[Particularities of arterial stiffness dynamics on the background of breast cancer chemotherapy].

BACKGROUND: Modern breast cancer chemotherapy regimens (BC) consider individual patient parameters and ranges of cardiotoxic doses. However, clinicians often record clinical and laboratory-instrumental signs of cardio- and vasculotoxicity in patients, which emphasizes the high importance of searching for markers of early toxic response. AIM: To study the characteristics of the response of arterial stiffness on the background of anthracycline-containing chemotherapy to determine potential markers of vasculotoxicity in BC patients. MATERIALS AND METHODS: 20 women with a BC were included. The patients received 4 cycles of chemotherapy in the doxorubicin + cyclophosphane (AC) regimen with an interval of 2-3 weeks, then they were injected with paclitaxel weekly for 12 injections, or docetaxel once every 3 weeks. All patients underwent TTE, arterial stiffness determination by the "gold standard" method and using volumetric sphygmography before the start of treatment, after the completion of the anthracycline component and after the end of taxanes. RESULTS: The average age of the patients was 45.5±5.31 years. After completing the course of anthracyclines, there was a significant increase in heart rate (from 65.6±9.3 to 73.3±10.1 beats/min.), a decrease in SBP (from 122.6±9.9 to 116.5±12.3 mmHg) and DBP (from 78.9±8.5 to 76.2±8.6 mmHg), a decrease in carotid femoral pulse wave velocity (cfPWV) (from 9.32±1.41 to 7.85±1.57 m/s), CAVI index on the left (from 6.78±0.81 to 6.5±0.88), the velocity of the cardio-ankle pulse wave on the right and left (from 6.7±0.6 to 6.5±0.7 m/s; from 7.0±0.6 to 6.3±0.8 m/sc, respectively). After the completion of the taxane, there was a tendency to increase these indicators, however, they remained significantly lower compared to the values before the start of treatment. CONCLUSION: A comparative analysis of arterial stiffness indicators at different stages of chemotherapy showed a more pronounced reaction of cfPWV, CAVI, cardio-ankle pulse wave to the administration of anthracyclines, which presumably may be associated with concomitant hemodynamic restructuring.

[The use of digital radiography in the morphological evaluation of tumor response to neoadjuvant treatment of breast cancer]. / Primenenie tsifrovoi rentgenografii pri morfologicheskoi otsenke otveta opukholi na neoad"yuvantnoe lechenie raka molochnoi zhelezy.

OBJECTIVE: To optimize the morphological assessment of tumor response to neoadjuvant therapy in breast cancer. MATERIAL AND METHODS: A retro- and prospective cohort study was conducted. The object of the study was the surgical material. Macroscopic parameters of residual tumor without and with the use of digital radiography (digital X-Ray) are described and analyzed. PathVision Faxitron imaging system was used for digital X-ray samples. An analysis of dynamics of clinical characteristics was carried out. Two methods of tumor bed examination were compared. RESULTS AND DISCUSSION: The study cohort included 32 women, mean age 45.5±14 years. The correlation of the results of instrumental methods was 0.66 ([95% CI: 0.28; 1], p=0.0002). Microcalcinates were detected by digital X-Ray in 29 (90.6%) cases. Tumor bed sizes determined macroscopically (mean maximal size 6.1 (3.3) cm, median 5.2 (3.4-8.0) cm) and by using digital X-ray (mean maximal size 4.8 (2.6) cm, median 4.1 (2.7-6.2) cm), had statistically significant differences (p<0.0001). The agreement between the two methods of studying the tumor bed was 96.9%. The Cohen's kappa value was 0.95 (p<0.0001). CONCLUSION: Morphological study is an integral part of clinical trials of drug efficacy. With the help of digital X-Ray, the identification of metal markers placed in the tumor bed and microcalcinates is facilitated by the morphologist, and the visibility of the boundaries of the tumor bed is also improved. The results obtained showed that the use of digital X-Ray can improve the accuracy of assessing the degree of morphological regression of breast cancer in response to treatment.

[Urinary biomarkers of kidney injury in patients treated with anti-VEGF drugs].

BACKGROUND: Antiangiogenic drugs are widely used in oncological practice and are aimed at inhibiting angiogenesis. Despite the high antitumor efficacy, their use may be limited by nephrotoxicity, and therefore the search for early biomarkers of kidney damage remains relevant, which will preserve a favorable safety profile of therapy. AIM: To determine urinary biomarkers of tubular and podocyte damage in patients receiving treatment with antiangiogenic drugs. MATERIALS AND METHODS: The study included patients (n=50) who received intravenous anti-VEGF drugs (aflibercept, bevacizumab, ramucirumab) in various chemotherapy regimens. Concentrations of tubular damage markers KIM-1 (Kidney Injury Molecule-1) and NGAL (Neutrophil Gelatinase-Associated Lipocalin), hypoxia marker HIF-1 (Hypoxia-Inducible Factor 1-alpha) in urine samples were determined by enzyme-linked immunosorbent assay (ELISA) before treatment, and during 8 weeks of treatment. To assess the risk factors for kidney damage, a logistic regression analysis was performed with the inclusion of the main clinical and laboratory parameters. RESULTS: A decrease in the calculated GFR of CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration Formula) of less than 60 ml/min per 1.73 m2 at week 8 of treatment was noted in 42% of patients. An increase in NGAL, KIM-1, HIF-1 and nephrin in urine during the first two weeks of therapy predicted the development of renal damage by the 8th week of follow-up. When constructing ROC-curves, the high sensitivity and specificity of these urinary indicators as prognostic markers were established. Among the clinical and laboratory indicators, independent unfavorable prognostic factors of nephrotoxicity were an initial decrease in eGFR, a history of hypertension, an increase in the concentration of KIM-1 and HIF-1 in urine during the first two weeks of therapy. CONCLUSION: The predictors of renal damage in the treatment with antiangiogenic drugs were previously an increase in NGAL, KIM-1 and HIF-1 in urine during the first two weeks after the start of therapy.

[Clinical and laboratory signs and risk factors for nephrotoxicity, associated with antiangiogenic drugs].

BACKGROUND: Anti-angiogenic anticancer drugs that block the vascular endothelial growth factor signaling pathway can cause renal damage. Assessment of the risk of nephrotoxicity allows developing optimal treatment approaches and ensuring the relative safety of therapy. AIM: To assess early clinical and laboratory manifestations and risk factors for nephrotoxicity of antiangiogenic drugs. MATERIALS AND METHODS: The study included 50 patients who received antiangiogenic drugs in different regimens of chemotherapy. Demographic factors, body mass index, blood pressure levels, type of antiangiogenic drug, and concomitant therapy were assessed. Before treatment and over a period of 8 weeks, the levels of hemoglobin, number of platelets and schistocytes, D-dimer levels, serum lactate dehydrogenase (LDH) levels, as well as daily proteinuria and serum creatinine and eGFRCKD-EPI were assessed. Linear regression analysis was performed to assess risk factors for nephrotoxicity and arterial hypertension (AH). RESULTS: The median age of patients was 46 [3457] years, 22 (44%) men and 28 (56%) women. AH developed in 52%, a decrease in eGFR in 42%, along with a decrease in hemoglobin levels and an increase in LDH levels at 2 weeks of therapy. The numbers of schistocytes and platelets significantly decreased by 8 weeks of therapy. Risk factors for impaired renal function during treatment with antiangiogenic drugs were an initial decrease in GFR less than 80 ml/min/1.73 m2, an increase in D-dimer levels, and a decrease in hemoglobin levels by 8 weeks of treatment. The risk factors for AH during therapy were the initial decrease in eGFR less than 80 ml/min/1.73 m2 and no prophylactic anticoagulant therapy. CONCLUSION: Early signs of nephrotoxicity of antiangiogenic anticancer drugs were a decrease in eGFR and AH. The independent risk factors for nephrotoxicity were the initial decrease in eGFR, an increase in D-dimer levels, and a decrease in hemoglobin levels at 8 weeks of treatment, while the prophylactic use of anticoagulant therapy reduced this risk in our study.

[Role of clustered HER2/neu amplification as a marker for a special sensitivity to neoadjuvant anti-HER2 therapy with trastuzumab in patients with stage II-III breast cancer]. / Rol' klasternoi amplifikatsii gena HER2/neu kak markera 'osoboi' chuvstvitel'nosti k neoad''iuvantnoi anti-HER2-terapii trastuzumabom pri rake molochnoi zhelezy II­III stadii.

OBJECTIVE: To evaluate the influence of clinical and morphological factors and HER2 copy numbers on pathologic complete response (pCR) rates in patients with HER2-positive stage II-III breast cancer (BC). MATERIAL AND METHODS: Treatment results were studied in 73 patients with HER2-positive Stage II-III BC, who received treatment at the N.N. Blokhin National Medical Research Center of Oncology in 2015 to 2018. Treatment included neoadjuvant chemotherapy (NACT) with HER2-blockade and radical surgery followed by the evaluation of a pathologic response in the primary tumor and regional lymph nodes. The patients` age varied from 29 to 71; its median was 51.5; 45.2% of patients had primary operable stages (T1-3N0-1) and 54.8% had locally advanced tumors. All the patients had grade 2-3 anaplasia; luminal HER2-positive BC was diagnosed in 41.4% of patients; hormone-negative tumors were seen in 58.9%; 91.5% of patients had Ki-67 ≥20% in 75.3% of patients, preoperative systemic therapy included anthracycline-containing regimens (4AC + 4 x paclitaxel 175 mg/m2/12 × weekly administrations of paclitaxel 80 mg/m2; trastuzumab therapy was simultaneously performed with the administration of taxanes in the standard regimen) and anthracycline-free regimen TCH ± Pertuzumab regimen in 24.7% of cases. After NACT patients underwent surgery (radical mastectomy in 78.1%, breast-sparing treatment in 21.9%) with the assessment of morphological findings. Biopsy specimens obtained before the treatment was restudied; HER2 amplification was detected using a Dako HER2 IQFISH pharmDx kit according to its instruction and the 2018 ASCO/CAP guidelines. In 87.1% of cases, the HER2-positive status corresponded to the first category of the 2018 ASCO/CAP criteria for HER2-positive BC; clustered HER2 amplification was found in 30.1% of cases. The authors analyzed the frequency of bpCR and tpCR attainment by various clinical and morphological factors, as well as the impact of a HER2 amplification level on pCR rates. RESULTS: A breast pCR (bpCR) was achieved in 57.4% patients; bpCR and lymph node CR (lnCR) were noted in 48.9% patients. The rates of bpCR significantly depended on female age, chemotherapy regimen, addition of Pertuzumab, and HER2 copy number. That of bpCR in women less than 35 years of age, in those aged 36-50 years, and in those aged older than 50 years was 22.2, 57.7 and 71.9%, respectively (p=0.026). The maximum bpCR rate observed with the TCH±P regimen was 80.0%, that with anthracycline-containing regimes was 52.8% (p=0.045), and the addition of Pertuzumab increased complete response rates up to 88.9% (that with Trastuzumab was 54.2% (p=0.049). The relationship of bpCR rates to the detection of cluster amplification turned out to be highly significant (81% in its detection and 48.9% in its absence (p=0.013). In addition, clustered HER2 amplification was the only significant predictive factor for complete regression in the primary tumor and lymph nodes: in its presence, the tpCR rate reached 68.8% versus 38.7%. CONCLUSION: Clustered amplification of the HER2 gene is the most significant factor of sensitivity to anti-HER2 therapy for Stage II-III BC, and is associated with the maximum rate of both bpCR and total pCR. Further study of this factor may assist in optimizing the treatment algorithm for HER2 + BC.

[Breast cancer with triple-negative phenotype in the Russian patient population. Clinical and morphologic features].

The purpose of this study was to examine the incidence of breast cancer with triple-negative phenotype (TN BC) in the Russian population as well as to compare the clinical and morphological features and outcomes for women with TN BC with other types of breast cancer. We studied a cohort of 499 patients with breast cancer without distant metastases, diagnosed between 2002 and 2011 at N.N.Blokhin Russian Cancer Research Center in Moscow. Triple-negative breast cancers were defined as those that had "negative" level of estrogens and progesteron receptors and were HER2neu negative. 330 (66.2%) of patients has triple negative tumors, 81 (16.2%)--ER and PR negative and HER-2 positive tumors, and 88 (17.6%)--ER and/or ER positive and HER-2 negative tumors. Further was evaluated disease-free and overall survival. 18.5 % of all analyzed patients had triple negative phenotype. Median follow-up was 40.5 months. Characteristic features of the TN BC were: TN breast cancer, compared with other subtypes, characterized by a higher incidence of clinical and morphological features associated with an aggressive course of the disease: the age less than 35 years, grade 3, non- specified invasive histology, high level of Ki-67, the rapid development of the disease, which manifests itself in small terms of the first complaints before the diagnosis. TN BC patients has poorer 5-year overall survival (73.6 + 3.6%) and the 5-year disease-free survival (70.6 + 3.5%), which is significantly lower than the comparable survival of patients with other subtypes of breast cancer (p < 0.001). The results of our study confirm the similarity of majority of clinical and morphological characteristics, course and prognosis of the disease of the Russian population of TN BC patients with those in Europe and the United States.

[Her-2/neu, Ki-67 expression and ploidy in breast carcinoma]. / Ekspressiia Her-2/neu, Ki-67 i ploidnost' pri rake molochnoi zhelezy.

Expression of the markers was studied immunocytochemically on cytological preparations of breast tumor, ploidy was assessed by flow cytofluorimetry. The material was divided into 2 groups: diploid--41.4% cases and aneuploid--58.6%. Hyperexpression of Her-2/neu in the first group was observed in 54.5%, in the 2nd group in 48.6% cases. Expression of Ki-67 in 63.4% and in 68.9%, respectively. Tumours with high proliferative activity were numerous in aneuploid tissues, and in diploid tumours moderate activity prevailed (p = 0.006). Direct correlation between the markers was observed, high expression of Ki-67 more frequently was associated with positive expression of Her-2/neu. Thus, aneuploid tumours with high proliferative activity and hyperexpression of Her-2/neu are more aggressive tumours of a large size.

Expression of Flt-1 and Flk-1 receptors for vascular endothelial growth factor on tumor cells as a new prognostic criterion for locally advanced breast cancer.

We studied expression of Flt-1 and Flk-1 receptors on tumor cells obtained from 83 patients with locally advanced breast cancer after neoadjuvant chemotherapy. The mean period of observations was 32.3 months. The median recurrence-free survival periods for Flt-1(+) and Flt-1(-) patients were 55 and 32 months, respectively (p=0.0064). The overall survival periods for Flt-1(-) and Flt-1(+) patients were 45 and 67.6 months, respectively (p=0.014). The mean recurrence-free survival periods for Flk-1(+) and Flk-1(-) patients were 40.8 and 60.9 months, respectively (p=0.035). Expression of VEGF had no prognostic value. Our results show that overexpression of Flk-1 on breast cancer cells in patients receiving neoadjuvant chemotherapy is associated with a poor prognosis. By contrast, overexpression of Flt-1 improves survival.

[Comparison of immunocytochemical and immunohistochemical methods for biomarker detection in breast cancer]. / Sravnenie immunotsitokhimicheskogo i immunogistokhimicheskogo metodov opredeleniia biomarkerov pri rake molochnoi zhelezy.

The detection of the biological parameters of the tumor before the treatment beginning becomes of more importance. The present study aimed to carry out the comparative analysis of the molecular markers expression (P53, Ki-67, Her-2/neu, Bcl-2, Bax, ER, FasL and CD95) at the cytologic and the correspondent histologic samples. The 18 tissue samples of the breast cancer were investigated. The immunocytochemical and the immunohistochemical methods of the molecular markers determination were used. Our study showed the correlation between two methods and the possibility of the use of the immunocytochemical staining as routine method of the molecular markers expression determination.