Pathological Characteristics Of Breast Cancer Patients Research Articles

Abstract PO5-09-04: Oncotype DX Breast Recurrence Score® analysis in early-stage breast cancer associated with CHEK2, ATM and PALB2 germline pathogenic variants

Abstract Background: The 21-gene assay (Oncotype DX Recurrence Score, RS) is the only clinically validated assay to determine the prognosis in hormone-positive, HER2-negative breast cancer (BC) patients treated with endocrine therapy alone by predicting locoregional and distant recurrence. Outcomes of Oncotype RS in BRCA-associated BC has been studied previously, but the results of RS analysis in BC patients with the other BC susceptibility genes have not been documented. This study evaluates the clinical and pathological characteristics of BC patients with ATM, CHEK2 and PALB2 germline pathogenic variants (PV). Methods: Patients with invasive hormone-positive, HER2-negative BC who have had Oncotype DX Breast Recurrence Score® testing and who underwent genetic testing in the Breast Medical Oncology and the Breast Clinical Cancer Genetics Clinic at the University of Texas MD Anderson Cancer Center (MDACC) were identified from the prospectively maintained research database. Clinical and tumor characteristics were analyzed using descriptive statistics. Results: Between 1996 and June 2023, 5652 patients with Oncotype RS were included in this analysis. Amongst those 828 BC patients had genetic testing and 81 patients were found to have a pathogenic variant: 17 patients with a CHEK2 mutation, 10 patients with an ATM mutation, and 18 patients with a PALB2 mutation. Among patients with CHEK2 PV, median Oncotype RS was 17 (5–32) overall, 21 (13–32) for patients age < 50, and 14.5 (5–28) for patients age ≥50 (p= 0.2). Among patients with ATM PV, median RS was 16.5 (3–54) overall, 25 (10–54) for patients age < 50, and 14.5 (3–29) for patients age ≥50 (p= 0.19). Among patients with PALB2 PV, median RS was 26.5 (15–40) overall, 20 (15–40) for patients age < 50, and 31 (26–37) for patients age ≥50 (p= 0.012). Further patient and tumor characteristics are shown in Table 1. Conclusion: This is a single-institutional cohort of hormone-positive, HER2-negative BC patients who had Oncotype RS and who underwent genetic testing. Further analysis on clinical and tumor pathological characteristics and long-term outcome is ongoing. Table1. Patient and tumor characteristics Citation Format: Fatma Akkoc Mustafayev, Angelica Gutierrez Barrera, Diane Liu, Banu Arun. Oncotype DX Breast Recurrence Score® analysis in early-stage breast cancer associated with CHEK2, ATM and PALB2 germline pathogenic variants [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-09-04.

Analysis of Turkish Breast Cancer Patients With ATM-Heterozygous Germline Mutation According to Clinicopathological Features.

The ATM gene is one of the most common breast cancer (BC) susceptibility genes after BRCA1/2 and has been shown to be a moderate BC susceptibility gene. The association between ATM germline mutation and clinical features of BC is now unknown. In this article, clinicopathological features of BC patients with ATM germline heterozygous mutation were investigated. Patients admitted to the Medical Genetics departmentof a tertiary hospital between January 2020 and December 2022 were examined. Only invasive BC patients with pathogenic mutation, likely pathogenic mutation, or variants of uncertain significance (VUS) were included in the study. In all, 121 patients were included in the study. The median age at the first cancer diagnosis of the patients was 44 years. Of the total number of patients, 75.2% (91) had the histological subtype of infiltrating ductal carcinoma, and 43% (52) had Luminal B molecular subtype features. At a median follow-up of 16 months, 5.8% (7) of patients developed cancer in the contralateral breast. In addition, 7.4% (9) of the patients developed a second primary cancer during follow-up. When the patients were compared according to ATM variant classification, the localization, histologic types, and molecular subtypes of the BC were not different between all groups (respectively; p=0.68, p=0.65, p=0.32). To the best of our knowledge, this is the first publication that evaluates the clinical and pathological characteristics of BC patients with germline heterozygous ATM mutations in the Turkish population. When patients were compared according to variant classifications of ATM mutation, patients' histological and molecular subtypes were similar.

ASSOCIATION OF CD44+CD24−/low WITH MARKERS OF AGGRESSIVENESS AND PLASTICITY OF CELL LINES AND TUMORS OF PATIENTS WITH BREAST CANCER

To search for additional molecular-biological markers of cancer stem cell (CSC) involved in the development of intra-tumor heterogeneity for the detection of features of the breast cancer (BC) pathogenesis. Expression of estrogen receptors (ER), progesterone receptors (PR), Her2/neu, E- and N-cadherin, CD24, CD44, Bcl-2, Bax, Slug, P-gp, glutathione-S-transferase (GST) and metallothionein in cell lines was determined by the immunocytochemical method. Expression of ER, PR, Her2/neu, CD24and CD44in the surgical material of BC patients were determined by the immunohistochemical method. The levels of the miRNA were determined using real-time polymerase chain reaction. Cells of high-grade malignancy (HGM), MDA-MB-231and MDA-MB-468 are characterized by high expression of stem cell markers compared to the cells of low-grade malignancy (LGM), T47D and MCF-7: CD44levels in T47D and MCF-7cells were in range of 72-79points, which is significantly lower than in HGM cells (p < 0.05). Also, HGM cells with the properties of CSC were characterized by high expression of antiapoptotic proteins, the transcription factor Slug, and low levels of proapoptotic protein Bax (p < 0.05) compared to LGM cells. In cells with CSC characteristics an increased expression of transferrin and its receptor, ferritin, fentorin and hepcidin was revealed indicating activation of the endogenous iron metabolism. The characteristic feature of HGM cells with CSC phenotype were the increased levels of oncogenic miR-221, -155and -10b by 60%, 92% and 78%, respectively, and decreased levels of oncosuppressive miR-29b, -34a and -200b by 8.4 ± 0.3, 4.6 ± 0.2, and 3.4 ± 0.6times compared to MCF-7line cells. It has been established that the development of resistance to cytostatics is accompanied by increased aggressiveness of tumor cells, loss of expression of hormonal receptors and acquiring of stem phenotype. In particular, increased expression of P-gp was observed in BC cells during the development of resistance to doxorubicin, of GST during the development of resistance to cisplatin along with increased CD44expression (p < 0.05). We have revealed the relation between the presence of cells with the CSC phenotype (CD44+CD24-/low) and clinical and pathological characteristics of BC patients, their survival and BC sensitivity to neoadjuvant therapy (p &gt; 0.05). The dependence between the expression of CSC markers and the degree of malignancy of tumor cells, development of resistance to cytostatics in vitro was established as well as the predictive value of the detection of the CSC for the individual prognosis of the BC course and sensitivity of the tumors to the treatment.

OSTEOPROTEGERIN AS A PREDICTIVE MARKER OF THE COURSE OF BREAST CANCER

Despit e th e considerable progress in research of breast cancer (BC), taking into consideration the division into molecular subtypes, the mechanics of metastasis development in BC patients are not definitely investigated, especially at favorable prognosis. Research of new informative diagnostic and prognostic markers represents the modern problems of BC pathology in a new way. Thi s paper is devoted to study of osteoprotegerin (OPG) expression levels in tumor cells in BC patients. The study covered 83 female patients with regional BC (T2–4N0–3M0), treated from 2003 to 2010. The inclusion criteria were histologically proved diagnosis of invasive BC, age over 18 y. o., ECOG 0 or 1. In order to study OPG levels, we carried out immune histochemical test, which was carried out according to standard protocol on the sections of biopsy material. The OPG antibody from GeneTex, used in the study, was rabbit polyclonal, dilution 1:1000, incubation time – 30 minutes. Vizualization system was Real EnVision, anti-rabbit (by DAKO, Denmark). Immunohistochemical staining was studied by counting of number of positive cells in reference to total number of malignant cells. Expression over 50 % of cells was regarded as high, less than 50 % – as low. Average value of OPG expression level was 49 %, median – 50 %. Minimal value – 0 %, maximum value – 90 %. The patients were divided into 2 groups according their expression levels: Group 1 – OPG (high) expression (more than median), Group 2 – OPG (low) expression (less than median). OPG (high) Group was made by 47 patients, OPG (low) Group – by 36. When analyzing clinical and pathological characteristics of BC patients, taking into consideration OPG expression, there were noticed no reliable differences with respect to availability o r absence o f affected regional lymph nodes, category T and Ki-67 indice. The group with positive estogen-progesteron receptors showed reliably more often the high values of OPG than the group with negative receptors (p < 0,05). When analyzing the duration till the progression and overall survival, a difference between the survival and time to progression (rise of metastases) in patients with low OPG levels and the same exponents in patients with high OPG levels was established.

Prognostic value of receptor activator of nuclear factor kappa-B (RANK) marker in patients with breast cancer

Despite notable progress made in studying breast cancer (BC), the mechanisms of metastases, in view of the classification into molecular subtypes, in patients with BC remain to be fully uninvestigated, in the presence of a good prognosis in particular. To study novel diagnostic and predictive markers in a new way presents current problems in the pathology of BC. This investigation deals with the expression of osteoprotegerin (OPG) in the tumor cells of patients with BC. It enrolled 83 patients with locally advanced BC (T2–4N0–3M0) who had been treated in 2003 to 2010. The inclusion criterion was a histologically verified diagnosis of invasive BC. To study the level of OPG, the investigators conducted an immunohistochemical study of biopsy sections according to the standard protocol. The mean expression of receptor activator of nuclear factor kappa-B (RANK) in the BC cells was 18.7 %; its median was 5 % (range, 0–90 %). The patients were divided into 2 groups according to the level of RANK expression: 1) high (higher than the median); 2) low (lower than the median). The high RANK group included 39 patients; the low RANK group comprised 44 patients. Analysis of the clinical and pathological characteristics of BC patients with regard RANK expression did not show any statistically significant differences in the presence or absence of affected regional lymph nodes, T category, and Ki-67 index. The analysis of clinical and pathomorphological and immunohistochemical characteristics in patients with breast cancer, taking into consideration RANK expression level, did not show any statistically significant differences with respect to presence or absence of affected regional lymph nodes, age, T category and Ki-67 index (р &gt; 0.05). However, it revealed the following pattern: the high expression of RANK was more common in patients positive for estrogen and progesterone receptors than in those for negative receptors (p = 0.04).