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Almuradova Dilbar Muradovna, Assistant of Department of Oncology and Radiation Diagnosis of Tashkent Medical Academy, Uzbekistan Atakhanova Nigora Ergashevna, Head of Department of Oncology and Radiation Diagnosis of Tashkent Medical Academy, Uzbekistan E-mail: evovision@bk.ru
THE IMPORTANCE OF ANDROGEN RECEPTORS AS A FACTOR OF PROGNOSIS IN TRIPLE NEGATIVE BREAST CANCER
Abstract: Triple negative breast cancer (TNBC), in which tumor cells do not express estrogen and progesterone receptors and do not contain amplification sites for the Her-2 / neu gene, has attracted the attention of an increasing number of researchers in the field of both clinical and theoretical oncology in recent years, and this is not surprising. Triple negative breast cancer (TNBC) is approximately 15% -20% of all diagnosed breast cancers and is characterized by a lack of expression of estrogen receptor (ER), progesterone receptor (PR), and lack of expression of the human epidermal growth factor protein (HER2) squirrel. The heterogeneity of the triple negative breast cancer is the main obstacle in the treatment of this tumor subtype. Although the estrogen receptor (ER) and the human epidermal growth factor receptor (HER2) are the main therapeutic targets in breast cancer, the androgen receptor (AR) has been recent developed as a molecular target in the treatment of tumors resistant to standard therapies.
Keywords: triple negative breast cancer, histological subtypes, androgen receptors, prognosis factor.
Breast cancer (breast cancer) is one of the most common forms of cancer in women and one of the main causes of death of women around the world. That is why the search for new ways of treating breast cancer is a paramount task of modern oncology [1-3]. Despite the success of experimental and clinical oncology, breast cancer (breast cancer) remains the most common oncological disease in women. Triple-negative BCs are characterized by the negative estrogen and progesterone receptors and negative HER2, and represent 12-18% of all BCs. Breast cancer is the most common oncological disease in women in the Uzbekistan. The highest standardized incidence rates registered in Tashkent city (22.5%), Navaiy (12.4%), Bukhara (11.1%) and Tashkent regions (11.0% and lowest in Surkhandarya (6.3%) and Kashkadarya (7.5%). (13.2%) than rural (8.5%) [1, 3]. In Russia, at least 54000 new cases of breast cancer are diagnosed every year [4, 7]. The highest rates were recorded in Moscow - 52.3 and St. Petersburg - 48.1 per 100 thousand
women [7-9]. In the United States, in 2013, there were 232, 332 new cases and 39,620 deaths [10, 11]. In the literature, there is an increased interest in the study of androgen receptors (AP) at various molecular subtypes ofbreast cancer (BC), but we have not found a consensus on the effect of androgen levels and their metabolites in biological fluids on the development of triple negative breast cancer [12, 13]. Determining the level of androgen receptors in a tumor in patients with breast cancer is a very relevant and promising direction in studying the prognosis of the disease and finding new additional approaches to endocrine therapy for breast cancer, especially with a basal-like molecular subtype. In the domestic and foreign literature, there has recently been an increased interest in the study of androgen receptors (AP) at various molecular subtypes of breast cancer. There are many publications on the role of androgen receptors in breast tumors, which points to the need for their more thorough research using molecular biological methods,
including IHC [14]. Data on the role of androgen receptors in breast cancer are highly controversial, but the prevailing view is that patients with tumors expressing AR are characterized by a better prognosis of the disease. This suggests that further study ofAP in various biological subtypes of breast cancer should be considered, not only with triply negative breast cancer, but also with lu-minal subtypes.
The aim of the study was to study the incidence of AP in patients with triple negative breast cancer subtypes, to analyze their relationship to the outcome of the disease, and to determine the future prospects of modern and future anti-androgen strategies in the treatment of breast cancer.
Material and methods of research. The analysis of retrospective data of 96 patients with triple negative breast cancer, who were treating during the 2010-2017 years in the departments of the Tashkent City Oncological Dispenser and the Institute of Oncology and Radiology Kazakhstan, studied the levels of expression of AR in triple negative breast cancer. The average follow-up time was 87.9 ± 47.4 months (from 3.4 to 179.2 months, median - 87.9 months). The age of the patients varied from 32 to 67 years (mean age - 49.9 ± 11.5 years, median - 50 years). All patients received combined treatment, only 3% of patients were treating only surgically. All patients were dividing into stages of disease, morphology and malignancy of the tumor in comparison with the expression of androgen receptors and the features of the course of the disease. The greatest number of patients had stage II disease - 37.1%, the average age of patients was 54.8 ± 11.7 years [28]. Based on the results of the morphological investigation, invasive ductal carcinoma G2-3 was diagnosed in 36 (74.4%) cases, invasive lobular carcinoma G2-3 in 34 (10.3%), 11 (10.3%) - medullary (G3) and in 15 (5%) - undifferentiated cancer (G3). the average age of patients is 52.6 ± 11.8 years. Note: in this group of patients, the percentage of detection of the mutation BRCA1 was statistically significant (^2 = 4.87, p = 0.0274) higher than in the group of women without taking into account hereditary burden with diagnosis of breast cancer. Histological three cases of thrice negative breast cancer were evaluated as invasive ductal cancer (1 - G2 and 2 - G3), 1 case - as medullary and 1 - undifferentiated cancer (G3). The stage I disease was not identified,
IIa 11 (11.4%), IIb 18 (18.75%), IIIa 23 (23.95%), IIIb 24 (25.0%), IV 30 (31.25% According to the molecular genetic classification, taking into account the parameters of the receptors of estrogens (RE), progesterone receptors (RP), Her-2 / neu and Ki 67, all patients had triple negative breast cancer.
Statistical analysis of the results of the study was carried out using the analytical package Statistica 7.0. A comparison of the two independent samples by the quantitative trait was made using the Mann-Whitney test, the differences were considered significant at p < 0.05. To compare the frequencies of occurrence of symptoms in different groups, the X test.
Results. In all patients, the expression of androgen receptors was evaluated by an immunohistochemical method on an 8-point scale. In most cases, the level of expression of AR corresponded to 7 points - 47.2% (Table 1). In the absence of AR expression, all patients were in a subgroup with a nonspecific form of breast cancer with grade II or III malignancy.
When analyzing the distribution of patients with triple negative subtypes of breast cancer, it was found that the expression ofAR significantly more often (p = 0.034) was observed in patients with triple negative breast cancer. In a statistical analysis of the survival rates of breast cancer patients, life expectancy was significantly higher (p = 0.007) in patients with high level of AR expression. In patients with high androgen receptor expression, the 5-year survival was 91%, the 10-year survival rate was 83%, respectively. While in the group of patients with breast cancer with a negative value ofAR, the 5-year survival was 33.3% (p = 0.0007), no patient overcame the 10-year line after treatment. Thus, it can be concluded that the absence of AR expression determines a worse prognosis, even in spite of the more favorable molecular subtype of the tumor. Overall survival of breast cancer patients depending on the level of androgen receptor expression as a function of long-term outcomes. AR-status (n = 96) - Negative (n = 44) Positive (n = 52) 1-year survival rate 85.4 ± 2.6%, 3-year survival 56.7 ± 19.2%, 5-year survival 23.3 ± 19.2% median survival, month 39.9. Differences are statistically significant in comparison with the group of patients with AR-negative status (p = 0.007).
Discussion. In recent years, the notion of the features of the biology of breast cancer has expanded sig-
nificantly, and a number of characteristic genetic and crease in the incidence of metastases in the lymph nodes
molecular changes have been identified. Various biologi- [20,21], smaller tumor sizes, higher differentiation [26].
cal indicators that can have a certain prognostic value Perhaps these differences are associated with different
are studied, different markers of good and poor progno- approaches to assessing the positivity of AR expression
sis of the disease are studied in patients suffering from [29]. In contrast, McGhan and co-authors showed that
BC [23, 25]. The authors concluded that the positive AR expression correlates with a higher clinical stage and
effect of positive AR expression could be the result of an increase in the incidence of metastases in the axillary
the androgen receptor inhibition of estrogen receptor lymph nodes [30].
signaling pathways. Similar data were obtained by us, in The conclusion. Patients with negative AP status
particular, in the overwhelming majority of cases in AR had a nonspecific histological form of BC and a grade II
positive patients, breast cancer of stage I and tumors of or III tumor malignancy. In patients with triple-negative
grade II malignancy were determined. The prognostic breast cancer, the level of AR expression is significantly
value of AR has been evaluated in several studies that higher (p = 0.034) compared to other molecular sub-
have yielded conflicting results [24, 26]. For example, types of breast cancer. The long-term survival rates are
Hu and co-authors, analyzing the expression of AP significantly higher in patients with high-grade breast
in 211 cases of TNBC, noted that overall mortality is cancer. AR are a promising factor in predicting the course
higher in the AR negative group [27, 28]. In some AR of breast cancer in all molecular subtypes and can be a
studies, positive TNBC have been characterized by a de- promising target for targeted therapy.
References:
1. Khudaykulov T. K., Khudaykulov A. T. Epidemiological aspects of breast cancer in Uzbekistan // Bulletin of the Tashkent Medical Academy.- 2013.- No. 3.- P. 95-97.
2. de Ruijter T. C., Veeck J., de Hoon J. P., van Engeland M., Tjan-Heijnen V. C. Characteristics of triple-negative breast cancer // J Cancer Res Clin Oncol.- 2011. -Vol. 137.-P. 183-92.
3. Bosch A., Eroles P., Zaragoza R., Vina J. R., Lluch A. Triple negative breast cancer: molecular features, pathogenesis, treatment and current lines of research // Cancer Treat Rev.- 2010.- Vol. 36.- P. 206-15.
4. Dent R., Trudeau M., Pritchard K. I., Hanna W. M., Kahn H. K., Sawka C. A. Triple-negative breast cancer: clinical features and patterns of recurrence // Clin Cancer Res. - 2007. -Vol.13. - P. 4429-34.
5. Metzger-Filho O., Tutt A., de Azambuja E., Saini K. S., VialevG., Loi S. Dissecting the heterogeneity of triple-negative breast cancer // J Clin Oncol.- 2012.- Vol. 30.- P. 1879-87.
6. Jiao Q Wu A., Shao G., Peng H., Wang M., Ji S. The latest progress in research on triple negative breast cancer (TNBC): risk factors, possible therapeutic targets and prognostic markers // J Thorac Dis.- 2014.- Vol.6.-P. 1329-35.
7. McNamara K.M., Yoda T., Takagi K., Miki Y., Suzuk T., Sasano H. Androgen receptor in triple negative breast cancer // J Steroid Biochem Mol Biol.- 2013.- Vol.133.- P. 66-76.
8. McNamara K.M., Moore N. L., Hickey T. E., Sasano H., Tilley W. D. Complexities of androgen receptor signalling in breast cancer // Endocr Relat Cancer.- 2014.- Vol. 21.- P. 161-81.
9. Safarpour D., Pakneshan S., Tavassoli F. A. Androgen receptor (AR) expression in 400 breast carcinomas: is routine AR assessment justified? // Am J Cancer Res.- 2014.- Vol. 4.- P. 353-68.
10. Crown J., O'Shaughnessy J., Gullo G. Emerging targeted therapies in triple-negative breast cancer. Ann Oncol -2012; 23(Suppl 6): vi56-65.
11. Gao W. Androgen receptor as a therapeutic target // Adv. Drug. Deliv. Rev.- 2010.- Vol. 62.- No. 13.- P. 12771284.
12. Hu Z., Fan C., Oh D. S. The molecular portraits of breast tumors are conserved across microarray platforms // BMC Genomics.- 2006.- Vol. 7.- 96 p.
13. Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours - Nature.- 2012.- Vol. 490.- P. 61-70.
14. Lehmann B. D., Bauer J. A., Chen X., Sanders M. E., Chakravarthy A. B., Shyr Y. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies // J Clin Invest.-2011.- Vol. 121.- P. 2750-67.
15. Xu H., Eirew P., Mullaly S. C., Aparicio S. The omics of triple negative breast cancers // Clin Chem.- 2014.- Vol. 60.- P. 122-33.
16. Perou C. M. Molecular stratification oftriple-negative breast cancers // Oncologist.- 2010.- Vol. 15 (Suppl 5).-P. 39-48.
