CC BY
15
Yusupova Dilnoza Bakhtiyarovna, assistant of the oncology department of the Tashkent Medical Academy Mirza Allayarovich Gofur-Okhunov, professor, Head of the Oncology Department of the Institute for Advanced Medical Studies Tashkent Medical Academy, Tashkent E-mail: [email protected]
THE ROLE OF IMMUNOHISTOCHEMISTRY IN THE TREATMENT OF BREAST CANCER IN ELDERLY AND SENILE PATIENTS
Abstract: Currently, there are the following subtypes ofbreast cancer: luminal A, luminal B, triple negative (TH) / basal-like, non-terminal HER2 positive and 5th - "unclassifiable". Such a subdivision into types, having already reached the level of a standard procedure in medical practice, is reflected in the features of the course of the disease, the prognosis and outcome has age priorities.
Keywords: luminal type, breast cancer, elderly and senile age.
Breast cancer (BC) is the 1st among cancer patients, and and age period), it seems that the risk of developing luminal is the 2nd cause of death after cardiovascular disease. Breast carcinomas (both A and B) increases in women who have not cancer is manifested by pronounced heterogeneity, which is given birth, as well as in menopause over the age of 53-55 probably due to the presence or absence of steroid hormone receptors in the tumor, primarily estrogen and progesterone. As might be expected, one of the leading factors among such factors was the age of patients with a boundary, often passing at the turn of the end of the reproductive period and the onset of menopause. According to materials provided by the Danish Breast Cancer Cooperative Group, the frequency of ER + PR + neoplasms (about 63% of all observations) increased steadily with age, showing a transient decrease only in the range of43-47 years. The frequency ofthe opposite, receptor-negative, variant of tumors (ER - PR-), averaging 17.6%, increased to 50 years, after which it remained unchanged. The share of the ER + PR- subtype (on average, 13.9%) grew quite rapidly immediately at the onset of menopause, after which this increase slowed down. In contrast, the incidence of rarely detected ER - PR + tumors (5.6%) increased only until the age of 43-45 years and then decreased.
In a later work, A. Kurianetal (2010) confirmed that the peak of detection of luminal neoplasms occurs in women over the age of 70 years (about 32-35% of tumors of this kind versus 20-23% at the age of 50-59 and 60-69 years). HER2 -positive and triply negative carcinomas, as noted earlier, were characterized by a peak in the range of 40-59 years. Such repeatedly witnessed "linking" to the stages of carcinogenesis, characterized, in particular, by lower or greater estrogen saturation, allows you to refer to information that describes the state of the reproductive function of patients with different subtypes of breast cancer based on anamnestic and epidemio-logical data. Despite the variability (from the ethnic factor
years, and may decrease with prolonged feeding in excess of 6 months. The arrival of menarche earlier than 13 years was associated with cases of breast cancer characterized by HER2 + overexpression, but, unlike the previously expressed point of view, it did not increase, but reduced the risk of occurrence of TN (basal cell) carcinomas. With the same TN breast cancer, the lack of childbirth in history does not affect the degree of risk. Age at first birth older than 30 years, according to recent observations, has little to do with the risk of luminal or TN neoplasms, but it increases the risk of HER2 + breast cancer. That is, it is possible that non-terminal variants of the disease also have a certain hormonal sensitivity and dependence on the hormonal and metabolic status.
The molecular subtype of breast cancer was determined on the basis of gene expression (validated immunohisto-chemical surrogate pane; l) The following subtypes were identified: 1) luminal A-type (ER + and / or the presence of PR +, HER2-, Ki-67 receptors, < 14%); 2) luminal B-type (ER + and / or PR +, HER2-, Ki-67 14%); 3) luminal HER2-type (ER + and / or PR +, HER2 +); 4) HER2-positive type (ER- and PR-, HER2 +); 5) basal-like type (ER-, PR-, HER2-, cytokeratin 5/6 + and / or HER1 +); 6) nonbasic type - (ER-, PR-, HER2-, cytokeratin 5/6- and /or HER1). Tumors with a necrotic factor tumor (TNF) without expression of EGFR and CK 5/6 were classified as non-basaloid with TNF and isolated into a separate group.
Another achievement is based on the involvement in the analysis of the so-called genetic "portraying" (or profiling) of mammary carcinoma tissue. At the same time, using
microarray analysis of complementary DNA in tumor material, the expression of several thousand biologically significant genes was evaluated, processing of which led to the selection of several of the most typical and differing variants. These subtypes: luminal A, luminal B, three times negative (TN)/basal-like, HER2 and 5th - "unclassifiable".
In fact, the classification itself is built on the basis of such characteristics as the progenitor cell (luminal or basal epithelium); the presence or absence in the tumor of steroid receptors and receptors HER2 (ErbB-2) - receptor tyrosine kinase, a member of the family of epidermal growth factor; proliferative potential; the presence or absence of cytokera-tin 5/6, characteristic of myoepithelial (basal) cells. Such a subdivision into types, having already reached the level of a standard procedure in medical practice, is reflected in the features of the course of the disease. For example, according to the cited information, the luminal subtype A is characterized by the best prognosis, the highest survival rate of patients and a rather low frequency of disease return, and vice versa, triple negative breast cancer is characterized by high malignancy, aggressive course of the disease and an unsatisfactory response to standard therapy. The luminal subtype B is closer in this respect to the luminal subtype A, and the subtype with overexpression of HER2 is closer to TH.
According to materials provided by the Danish Breast Cancer Cooperative Group, the frequency of ER + PR + neoplasms (about 63% of all observations) increased steadily with age, showing a transient decrease only in the range of 43-47 years. The frequency of the opposite, negative receptor, variant of tumors (ER - PR-), averaging 17.6%, increased to 50 years, after which it remained unchanged. The share of the ER + PR-subtype (on average, 13.9%) grew quite rapidly immediately at the onset of menopause, after which this increase slowed down. In contrast, the incidence of rarely detected ER - PR + tumors (5.6%) increased only until the age of 43-45 years and then decreased [1].
A number of other works of this kind have been considered by W. Andersonetal. (2006) not so much as a reflection of bimodality in the age-dependent distribution of the frequency of breast cancer, but rather as confirmation of a longstanding viewpoint on the existence of two main forms of the disease: pre- and postmenopausal, differing primarily in their estrogen dependence. As additional evidence, the authors relied on data on the distribution of individual morphological variants of mammary gland tumors by age group, showing that intraductal, tubular and lobular carcinomas are characterized in this regard by double-vertex; - in 65-70 years. Comparing these observations with data on the discovery of steroid hormone receptors in the same tumors, W. Andersonetal. (2006) found a certain compliance with their expectations, with the
exception of information regarding medullary carcinoma. However, extrapolating their results to the above-mentioned classification of subtypes of breast cancer, they concluded that the combined group of luminal neoplasms (luminal A and B) is characterized for Europeoids in addition to steroid receptor positivity with an age peak of about 74 years, and the group "basal and HER2-expressing receptor-negative tumors, a significantly different peak at the age of 50-52 years. Ethnicity turned out to be an important factor modifying both the receptor phenotype of breast tissue and the frequency of detection of individual disease subtypes, as can be seen, for example, in the example of the Japanese and African American populations [2].
In the later work ofA. Kurianetal. (2010) confirmed that the peak of detection of luminal neoplasms occurs in women over the age of 70 years (about 32-35% of tumors of this kind against 20-23% between the ages of50-59 and 60-69 years). HER2 and triply negative carcinomas, as noted earlier, were characterized by a peak in the range of 40-59 years. Such repeatedly witnessed "linking" to the stages of carcinogenesis, characterized, in particular, by lower or greater estrogen saturation, allows you to refer to information that describes the state of the reproductive function of patients with different subtypes of breast cancer based on anamnestic and epidemiological data. Despite the variability (from the ethnic factor and age period), it seems that the risk of developing luminal carcinomas (both A and B) increases in women who have not given birth, as well as in menopause over the age of 53-55 years, and may decrease with prolonged feeding in excess of 6 months. The arrival of menarche earlier than 13 years was associated with cases of breast cancer characterized by HER2 + overexpression, but, unlike the previously expressed point of view, it did not increase, but reduced the risk of occurrence of TH (basal cell) carcinomas. With the same TN breast cancer, the lack of childbirth in history does not affect the degree of risk. Age at first birth older than 30 years, according to recent observations, has little to do with the risk of luminal or triply negative tumors, but it increases the risk of HER2 + breast cancer. That is, it is possible that non-terminal variants of the disease also have a certain hormone-sensitivity and dependence on the hormonal and metabolic status [3].
Clinical and morphological variants of breast cancer (BC), used by various classifications, including WHO, do not exhaust the entire morphobiological diversity of this category of tumors. The establishment of an infiltrating nonspecific breast carcinoma is not always justified, since in a number of observations the tumor has a heterogeneous structure represented by different types of cells. In this case, the assessment of the biological properties of the tumor itself makes it possible to evaluate its histogenesis, secretory and hormonal activity,
and therefore to judge the invasive properties and the possibility of using targeted treatment [4].
Based on the above data, it was proposed to determine several molecular genetic forms of breast cancer.
1. Breast cancer, corresponding to the level of the stem cell of the breast. The genes of the cloudin family are disabled."
This form occurs in 5-10% of patients, often at a young age. It is determined by the following characteristics: the genetic profile of the tumor is similar to that of the MF stem cells. Often reveal: lymphocytic infiltration, ER-, PR-, HER2-, Grade III. This form is distinguished by relatively less chemosensitivity, lack of effect after the use of targeted drugs, poor prognosis. Requires aggressive treatment.
2. Breast cancer, corresponding to the level of the bipotent and early luminal precursor (BRCA1 - mutated or its expression is sharply reduced); basal variant. This form occurs in 10-25% of patients, often at a young age. It is determined by the following characteristics: ER-, PR-, HER2-, Grade III, sometimes with the expression of steroid hormone receptors, Tet 5/6-60%, EGFR - in 50-70% of cases. Histologically - invasive ductal or (less commonly) lobular carcinoma, metaplastic carcinoma, oat cell carcinoma. The form is characterized by a special genetic profile, unfavorable prognosis. Often, metastases to visceral organs and the brain are detected. However, with this form, a relatively high chemosensitivity of the tumor was noted. The prescription of platinum drugs, PAPP inhibitors, angiogenesis inhibitors, and dose-intensive therapy is effective. The rapid development of chemoresis-tance is noted. This form requires aggressive treatment.
3. Breast cancer, corresponding to the level of late luminal precursor. HER2 + option. This form occurs in 10-15% of patients, from young age to menopause. It is determined by the following characteristics: ER-, PR-, HER2 +, Grade, in 1/3 of the patients Toro2a overexpression is detected. The form is characterized by an unfavorable prognosis. Metastases to the visceral organs and the brain are often detected. In this form, a high chemosensitivity of the tumor was noted. High effectiveness of adjuvant and neoadjuvant chemotherapy (CT) with the appointment of trastuzumab (anti-HER2 monoclonal antibody) and lapatinib (inhibitor of tyrosine kinase HR1 and HER2). This form requires aggressive treatment.
4. Breast cancer (luminal type B), corresponding to the level of differentiated cells. Form occurs in 10-15% of patients. Identified in young, perimenopausal and early postmenopausal age. Characteristics: ER ±, PR ±, HER2 ±, Grade II - III; Toro2a overexpression is possible, in combination with HER2 overexpression. The form is characterized by a poor prognosis. Often, metastases to visceral organs, brain, bones and soft tissues, skin, lymph nodes (LN) are detected. High chemosensitivity of the tumor was noted to
anthracyclines (with overexpression of Toro2a), taxanes, and other drugs.
Currently, neoadjuvant systemic therapy is used not only for locally common process, but also for operable stages (cT2N1, with T3N0 stages) both to achieve the possibility of performing organ-preserving treatment instead of radical mutilation, and to determine sensitivity to systemic types of treatment [5; 6]. The effectiveness of non-adjuvant systemic therapy in patients is determined using physical methods (palpation), as well as instrumental (radiation) methods, where the response criterion is the reduction in the size of the tumor and metastatic lymph nodes. Pathological assessment of the tumor response to treatment is determined by changes both at the cellular level (dystrophy, apoptosis) and tissue (formation of necrosis fields, development of foci of fibrosis and sclerosis, which constitute the tumor bed. The most accurate method is microscopic evaluation of tumor size [7]. In addition, there is the concept of a complete pathological response.
According to a study conducted on the archival material of the pathoanatomical department with a prosektur and surgical department of mammary gland tumors, N. N. Petrov Federal Institute for Oncology and Oncology, obtained in 2011-2017. The research materials of which were trepanobi-pticular breast tumors, taken before the start of neoadjuvant systemic therapy, and surgical material obtained after its completion. According to the results of the study, it was revealed that most often the complete pathological morbid response is observed with Her 2 positive and triple negative breast cancer. This undoubtedly does not mean that the prognosis and long-term results of treatment of Her 2 positive and three-fold negative subtypes of breast cancer are better than the luminal A subtype, in which complete regression of the tumor rarely occurs, but 5-year and 10-year survival is incomparably higher than with Her 2 positive and triply negative breast cancer [8].
Observations have shown the effect of cancer type on the process of metastasis, which is of clinical significance. Previous studies have shown significant differences in the timing of long-term recurrence: early reversal metastasis is characteristic of re-negative tumors, and later remission is characteristic of repositive tumors. A high frequency of early relapses is detected in basaloid breast cancer with HF breast cancer and HER2 + subtypes. Luminal A tumors metastasized less frequently than others for 15 years after diagnosis. The cumulative frequency of metastases in the bones with luminal B, luminal HER2 + and HER2 + subtypes of early breast cancer exceeded 30%, that is, bones are the most frequent target of distant metastasis.
Molecular subtypes (luminal A, luminal B, luminal B Her2/neu +, Her2/neu +, triple negative) were found to be of great prognostic value in the elderly population, even after stating competing mortality [9]. This study partially rejects
the hypothesis that the nature of the tumor in the elderly is different or has a more favorable course than in younger patients, since it was shown that the most aggressive tumor subtypes in young patients (ERBB2 + and triple negative) also predict a worse prognosis. At the same time, a sample of elderly patients was more likely to have a more favorable luminal A type than
in previous studies conducted in middle-aged patients. Less controversy and uncertainty exist around hormone therapy (HT) in elderly patients. For patients with HR + metastatic breast cancer guidance from the National Comprehensive Cancer Network (NCCN), endocrine therapy is a first-line treatment [10].
References:
1. Пак Д. Д., Рассказова Е. А. Органосохраняющее лечение рака молочной железы.- М., 2012.- 191 с.
2. Anderson W. F., Pfeiffer R. M., Dores G. M., Sherman M. E. Comparison of age distribution patterns for different histopathologic types of breast carcinoma. Cancer Epidemiol Biomarkers Prev 2006; 15(10): 1899-905.
3. Kurian A. W., Fish K., Shema S. J., Clarke C. A. Lifetime risks of specific breast cancer subtypes among women in for racial / ethnic groups. Breast Cancer Res 2010; 12(6): 99.
4. Иммуногистохимические методы: руководство. Русское издание под редакцией Г. А. Франка и П. Г. Малькова // 2011.- С. 91-97
5. Семиглазов В. Ф., Патлуев Р. М., Манихас А. Г. и др. «Золотой стандарт»диагностики и лечения рака молочной железы М.: АБВ -Пресс, 2016.- 447 c
6. Семиглазов В. Ф., Семиглазов В. В., Лечение рака молочной железы. Клинико-биологическое обоснование. Руководство для врачей.- М.: СИМК, 2017.- 277 с.
7. Лисаева А. А., Вишнявская Я. В., Рощин Е. М. и др. Лечебный патоморфоз злокачественных опухолей: клинические и морфологические характеристики. Классификации.Прогностическое значение лечебного патоморфоза при раке молочной железы и других опухолях. Опухоли женской репродуктивной системы 2011; (4): 19-23 D0I:10.17650/1994-4098-2011-0-4-19-23.
8. Башлык В. О., Семиглазов В. Ф., Кудайбергенова А. Г., Артемьева А. С., Семиглазова Т. Ю. и др. «Оценка изменения морфологических и иммуногистохимических характеристик карцином молочной железы при проведении неоадьювантной системной терапии» журнал Опухоли женской репродуктивной системы № 1. 2018.
9. Engels C. C., Kiderlen M., Bastiaannet E. et al. The clinical prognostic value of molecular intrinsic tumorsubtypes in older breast cancer patients: A FOCUS study analysis. Mol Oncol 2016; 10(4): 594-600. DOI: 10.1016/j.molonc.2015.11.002. PMID: 26706834.
10. Daly M. B., Pilarski R., Axilbund J. E. et al. NCCN Guidelines Insights: Genetic / Familial High-Risk Assessment: Breast and Ovarian, Version 2. 2015. J Natl Compr Canc Netw 2016; 14(2): 153-62. PMID: 26850485.
