients.

[Effect of previous diabetes therapy on tumor receptor phenotype in breast cancer: comparison of metformin and sulphonylurea derivatives].

According to some existing data, unlike sulphonylurea (SU) and insulin derivatives, treatment with biguanide metformin, for reasons still unknown, may diminish breast cancer (BC) morbidity in diabetic females. For its part, diabetes is known to worsen survival of BC patients although there is no evidence of a pathway by which antidiabetic therapy might influence the key prognostic feature of BC tissue--the tumor receptor phenotype. Combination of BC and diabetes (n=90) was studied. SU drugs were received for at least 12 months by 22 patients, biguanide metformin alone or in conjunction with SU by 15, insulin by 5, and dietary treatment alone--by 48 pts. Percentage of estrogen receptor-positive tumors did not vary significantly from group to group. However, progesterone receptor-positive (PR+) tumors in metformin-treated patients were revealed more often than in those receiving SU alone (p = 0.43) or with insulin (p = 0.041), respectively. Hence, previous treatment with metformin is expected lead to higher incidence of PR+ tumors which in turn may stimulate efficiency of hormonal therapy only in relevant group of diabetic BC patients.

[Progenotoxic shift in mammary adipose tissue (adipogenotoxicosis): association with clinical and biological characteristics of breast cancer].

The study is concerned with identification of a relationship between levels of production and accumulation of compounds capable of hormonal and progenotoxic effects in mammary fat, on the one hand, and characteristics of tumor tissue in breast cancer, on the other. Mammary fat was sampled at a distance of 1.5-2 cm from tumor edge (79 pts.). Case histories were used to provide data on clinical stage, size, grade and regional lymph node involvement. Levels were assayed of leptin, adiponectin, tumor necrosis factor (TNF-alpha), interleukin-6 (IL-6), nitric oxide (NO), thiobarbiturate-reactive products (TBRP) and DNA oxidative damage marker (8-OH-dG) from 4hr-incubates of fat tissue culture. Mammary fat aromatase was assayed by radiometrical means while macrophage-assisted fat infiltration (CD68) and estrogen-4-hydroxylase (CYP1B1) expression were evaluated immunohistochemically. Radio-competitive and immunohistochemical methods were used to assay estrogen (ER) and progesterone (PR) receptor levels in tumor and tumor-related expression of cytokeratins 5/6 ("basal") and 7/8 ("luminal" epithelium), respectively. As far as hormonal properties of mammary fat were concerned, there were direct correlations between aromatase concentration, on the one hand, and tumor stage and size, on the other, and adiponectin secretion and CK7 expression in tumor. Besides, an inverse correlation was found between mammary fat-mediated release of leptin and adiponectin, on the one hand, and stage and regional lymph node involvement, on the other. The following main relationships were identified by comparison of the clinico-biological characteristics of tumor and markers of proinflammatory/progenotoxic properties of mammary adipose tissue: tendency toward direct correlation with IL-6 and 8-OH-dG in fat (tumor progress stage); direct correlation with TNF-alpha secretion rate (malignancy grade); lymph node involvement--tendency toward direct correlation with NO generation; CK5 expression in tumor--tendency toward direct correlation with 8-OH-dG, TBRP and CD68 fat infiltration; CK7 expression in tumor--tendency toward inverse correlation with NO generation in adipose tissue; ER-negative phenotype of tumor--tendency toward higher generation of TBRP, NO and TNF/leptin in fat. Hence, shift toward predominance of proinflammatory/progenotoxic properties of mammary adipose tissue (adipogenotoxicosis) is associated with signs of less favorable course of tumor process in the mammary gland which calls for working out adequate measures.

[Gail coefficient as a risk factor and prognosticator for the course of breast cancer: correlation with hormonal and metabolic parameters and clinical and morphologic features].

Gail coefficient (GC) generally used in breast cancer predictions for the next 5 year--or entire survival was determined in both patients and healthy controls of the same age, residents of St. Petersburg. Simultaneously, a correlation was established with hormono-metabolic indices, receptor pattern, tumor stage and size and some other characteristics. GC in cancer patients with age <50 was significantly higher than in control. In menopausal cancer patients, greater GC correlated with such parameters as body mass, weight index, glucose, total cholesterol and low density lipoproteids after fasting. The latter group showed a tendency towards enhanced estradiol and testosterone in blood serum. In reproductive patients with elevated GC, estradiol level rise was significantly lower and most tumors were receptor-negative. However, involvement of regional nodes was relatively rare. To summarize, GC determination characterizes risk and certain clinico-morphological features of distinction between reproductive and menopausal patients.

[Endocrine-genotoxic switchings as promoter of main noninfectious diseases].

Peculiarities of the incidence and spread of main non-infectious diseases (MNID) are in one or another way connected with the conception of "normal" and "successful" aging. The age-related increase in the frequency of MNID, associated with estrogen deficiency or excess, can be explained by the presence of estrogen effect switching phenomenon. The increase in the genotoxic effect of estrogens, isolated or combined with the weakening of the hormonal effect, can worsen the clinical course of MNID (including malignant tumors of hormone-dependent tissues). The effects of two other endocrine-genotoxic switchings (the joker function of glucose and adipogenotoxicosis) may realize in the same direction. The three mentioned phenomena form the so called basic triad, separate elements of which can interact. Endocrine-genotoxic switchings and their inductors are targets for prophylactic measures and, possibly, therapeutic ones. Both approaches may be divided into several groups with different points of application, whereas their ultimate goal is optimal balance between hormonal and DNA-damaging effects of estrogens, glucose, and adipose tissue-associated factors.

[Estrogen-dependence of thyroid carcinoma: testing with estradiol preparations and tamoxifen].

Twenty-four patients with thyroid carcinoma receiving thyroxine were examined. The thyroid gland had been extirpated in 20; hemithyreoidectomy (4). Tests with ethinyl estradiol (50 mcg, per os, 6 days) (8), estradiol valerate (2 mg, per os, 12 days) (10), and tamoxifen (40 mg, per os, 14 days) (6) were carried out on the assumption of normal and neoplastic thyroid epithelium sensitivity to estrogen stimulation. Blood thyroglobulin, TSH and estradiol levels were assayed before and after loading. Thyroglobulin concentrations increased in 5 out of 24 patients (ethinyl estradiol--1 out of 8, estradiol valerate--2 out of 10 and tamoxifen--2 out of 6); those of TSH--in 6 out 24 (3 out of 8, 2 out of 10 and 1 out of 6, respectively). Enhanced thyroglobulin correlated with higher levels of TSH in 2 out of 5 and with blood-estradiol--in 4 out of 5. It was suggested that at least, in some patients, the preparations might produce a direct stimulating effect on thyroglobulin biosynthesis in the thyroid tissue remnants. Further research is suggested or on whether tamoxifen exerts pro- or antiestrogenic influence on thyroid epithelium.

[Hormonal and progenotoxic properties of mammary fat in pre- and postmenopausal cancer patients].

Since breast cancer may emerge both before and after menopause onset, relevant forms of the disease show marked biological and clinical differences. Intrinsic properties of mammary fat located in the vicinity of tumor, which play a definitive role in stromal-epithelial interactions, are an important factor of development of such differences. The DNA damage promoting hormonal (leptin and adiponectin production, aromatase activity) and progenotoxic. The properties of mammary fat such as formation of tumor necrosis factor, interleukin-6, nitric oxide, malonic aldehyde, macrophage/histiocyte infiltration and estrogen 4-hydroxylase expression, were studied in mammary fat tissue of 95 patients with receptor-positive or receptor-negative breast tumors (reproductive--25, menopausal--70). It was found that progenotoxic properties might somewhat predominate, as far as differences in parameters and pathways are concerned, both in menopausal and still cycling patients. Hence, progenotoxic damage which represents mammary fat tissue status is perhaps modified by a number of genetic and mitochondrial factors. It may exert unfavorable effect on the course of the disease within a fairly wide period.

Genotoxic factors associated with the development of receptor-negative breast cancer: potential role of the phenomenon of switching of estrogen effects.

AIM: About 30-40% of breast cancers lack steroid receptors (ER and/or PR) at diagnosis that worsen prognosis and limit the usage of hormone therapy. The aim of this paper has been to study the role of DNA-damaging factors as the potential modifiers of the receptor-negative tumors incidence. MATERIALS AND METHODS: The investigation consisted of two principal parts. In one of them ER and PR content was measured in breast cancer samples from 2284 primary patients (350 of them - current or previous smokers). In separately studied subgroup of 1010 patients 95 suffered with diabetes mellitus type II. RESULTS: As it was shown, smokers and diabetics carry more frequently (p = or < 0.05) tumors with phenotypes ER+PR- and PR- only in the group of women with conserved menstrual cycle that is in case of relatively higher estrogenic stimulation. In another part of the investigation immunohistochemical study of DNA damage marker - 8-hydroxy-2-deoxyguanosine (8-OH-dG) in 16 R(-) and 18 R(+) breast cancer specimens demonstrated more frequent positive staining in the former group of samples (p = 0.05). Besides, as it was revealed in breast cancer cell line MCF-7 the combination of estradiol with aryl hydrocarbonic receptors agonist beta-naphtoflavone induced pronounced genotoxic damage (by 8-OH-dG content) in association with the loss of ER. CONCLUSION: Thus, pro-genotoxic status (smoking, diabetes) and direct signs of genotoxic injury, in accordance with regularities of the phenomenon of switching of estrogen effects can be reckoned among the factors promoting the development of receptor-negative breast cancer.

[Correlation of hormone-metabolic status in breast cancer and effectiveness of adjuvant hormone therapy].

Hormono-metabolic status was assayed before and after month 6, 12, 24, 36, 48, 54 and 60 of therapy in 72 patients with receptor-positive tumors of the breast who completed 5 years of adjuvant tamoxifen (20 mg/24 hrs) or letrozole (2.5 mg/24 hrs). Eleven patients were not followed up, 11 relapsed and had metastases while 50 completed therapy. Significant fall in body mass (Ketle's index), in C-peptide concentration after an insignificant rise and C-peptide/insulin ratio 129 min after glucose loading, low basal blood level of estradiol as well as stable estradiolemia throughout treatment were characteristic of cases of pre-treatment recurrence and metastastic spread. Insulin resistance status, basal serum-estradiol level and fasting its course of development during hormonotherapy should be the subject of further research in criteria for adjuvant hormonotherapy efficacy.

Content of 8-hydroxy-2-deoxyguanosine in steroid receptor-positive and receptor-negative breast cancer cells.

The content of DNA damage marker 8-hydroxy-2-deoxyguanosine in 16 receptor-negative and 18 receptor-positive human breast neoplasms was measured by immunohistochemical methods. Positive staining was revealed in 81.3 and 50.0% samples of groups 1 and 2, respectively. The effect of arylhydrocarbon receptor agonist beta-naphthoflavone on the content of 8-hydroxy-2-deoxyguanosine and number of estrogen and progesterone receptors was evaluated in MCF-7 breast cancer cells. The degree of genotoxic damage significantly increased 1 h after combined treatment with estradiol and beta-naphthoflavone (in contrast to individual treatment) and remained practically unchanged in the follow-up period. According to the estrogen effect-switching phenomenon, genotoxic damage can contribute to the development of R(-)-breast cancer.

[Breast cancer receptor status in smoking and diabetic patients].

Estrogen (ER) and progesterone (PR) receptor levels were assayed in 2,284 primary breast cancer patients who either smoked (350) or suffered diabetes mellitus type 2 (1997-2003). In a group of 1010, 95 patients had diabetes mellitus type 2 whereas 393--such signs of cardiovascular pathology as atherosclerosis, arterial hypertension and ischemic heart disease (2000-2003). Among the premenopausal smokers, the ER+PR-phenotype predominated (t = 2.18, p < 0.05) as well as among the diabetics (t = 2.01, p < 0.05). In reproductive diabetics, the share of PR- tumors was significantly higher than in diabetes-free patients (t = 2.17, p < 0.05). There was no correlation between diabetes and the tumor receptor phenotype in the menopausal group, while ER + tumors--occurred more frequently in smokers (t = 2.33, p = 0.02). There was no link between cardiovascular pathology and receptor status in either of the age groups. Hence, the increasing proportion of ER + PR--tumors in smokers and diabetes mellitus patients occurs in a random manner in menstruating women, which is associated with elevated estrogenemia. This indicates the phenomenon of switching of estrogen effects involving disturbed transduction of estrogen signals.

[Comparison of letrozole and exemestane used in non-adjuvant therapy of endometrial carcinoma].

The clinical and endocrine-related effects of 2-week preoperative treatment of endometrial carcinoma patients with a non-steroid inhibitor of letrozole aromatase (femara 2.5 mg/day, n=10) and a steroid inactivator of the enzyme (exemestane 25 mg/day, n=13) were compared. In the first group, pain relief in the lower part of the belly and/or decreased uterine discharge were reported in two cases, as well as a 31% drop in the mean endometrial M-echo (ultrasound) signal. In the exemestane group, two patients revealed moderate uterine discharge decrease matched by a 15.6% decrease in M-signal intensity; no tumor was detected in another patient on completion of the course. Letrozole effect was relatively greater when such parameters as tumor-tissue aromatase level, estrogen concentration in vaginal smear and blood-cholesterol, FSH and LH levels were taken into consideration. However, exemestane therapy involved a relatively sharper drop in the levels of tumor receptors of progesterone and a significantly higher estrogen/progesterone receptor ratio. Hence, no matter how short treatment duration was, both steroid and non-steroid aromatase inhibitors induced effects predominantly associated with lowering estrogen production in endometrial carcinoma patients. This makes a case for further clinical trials of these drugs to deal with the pathology.