Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer (BC), comprising approximately 20% of newly diagnosed BC cases. The poor prognosis, high recurrence rates, and inefficacy of hormone-based therapies make TNBC one of the greatest challenges in contemporary oncology. The unique immunological features of TNBC, including relatively high tumor mutational burden, abundance of tumor-infiltrating lymphocytes, and elevated PD-L1 expression, offer a wide range of opportunities for immunotherapeutic approaches, of which the most progressive and promising are neoantigen-driven ones. This review examines the current landscape of neoantigen-based therapeutic approaches in TNBC treatment, spanning from discovery methodologies to clinical applications. We provide a critical analysis of the tumor microenvironment (TME) in TNBC, highlighting the balance between its immunoactivating (CD8+ T-cells, dendritic cells) and immunosuppressive (regulatory T-cells, M2 macrophages) components as the key determinant of therapeutic success, as well as reviewing the emerging approaches to TME reprogramming and recruiting in favor of better outcomes. We also present state-of the-art methods in neoantigen identification and prioritization, covering the landscape of technological platforms and prediction algorithms, addressing the existing accuracy limitations along with emerging computational solutions, and comprehensively discussing the TNBC neoantigen spectrum. Our analysis shows the strong domination of patient-specific (“private”) neoantigens over shared variants in the TNBC, with TP53 as the only gene with recurrent variants. Finally, we extensively cover neoantigen-recruiting therapeutic modalities including adoptive cell therapies, personalized vaccine platforms (peptide-based, mRNA/DNA vaccines, dendritic cell vaccines), and oncolytic viruses-based approaches. Our study of current clinical trials demonstrates the substantial gap between early proof-of-concept experiments and further applicability of neoantigen-driven therapies. The major challenges hampering the success of such methods include neoantigen prediction inaccuracy rates, high manufacturing costs, and time consumption. Promising ways to overcome these difficulties include the development of combinational strategies, TME modeling and modifying, and improvement of the therapy delivery properties, along with the optimization of production workflows and cost-effectiveness of vaccine development.

Next-generation sequencing (NGS) is increasingly used in laboratory diagnostics of solid tumors. The use of NGS allows for the detection of virtually all clinically significant molecular changes identifiable by standard molecular genetic investigation (MGI) methods. Data obtained through NGS on the prevalence of molecular genetic alterations necessitates updating existing MGI tests and their application for different patient groups. In some cases, nucleotide sequence variants detected by NGS tests must be validated by standard MGI methods. A patient’s mutational profile obtained through NGS can be used to develop individualized PCR-based test systems for monitoring minimal residual disease. The integration of NGS testing with standard MGI methods is a pressing task in modern laboratory diagnostics of oncological diseases. This article provides an overview of the most important examples of such integration.

Introduction: Langerhans cell histiocytosis (LCH) is a rare clonal myeloid disorder characterized by tissue infiltration with pathological antigen-presenting cells morphologically and phenotypically similar to Langerhans cells. Activating mutations in the MAPK/ERK signaling pathway play a key role in the pathogenesis of LCH. The aim of this study was to characterize the morphological and molecular features of the neoplastic process. Materials and Methods: This study presents a clinical case of a 34-year-old patient with a rare mixed form of LCH combined with Erdheim-Chester disease (ECD), involving multiple organs including kidneys, skin, bones, ENT organs, eyes, and the central nervous system. The patient also had diabetes insipidus, chronic external otitis, and presumptive hereditary forms of anemia and hemochromatosis. A comprehensive histopathological evaluation was performed, including histochemical, immunohistochemical, and immunofluorescent analyses, alongside molecular genetic testing using whole exome sequencing (WES) of blood and skin samples. The patient demonstrated a partial clinical and laboratory response to targeted therapy with trametinib and desmopressin. Results: Comparison of WES data from blood and skin revealed 71,953 shared variants consistent with likely germline changes, as well as 3,081 unique somatic variants in skin and 2,633 unique variants in blood. Low-level mosaic BRAF V600E mutation (VAF = 1%) was detected in the skin, alongside pathogenic germline variants in the STEAP3 (c.523-2A>T, NM_182915.3) and SLC40A1 (c.332T>A, p.Met111Lys, NM_014585.6) genes. Immunofluorescence analysis of the trephine biopsy revealed diverse cellular populations, including sparse tryptase-positive mast cells, which showed minimal contact with each other or other labeled cells. The populations of Vimentin⁺CD11b^–CD34⁺ and Vimentin⁺CD11b⁺CD34^– cells (excluding endothelial cells) accounted for median values of 0.68% and 7.78%, respectively, of the total Vimentin⁺ cells. Regarding CD68 and S100 expression, CD68⁺ cells predominated (median = 55.61%), S100⁺ cells constituted a median of 43.02%, whereas CD68⁺S100⁺ cells were the rarest (median = 2.174%), reflecting the transition of Langerhans cells to LCH cells, encompassing up to 4.81% of the cellular population. This hybrid microenvironment paralleled the patient’s systemic inflammatory activity (elevated acute-phase reactants), multi-organ involvement, and renal interstitial fibrosis/tubular atrophy with reduced kidney function, without serological or histological evidence of vasculitis. Conclusion: This case illustrates the histological heterogeneity and hybrid pathology of mixed histiocytosis, where canonical dendritic LCH cells coexist with macrophage-rich ECD-like stroma. An integrated approach involving a multidisciplinary clinical team, thorough molecular genetic testing, and the application of targeted therapy is essential for improving prognosis and quality of life in young patients.

ЦЕЛЬ ИССЛЕДОВАНИЯ Оценить частоту встречаемости молекулярных нарушений в образцах опухолей пациенток с местно-распространенным и метастатическим раком молочной железы (РМЖ) методом высокопроизводительного секвенирования (NGS) с последующей оценкой возможности использования результатов исследования для выбора тактики лечения. МАТЕРИАЛ И МЕТОДЫ Проведено молекулярно-генетическое исследование 76 образцов опухолевой ткани больных РМЖ методом высокопроизводительного секвенирования. Исследование выполнялось с использованием панели AVENIO Tumor Tissue Expanded Panel Kit (Roche, США), включающей 77 генов, ассоциированных с развитием злокачественных новообразований. РЕЗУЛЬТАТЫ В данной работе определены наиболее часто встречаемые патогенные мутации в генах TP53, PIK3CA, AKT1, MET при РМЖ, а также молекулярно-генетические нарушения в различных генах, встречающиеся в 1—4% случаев (BRCA2, PTCH1, ROS1, KIT, PDGFRA, GATA3, APC, PTEN, AR, PDCD1LG2, NTRK1, FLT3, EGFR, FLT1, MSH2, KRAS, RB1, EGFR-амплификация, PMS2, CSF1R). Отдельно стоит отметить, что в клинических рекомендациях от 2020 г. по диагностике и лечению РМЖ пациенткам с HER2-гормонозависимым РМЖ рекомендовано исследование мутаций в гене PIK3CA для решения вопроса о назначении таргетной терапии. Также определено, что частота встречаемости патогенных мутаций в гене PIK3CA в данной группе пациенток составила 38,2%, в других подгруппах (гормононезависимых, HER2-позитивных) оказалась также достаточно высокой (33,3%), что позволяет рекомендовать определение мутаций в гене PIK3CA и для других подтипов РМЖ. ЗАКЛЮЧЕНИЕ Использование высокопроизводительного секвенирования в обследовании пациенток с раком молочной железы позволит усовершенствовать алгоритм молекулярной диагностики заболевания, улучшить информативность результатов исследования за счет получения полной информации по исследуемым генам, сократить сроки проведения диагностики за счет возможности единовременного исследования сразу нескольких генов, повысить эффективность терапии благодаря своевременному и точному выявлению генетических маркеров, критически важных для назначения таргетной терапии.

Background/Objectives: Triple-negative breast cancer (TNBC) is enriched for germline pathogenic variants in BRCA1/2 and other DNA repair genes, but the additional value of extended germline profiling beyond BRCA1/2 remains insufficiently characterized in Russian patients. We aimed to characterize germline pathogenic/likely pathogenic variants (GPV/LPVs) and variants of uncertain significance (VUSes) in cancer predisposition and homologous recombination repair (HRR)-related genes in Russian TNBC patients and to assess the additional yield of extended germline profiling beyond BRCA1/2. Methods: We retrospectively analyzed germline DNA from 275 patients with histologically confirmed TNBC. Exome sequencing was performed for 204 patients and focused HRR-panel testing for 71 patients on the MGISEQ-G400 platform. Results: Overall, 114 patients (41.5%) harbored at least one germline GPV/LPV. BRCA1/2 GPV/LPVs were detected in 53 patients (19.3%), with BRCA1 predominating over BRCA2 (48 vs. 5 carriers) and the recurrent BRCA1 c.5329dup variant accounting for 23 cases. In the exome subset, 79 of 204 patients (38.7%) carried a GPV/LPV in Groups 1–3, including 48 (23.5%) with BC-related GPV/LPVs; non-BRCA Group 1 genes contributed seven additional carriers beyond BRCA1/2-only analysis. The expanded HRR set identified 52 GPV/LPV carriers (25.5%) versus 45 (22.1%) in the reference HRR panel, while the common HRR gene set identified 68 carriers (24.7%) in the full cohort. In addition, 183 unique VUSes were found in Groups 1–3 in the exome subset, affecting 128 patients (62.7%). Conclusions: Russian TNBC patients show a substantial germline GPV/LPV burden dominated by BRCA1/2 alterations and the recurrent BRCA1 c.5329dup founder variant. Extended germline profiling identified additional non-BRCA and HRR-related findings beyond BRCA1/2, but the incremental yield was moderate and accompanied by a considerable VUS burden. Broader germline testing may therefore support hereditary risk assessment and exploratory HRR-focused stratification, but non-BRCA HRR findings should not be considered sufficient for therapy selection without additional tumor-level or clinical evidence.

Malignant neoplasms have possible specific genetic characteristics that may determine the effectiveness of various treatments. Pharmacogenomics in oncology represents an advanced approach aimed at identifying the genetic features of tumors to select the most optimal therapeutic strategies. This review focuses on the role of pharmacogenomic approaches in the implementation of personalized treatment for oncological diseases. Pharmacogenomics is a cutting-edge field that relies not only on advances in next-generation sequencing but also on modern methods and algorithms for processing large volumes of data. This review discusses the relationship between pharmacogenomics and next-generation sequencing technologies, machine learning, and artificial intelligence. It emphasizes the importance of accumulating real-world data to enable the proper interpretation of identified genetic mutations and the use of this information in treatment personalization. The review also covers existing pharmacogenomic platforms and characterizes a domestically developed pharmacogenomic platform for making clinical decisions in oncology.