THE SIGNIFICANCE OF HORMONE RECEPTORS IN MALE BREAST CANCER

Background: Male mammary glands are usually considered a rudimentary organ. However, they may be exposed to similar pathological influences as female breasts. These pathological influences may cause the development of malignant breast tumors. nevertheless, it is a serious problem. According to numerous national cancer registries from around the world, this disease takes 1% on average in the structure of morbidity of malignant neoplasms of this organ in both sexes. Methods: In our study (168 patients) estrogen receptors were positive in the tumors of 75% of patients. The positive rate of progesterone receptors was observed in 44% of patients. The detection rate of steroid hormone receptors in malignant tumors of the male breast ranges from 65 to 100%, depending on the criteria for identifying their positivity level. The hormone therapy in the early and late stages of cancer include antiestrogens, steroid and non-steroid aromatase inhibitors, both as monotherapy and in combination with LHRH-agonists, fulvestrant and other hormonal agents. Results: There was no dependence found between the receptor status of the tumors and the age of patients with breast cancer. Breast cancer in men has a more aggressive course than the same disease in women. This means lower survival rate of male patients, greater number of locally advanced and metastatic cases, with delayed primary treatment, and resistance to treatment compared to female breast cancer patients. The incidence of receptor positive tumors in men does not increase with age, as observed in women with breast cancer. Despite numerous reports on the effectiveness of hormone therapy in men with breast cancer, many aspects of this type of therapy remain largely unexplained. Conclusions: Hormone therapy appears the most effective in patients with the so-called feminization syndrome, which includes signs of hyperestrogenemia, as well as in patients with multiple unfavorable prognostic signs (stage III of cancer, low differentiation of tumor cells, status of regional lymph nodes N2-3, medium, severe and morbid obesity). Orchiectomy does not increase the survival rate, therefore, its application is impractical.


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Male mammary glands are usually considered a rudimentary organ. However, they may be exposed to similar pathological influences as female breasts.
These pathological influences may cause the development of malignant breast tumors. Breast cancer in males is a rare disease, nevertheless, it is a serious problem. According to numerous national cancer registries from around the world, this disease takes 1% on average in the structure of morbidity of malignant neoplasms of this organ in both sexes. Thus, breast cancer takes 0.2% on average in the structure of the incidence of malignant neoplasms in men. The analysis of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) 1 data indicates an increase in the incidence of male breast cancer by 26% over the 30-year period since 1983. The mortality rate has remained relatively stable since 1975.
Today, many aspects of male breast cancer remain unexplored. The reason is that the information about the disease in question is based mainly on the retrospective analysis of small groups. Clearly, a prospective study of this problematic issue is associated with certain difficulties. These are, first of all, a considerable period of time necessary to accrue the sufficient number of patients with this rare nosological form, as well as changes in approaches to diagnosis and treatment observed in the long process of the examination of patients. Meanwhile, the treatment of males who developed breast cancer, used to be and still is based on the knowledge acquired in the course of the treatment of women with this disease. Testosterone is a powerful anabolic hormone whose concentration in blood plasma is low before puberty. With the beginning of puberty the amount of this hormone increases rapidly and reaches the normal adult male level.
There may be some decline in testosterone levels as males age. The body of a healthy male produces up to 7 mg (7000 µg) of testosterone per day, of which approximately 0.25% is transformed into estradiol. For comparison, an adult female produces up to 0.5 mg (500 µg) of testosterone per day, half the amount of which is transformed into estradiol. One of the ways of testosterone metabolism is the aromatase enzyme in peripheral tissues. As a 5 result of this process, extragonadal production of estrogens increases the production of estrogens in healthy males, in females of menopausal age and in certain pathological conditions. Estrogens in the male body are represented mostly by estradiol which is present in the blood plasma of healthy males in small concentrations. About testosterone, cortisol and neurosteroids. Progesterone inhibits the conversion process of testosterone, which, in turn, reduces the risk of benign hyperplasia and prostate cancer. In addition, progestrerone is a hormone that counteracts estrogen. Therefore, progesterone may moderate the effects of other female sex hormones in males with elevated estrogen levels due to feminization syndrome. 6 Progesterone inhibits monoamine oxidase which is an enzyme responsible for the breakdown of serotonin. It also improves the function of serotonin receptor in the brain, and its too high or low levels may cause serious problems in the chemical processes in the brain.
Sex hormone binding globulin (SHBG) binds testosterone and estradiol in plasma, but has a greater affinity to testosterone. SHBG concentration in male plasma is approximately 2 times higher than in females. The normal concentration of free testosterone in males is 1-2% of the total testosterone level. Changing the concentration of transport proteins, this ratio may change, therefore it is advisable to examine the level of SHBG in addition to measuring total testosterone. Free androgen index (FAI) is calculated as the ratio of the molar concentration of total testosterone to the SHBG molar concentration, expressed in percentage, correlates with the content of bioligically available free testosterone and is used as an informative marker of androgen status. If the SHBG concentraion decreases, the ratio of free testosterone to free estradiol increases, although there is absolute increase in the concentrations of both hormones. If the SHBG concentration increases, the ratio of free testosterone to free estradiol decreases. Thus, in both sexes high SHBG concentration results in enhancement of estrogen effects, while low SHBG concentration enhances androgen effects. Among all pathological processes in male mammary glands the development of breast cancer is of greatest importance. This problem has been studied insufficiently due to the rarity of the disease. Table 2 shows the reasons that can lead to breast cancer in men. Breast cancer in the family 4,6,7,19 Jewish origin 5,6,25,32 Effects of ionizing radiation 8,9 Elevated levels of female sex hormones 4,10,11,15 Threats related to professional activities: employment in the production of soaps and perfumes 4,13 performing work in hot shops, steel mills and blast fumaces 6,13,14 activities related to electromagnetic fields 6,13,14 harmful effects of petroleum on workers of petrol stations and car service stations 6,13,18 Reduced testicular function due to: post mumps orchitis 4,6,18 incorrect plastic of hernial ring in the inguinal hernia 6,18 cryptorchidism 4, 6, 18 -Klinefelter syndrome 17,18 Hyperprolactinemia due to: head trauma 6,18 prolactinoma 6, 18 use of medicines that increase the levels of prolactin in the blood 6,18 Peutz-Jeghers syndrome 20 Gynecomastia 17,22 Excess weight from an early age 23, 24, 26 9 As shown in Table 2, if we discard some genetic aspects and external influences (for example, ionizing radiation), the risk of developing breast cancer in men can increase due to the so-called feminization, which may be a result of both genetic influence and the unfavorable effects of the environment 10,15 . It concerns, first of all, men with testicular dysfunction, often caused by orchitis, for example. Increased risk of developing breast cancer in men is also associated with reduced testicular function due to incorrect plastic of hernia gate. Bilateral cryptorchidism also increases the threat of this disease 13,17 . The established causative link between breast cancer in men and Klinefelter's syndrome 17,18 (chromosomal disease in men caused by sex chromosome polysomy, characterized by primary hypogonadism, oligo-and azoospermia and eunochoidism). Such pathological conditions, as a rule, result in reduction or decline in testosterone levels that causes imbalance in estrogens-androgens ratio in the male body 22 . Similar imbalance of male and female sex hormones occurs in chronic liver diseases, for example, cirrhosis.
In this case, the level of estrogens increases due to insufficient estrogen disintegration 11 . Men who take estrogen for medical reasons also run the risk of developing breast cancer 12 .
Additional risk of breast cancer occurs for men in certain occupations, in particular, those exposed to constant overheating. Permanent long overheating can result in testicular dysfunction and reduced testosterone levels 6, 13, 14 .

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The relation of breast cancer to gynecomastia is controversial, but probable as gynecomastia is one of the manifestations of the above mentioned feminization 23,24,26 .

Hormone receptors in males within the normal range and in cancer
The first predictive molecular markers for breast cancer in women were estrogen receptors (ER) and progesterone receptors (PR). They are proteins that specifically bind these steroid hormones and then induce the In malignant tumors of male mammary glands the levels of hormone receptors is higher on average than in female malignant breast tumors 35 . This primarily concerns increased levels of estrogen and progesterone receptors.
Clinically significant levels of hormone receptors are found in over 85% of male breast tumors. Notably, the incidence of receptor positive tumors in men 13 does not increase with age, in contrast to women with breast cancer. The detection rate of receptor-positive tumors in men of any age group is roughly comparable with that of women at postmenopausal age. 13,14,18,31,35,38 S. Joslyn 32  With such consistently high levels of steroid hormone receptors found in men with breast cancer, it seems logical to assume that the application of antiestrogens and aromatase inhibitors, as well as orchiectomy (similar to ovariectomy in women) will have the most effective therapeutic effect on the pathological process. These approaches express a general tendency to extrapolate the knowledge acquired in the course of treatment of breast cancer in women on breast cancer pathology in men.
Chronologically, orchiectomy was the earliest hormone therapy of breast cancer in men. It was applied until about early 1970s on many patients along with surgery and radiation therapy. However, further studies showed that it did not result in higher survival rates of patients with breast cancer.
Since the beginning of tamoxifen era, this drug was tested for the treatment of male breast cancer. According to P.Borgen 45  Because of the low efficiency of orchiectomy, tamoxifen is used the standard modern hormone treatment of this disease. 39 On the other hand, Z.Nahleh 50 (2006) questions the effectiveness of hormone therapy in breast cancer patients due to biological differences between breast cancer in men and women. According to Z.Nahleh, these differences, especially concern the role of estrogens and male sex hormones in the pathogenesis of the disease. The author also claims that it is questionable that the positivity of steroid hormone receptors in malignant tumors of the male breast has the same prognostic value as in those occurring in women. Although current use of tamoxifen in breast cancer of men is accepted, the problem of hormone therapy for this disease, according to Z.Nahleh, needs further study.
R.Gennari et al. 51 (2004) also support the view that extrapolation of the principles of hormone treatment of breast cancer in women on male breast cancer is inappropriate. Attention is drawn to significant biological differences between male and female malignant breast tumors. According to the authors, although male patients with breast cancer recorded positive response to antiestrogens in some cases, the optimal regimen of hormone therapy for this disease is still unknown.

Methods
The study included 168 patients with breast cancer who were examined and treated at the Transcarpathian Regional Oncology Center, the Institute of

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There was no dependence found between the receptor status of the tumors and the age of patients with breast cancer. The analysis of survival of patients with different receptor status of the tumor has shown that there is no relationship between the levels of estrogen and progesterone receptors and life expectancy of patients with male breast cancer.
Thus, the level of steroid hormone receptors in male breast cancer is not a valid prognostic sign of survival and the metastasis free period in these patients. On the basis of a multifactor analysis by Cox regression method, it has been found that the most significant impact on the survival of men who have breast cancer has the status of regional lymph nodes (category N; Table   3). According to our data, in the group of patients with the positive receptor status of the tumor the use of antiestrogens did not have a statistically significant effect on the survival and the duration of metastasis free period without recurrence as compared to the patients who did not receive this type of hormone therapy.
The multifactor analysis of the effect of methods of treatment on the survival of patients with male breast cancer by the method of Cox regression has revealed that hormone therapy by antiestrogens does not have a statistically significant effect on the cumulative survival of patients with male breast cancer (Table 4). The results given refer to the total number of patients. To identify the impact of different methods of treatment on the survival rate of patients with unfavorable prognostic signs, a group of patients with the following 22 characteristics was formed: the third stage of the disease; N2-3; 2-nd and 3rd degree of malignant tumors (G2 -G3); medium, severe and morbid obesity. The summary of multifactor analysis by Cox regression are shown in Table 5. As we can see, for this group of patients hormone therapy by antiestrogens has become statistically significant (р = 0.038). Orchiectomy, chemotherapy and surgery had little or no effect in these cases.  However, all thee reports are based on a small number of cases.
Breast cancer in men has a more aggressive course than the same disease in women. This means lower survival rate of male patients, greater number of locally advanced and metastatic cases, with delayed primary treatment, and resistance to treatment compared to female breast cancer patients. This is primarily due to biological differences between male and female breast cancers. These differences concern different anatomical structure of the male and female breasts, different hormonal backgrounds of

Conclusions
Hormone therapy appears the most effective in patients with the so-called feminization syndrome, which includes signs of hyperestrogenemia, as well as in patients with multiple unfavorable prognostic signs (stage III of cancer, low differentiation of tumor cells, status of regional lymph nodes N2-3, 27 medium, severe and morbid obesity). Orchiectomy does not increase the survival rate, therefore, its application is impractical. This retrospective study meets ethical standards of the Uzhhorod National University EC\IRB as is recognized by its approval number 25643.

Concent for publication
Not applicable as this is a retrospective chart review.