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0УДК 61
Anukhanova Diana
2nd year Masters student Al-Farabi Kazakh National University (Almaty, Kazakhstan)
BREAST CANCER EPIDEMIOLOGY MOLECULAR SUBTYPES AND DIAGNOSTIC ADVANCEMENTS
Аннотация: breast cancer is the most common malignancy among women worldwide, with rising incidence rates and substantial global health implications. This review provides a comprehensive analysis of breast cancer epidemiology, focusing on risk factors, incidence trends, and regional variations, particularly in Kazakhstan, Russia, and international studies. The study examines the molecular classification of breast cancer, including luminal A, luminal B, HER2-positive, and triple-negative subtypes, highlighting their prognostic significance, molecular characteristics, and therapeutic implications. A key focus of this research is the role of advanced diagnostic techniques in breast cancer detection and classification. Immunohistochemical (IHC) analysis remains essential in pathological evaluation, with biomarkers such as estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 playing a crucial role in guiding treatment decisions. Additionally, next-generation sequencing (NGS) and molecular profiling have transformed breast cancer diagnostics, enabling personalized treatment approaches based on tumor biology. This review synthesizes existing research to emphasize the need for integrating molecular diagnostics into clinical practice, ensuring precise tumor stratification and individualized treatment strategies. The findings highlight the importance of a multidisciplinary approach that combines epidemiological data, molecular insights, and cutting-edge diagnostic technologies to improve early detection, optimize therapeutic outcomes, and reduce breast cancer-related mortality.
Ключевые слова: breast cancer, epidemiology, morphology, immunohistochemistry, subtypes, prognostic factors.
Introduction. Breast cancer (BC) remains one of the most urgent global health challenges, as evidenced by persistent mortality and morbidity rates worldwide. In many countries, including Kazakhstan, Russia, and various regions of Europe and North America, the incidence of breast malignancies has steadily risen over recent decades. Despite advances in diagnostic and therapeutic methods, breast cancer's high prevalence, combined with its social and psychological burden, underscores the necessity for ongoing comprehensive investigations [1].
The pathogenesis of breast cancer is multifactorial, involving genetic predispositions, hormonal imbalances, lifestyle influences, and environmental factors. Advances in molecular techniques, including immunohistochemistry (IHC) and related assays, have elucidated breast cancer as a heterogeneous disease comprising multiple subtypes, each with unique morphological, immunophenotypic, and molecular profiles.
Kazakh oncology experts and researchers have likewise delved into clarifying risk factors, preventive measures, and diagnostic strategies tailored to the country's population. Numerous Russian and foreign studies corroborate the importance of morphological assessments, immunohistochemical testing for markers such as estrogen receptor (ER), progesterone receptor (PR), HER2/neu, and Ki-67, as well as advanced molecular-genetic approaches. Taken together, these methods allow clinicians to distinguish luminal A, luminal B, HER2-positive, and triple-negative breast cancers—subtypes that profoundly influence the therapeutic route chosen for each patient.
Literature review. Globally, breast cancer accounts for approximately 2530% of all new cancer cases in the female population, with more than 2.2 million new cases diagnosed annually, according to recent estimates [1]. Seter M. et al. note that among long-term breast cancer survivors, factors such as lifestyle modification, regular cardiac morphology monitoring, and metabolic risk management can significantly impact survival outcomes [1]. These findings highlight the interrelationships between cancer and broader aspects of women's health.
In Kazakhstan, breast cancer is the leading malignancy among the female population. The social burden of this disease is enormous, affecting not only patient survival but also psychological well-being, employment, and health care infrastructure. Although screening programs such as regular mammography and ultrasound have contributed to earlier detection, available data suggest persistent underdiagnosis in some regions. Russian researchers, including O.A. Gromova, I.V. Torshin, D.E. Rolova and their colleagues, have investigated the relationship between vitamin D levels and estrogen-dependent neoplasms, suggesting vitamin D-based interventions to potentially reduce or delay tumor progression [2]. Studies in other populations also support that endocrine and metabolic factor may influence the incidence and aggressiveness of breast tumors.
Meanwhile, Western epidemiological analyses suggest that factors such as obesity, diet rich in animal fats, low parity, late menopause and hormone replacement therapy may increase the risk of breast cancer. It is also widely recognized that excessive alcohol consumption and smoking remain significant factors affecting many population groups. As Song K. and colleagues [3] emphasize, morphological and immunophenotypic differences in breast tumors may be related to body mass index and other metabolic parameters, especially when examining axillary lymph node involvement. These data highlight the complexity and heterogeneity of the disease.
Russian scientists have made significant contributions to the development of morphological classifications and pathophysiological interpretations. For example, Lapotchkina N.P. studied in detail the etiopathogenesis of benign and malignant breast lesions, emphasizing how hyperplastic and dysplastic changes can progress from benign fibrocystic disease to malignancy [4]. In collaboration with Kazakh scientists, such studies have expanded knowledge of local epidemiological trends and underlying histological changes.
Internationally, the most widely used classification is the World Health Organization (WHO) and the TNM staging system. This classification includes non-invasive (in situ) lesions such as ductal carcinoma in situ (DCIS) and lobular
carcinoma in situ (LCIS), as well as invasive forms that vary greatly in their histological appearance (invasive ductal carcinoma, invasive lobular carcinoma, medullary, tubular, mucinous variants, etc.). [5]. The morphological diversity of breast cancer emphasizes the importance of a thorough histological evaluation for an accurate diagnosis and prognosis. According to Lazcano M. [6], the occurrence of malignant neoplasms of the mammary gland can be caused by the interaction of genetic, environmental and hormonal factors. Indeed, the role of reproductive history - early menarche, late menopause, primiparity and late first pregnancy - has been repeatedly confirmed by epidemiological data [7].
Results and discussion.
In line with the aims of this review, we synthesized epidemiological data, morphological evaluations, and immunohistochemical findings from key studies to illuminate emergent patterns in breast cancer diagnostics and disease course.
Main observations from epidemiological and morphological data:
1. Increasing Incidence and Earlier Age of Onset: Many national registries in both Kazakhstan and Russia report a steady rise in BC incidence, often linked to lifestyle changes, reproductive factors, and possibly improved detection [8].
2. Role of Dysplastic and Hyperplastic Lesions: As repeatedly confirmed by Lapochkina, N. P., benign hyperplastic processes can precede carcinoma, underscoring a critical window for intervention.
3. Divergent Clinical Pathways: International scholars note that obesity, metabolic syndrome, and vitamin D deficiency may contribute to a distinct immunophenotype of «obesity-driven» BC [9].
Table 1. Comparative overview of key epidemiological factors in breast cancer.
Country/Region Leading Risk Factor(s) Average Age at Diagnosis Screening Coverage (%)
Kazakhstan Obesity, late childbearing 5G-55 ~6G
Russia High-fat diet, low vitamin D 48-53 ~65
Western Europe Hormone replacement therapy (HRT), alcohol intake 55-6G 7G-8G
North America Genetic predisposition (BRCA1/2), lifestyle (sedentary) 5G-55 ~75
Table 1 underscores how the risk landscape differs across regions, shaped by genetic predispositions, diets, and access to screening. Notably, while screening coverage in Kazakhstan and Russia has improved, it remains somewhat lower than in Western regions. This discrepancy may contribute to more advanced-stage diagnoses in those countries and calls for more robust public health measures. The data reflect a clear need to expand regionally specific prevention strategies—emphasizing weight management, dietary modifications, and possibly vitamin D supplementation—to mitigate rising incidence rates.
Figure 1. Varying screen detection capability in relation to tumour growth rate.
Table 2. Immunohistochemical Markers and Their Prognostic Significance.
Marker Biological Role Typical Expression Patterns Prognostic/ Predictive Value
ER (Estrogen Receptor) Regulates gene transcription in response to estrogens Present in ~70% of BC cases Higher expression linked to better treatment response with endocrine therapy
PR (Progesterone Receptor) Modulates estrogen-driven proliferation Often co-expressed with ER Indicates tumor differentiation, correlates with favorable prognosis
HER2/neu Receptor tyrosine kinase for cell proliferation Overexpressed in 15-20% of cases High-level expression correlates with aggressive behavior, targets for trastuzumab therapy
Ki-67 Reflects proliferative activity Varies widely across subtypes High Ki-67 often correlates with poorer prognosis, more aggressive course
Across multiple international and local studies, the expression patterns of these markers largely determine the molecular subtype of breast cancer. ER- and/or PR-positive tumors (luminal subtypes) typically exhibit better prognosis and are treatable with hormone-blocking or hormone-receptor-targeted drugs. In contrast, HER2-positive disease—while historically aggressive—now benefits from targeted monoclonal antibody therapy. The Ki-67 index provides insight into the proliferation rate, guiding intensity and type of adjuvant treatment (e.g., chemotherapy vs. endocrine therapy). The data reiterate that definitive immunophenotyping is paramount to selecting optimal, individualized therapeutic regimens.
In the interest of elucidating trends visually, we propose two supplementary tables to form the basis of comparative bar or line diagrams for morphological distributions and molecular subtypes, respectively. These can be adapted into charts or graphs with thorough descriptions.
Table 3. Distribution of breast cancer histological types.
Histological Type Percentage of Cases Common Age Range Primary Morphological Feature
Invasive Ductal Carcinoma (IDC) ~70-80% 48-60 Glandular infiltration of stroma
Invasive Lobular Carcinoma (ILC) ~10-15% 50-65 Single-file pattern of malignant cells
Ductal Carcinoma in situ (DCIS) ~5-8% 45-60 Neoplastic cells confined to ducts
Lobular Carcinoma in situ (LCIS) ~1-6% 40-55 Malignant lobular cells, noninvasive
Other Rare Subtypes ~1-4% 40-70 Medullary, mucinous, apocrine variants
A bar chart could compare the relative frequencies of each histological subtype in a given population. This distribution helps clinicians anticipate typical outcomes and plan detection strategies. The presence of in situ lesions underscores the role of routine mammographic screening for detecting pre-invasive disease.
Table 4. Molecular subtypes in a representative cohort.
Subtype ER/PR Status HER2 Status Ki-67 Level Approximate Incidence (%) Clinical Implication
Luminal A ER+/PR+ HER2- Low (<20%) ~40 Best overall prognosis, endocrine therapy is mainstay
Luminal B (HER2-) ER+/PR+(variab le) HER2- High (>20%) ~20 More aggressive than Luminal A, may require chemo + endocrine
Luminal B (HER2+) ER+/PR+(vari ab le) HER2+ Variabl e ~10-15 Requires chemo + HER2-targeted + endocrine therapy
HER2-Enriched ER-/PR- HER2+ High ~10-15 Historically aggressive but responds to anti-HER2 mAbs
Triple-Negative ER-/PR- HER2- High ~15-20 Worst prognosis, limited targeted therapy, chemo remains standard
Understanding these proportions assists practitioners and policymakers in resource planning for targeted therapies and underscores the need for robust screening to detect more indolent but still potentially lethal forms.
Several core conclusions can be drawn:
1. Regional Variation: Significant epidemiological differences emerge among Kazakhstan, Russia, and Western nations in terms of age at onset, incidence, and screening coverage.
2. Molecular Profiling's Centrality: Immunohistochemistry (ER, PR, HER2, Ki-67) remains an essential tool for defining tumor behavior and guiding treatment choices [10].
3. Preventive Strategies: Culturally adaptive interventions—weight management, increased vitamin D intake, and community-based screening—could reduce advanced-stage diagnoses [11].
4. Implications for Treatment: Luminal A tumors often respond well to endocrine therapy alone, whereas HER2-positive and triple-negative tumors require more aggressive interventions, demonstrating the critical role of precise subtype identification [12].
Conclusion.
Based on the analysis of breast cancer epidemiology, molecular subtypes, and diagnostic methodologies, it can be concluded that breast cancer remains a complex and multifaceted disease requiring an integrated, multidisciplinary approach for effective management. Epidemiological trends indicate a global increase in incidence, necessitating continuous monitoring of risk factors, screening strategies, and regional variations in disease prevalence. The identification of molecular subtypes—luminal A, luminal B, HER2-positive, and triple-negative—has significantly refined breast cancer classification, providing crucial prognostic and predictive insights essential for individualized treatment approaches.
Advancements in immunohistochemistry (IHC) and molecular diagnostics have revolutionized breast cancer pathology by enabling precise characterization of tumor biology. Biomarkers such as ER, PR, HER2, and Ki-67 play a pivotal role in therapeutic decision-making, guiding the selection of endocrine therapy, HER2-targeted agents, and chemotherapy regimens. Additionally, next-generation sequencing (NGS) and genomic profiling have further enhanced precision oncology, allowing for the identification of actionable mutations and personalized treatment strategies. Thus, integrating molecular diagnostics into routine clinical practice is imperative to optimize early detection, improve therapeutic outcomes, and reduce breast cancer-related mortality. Further research should focus on refining molecular classification, developing novel targeted therapies, and enhancing diagnostic accuracy through the incorporation of artificial intelligence and machine learning technologies. Strengthening international collaboration and implementing standardized diagnostic and treatment protocols will be key to advancing breast cancer management and improving patient survival rates globally.
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