Molecular genetic clusters of triple-negative breast cancer and their prognostic significance

Background. Triple-negative breast cancer is a group of tumors with different clinical and morphological features, prognosis, and response to therapy. There are from 4 to 6 molecular genetic varieties of this type of malignant neoplasm.

Aim. Identification of individual clusters of triple-negative breast cancer that differed in terms of overall and disease-free survival.

Material and methods. On the basis of the Regional Clinical Oncological Dispensary (Ulyanovsk) and “National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov” of the Ministry of Health of Russia (Moscow) in the period from 2017 to 2021, a molecular genetic analysis using a 45-gene signature in 246 patients with triple-negative breast cancer, confirmed by immunohistochemical method, was performed. Using the K-means clustering method, it was possible to form 4 molecular genetic clusters. When comparing clusters according to clinical and morphological features, the Student's t-test, Mann–Whitney U-test, Fisher's exact test, Pearson's χ2 test were used. Survival analysis was performed using the construction of Kaplan–Meier curves (the observation period was 3 years and 8 months). Comparison of clusters in terms of survival was carried out using a long-rank test. Multivariate analysis was used to determine the significance of variables affecting overall and disease-free survival. Differences between groups were considered statistically significant at p <0.05.

Results. Cluster 1 included patients with clinical stage IIA, invasive nonspecific subtype, G3, N0, Ki67 ≥31%, with hypoexpression of most genes, unstable prognostic outcome: high survival rate at stage IV (62%) and zero survival rate at stage IIIB. Patients of the 2nd cluster were associated with stage IIA, medullary histological subtype, G3, N0, Ki67 ≥31%, overexpression of genes for hormone receptors, growth factor receptors and transcription factors and a favorable prognosis: the best indicators of overall (100% in stage I, 66% in stage IV) and relapse-free (75% in stage I, 33% in stage IV) survival. Patients of the 3rd cluster more often had stage IA, invasive lobular and special histological tumor subtypes, N+, Ki67 ≤14%, high expression of genes responsible for the regulation of proliferation, mitosis, spindle formation and regulation of the cell cycle, genes that regulate cell transport, the processes of replication and repair of deoxyribonucleic acid, tumor cell differentiation markers, and genes that regulate immune processes, had a regular prognosis — with an increase in the clinical stage, a decrease in survival occurred. Cluster 4 patients correlated with stage IV, invasive non-specific subtype, G1–G2, N0, Ki67=15–30%, mean values of most genes, and worse overall and recurrence-free survival (64% in stage I, 0% in stage IV).

Conclusion. Based on the data of molecular genetic profiling of triple-negative breast cancer, it is possible to identify individual clusters that are statistically significantly different from each other in terms of survival rates.