[Tumor infiltrating lymphocytes (TILs) in triple negative breast cancer]. / Infil'triruyushchie opukhol' limfotsity (TILs) pri trizhdy negativnom rake molochnoi zhelezy.

BACKGROUND: Tumor infiltrating lymphocytes (TILs) are a promising inexpensive prognostic and predictive biomarker in breast cancer. High levels of TILs are associated with improved survival and higher probability to achieve pathological complete response in triple-negative breast cancer (TNBC). OBJECTIVE: To assess the level of TILs in TNBC samples and analyze the association between the level of TILs and the main pathological parameters, to identify their impact on long-term results. MATERIAL AND METHODS: The study included information on 140 patients with I-III stage TNBC and estrogen receptors <10%. Tumor tissue samples at baseline biopsies were evaluated the histological type, HER2 expression, estrogen expression levels, Ki-67 and TILs. The pathological response was evaluated according to the ypTNM, Miller-Payne, and RCB classifications. RESULTS: The average level of TILs in biopsy specimens before NACT was 29.3±23.1%. Low levels of TILs (<10%) were defined in 21% of cases, intermediate levels (≥10% to ≤40%) in 55% of cases, and high levels (>40%) in 24% of cases. Using the two-tiered system, low TILs (≤40%) were defined in 76% and high TILs (>40%) in 24% of cases. The level of TILs was correlated with histological grade (R=0.187; p=0.027) and estrogen receptor expression level (R=0.211; p=0.012). There were no significant differences depending on the level of TILs and other pathological parameters. Three-year event-free survival (EFS) in patients with high TILs levels was 95% versus 65% in the low TILs group (p=0.037). CONCLUSION: Stromal TILs are an important prognostic biomarker in TNBC. Using a cutoff of 40%, high TILs are significantly associated with longer EFS.

[Own experience of indocyanine green use in the diagnosis and treatment of breast cancer in N.N. Petrov NMRC of Oncology]. / Sobstvennyi opyt ispol'zovaniya indotsianina zelenogo v diagnostike i lechenii raka molochnoi zhelezy v NMITs onkologii im. N.N. Petrova.

OBJECTIVE: To evaluate the possibility of using the method of sentinel lymph nodes (SLN) detection with indocyanine green (ICG) in patients with early breast cancer and its informativeness. MATERIAL AND METHODS: A «Determination of sentinel lymph nodes by fluorescence method intraoperatively with the use of indocyanine green¼ study, in which 168 patients are currently included, is being conducted in the clinic of the N.N. Petrov NMRC of Oncology from 2017 through the present. All patients who underwent biopsy of sentinel lymph nodes (BSLN) were primary with a T1-2N0M0 stage of process. RESULTS: The average number of axillary lymph nodes removed in BSLN was 3 (1-5). Accumulation of ICG was found in 147 (88%) patients, accumulation of labeled radiocolloid - in 137 (82%), in combination of ICG/radiocolloid - in 167 (99%) based on the results of imaging. CONCLUSION: The obtained results prove that the informativeness and relative simplicity of this method use allow its application in any hospital where breast cancer is surgically treated, as well as in the absence of radioisotopic equipment.

A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4).

Background: Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models. Patients and methods: BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease. Patients were stratified by PI3K pathway activation and hormone receptor status. The primary endpoint was progression-free survival (PFS) in the full and PI3K pathway-activated populations. An adaptive interim analysis was planned following the phase II part of the study, after ≥125 PFS events had occurred in the full population, to decide whether the study would enter phase III (in the full or PI3K pathway-activated population) or be stopped for futility. Results: As of August 2014, 416 patients were randomized to receive buparlisib (207) or placebo (209) with paclitaxel. At adaptive interim analysis, there was no improvement in PFS with buparlisib versus placebo in the full (median PFS 8.0 versus 9.2 months, hazard ratio [HR] 1.18), or PI3K pathway-activated population (median PFS 9.1 versus 9.2 months, HR 1.17). The study met protocol-specified criteria for futility in both populations, and phase III was not initiated. Median duration of study treatment exposure was 3.5 months in the buparlisib arm versus 4.6 months in the placebo arm. The most frequent adverse events with buparlisib plus paclitaxel (≥40% of patients) were diarrhea, alopecia, rash, nausea, and hyperglycemia. Conclusions: Addition of buparlisib to paclitaxel did not improve PFS in the full or PI3K pathway-activated study population. Consequently, the trial was stopped for futility at the end of phase II.

Safety and immunogenicity of neoadjuvant treatment using WT1-immunotherapeutic in combination with standard therapy in patients with WT1-positive Stage II/III breast cancer: a randomized Phase I study.

PURPOSE: This Phase I, multicenter, randomized study (ClinicalTrials.gov NCT01220128) evaluated the safety and immunogenicity of recombinant Wilms' tumor 1 (WT1) protein combined with the immunostimulant AS15 (WT1-immunotherapeutic) as neoadjuvant therapy administered concurrently with standard treatments in WT1-positive breast cancer patients. METHODS: Patients were treated in 4 cohorts according to neoadjuvant treatment (A: post-menopausal, hormone receptor [HR]-positive patients receiving aromatase inhibitors; B: patients receiving chemotherapy; C: HER2-overexpressing patients on trastuzumab-chemotherapy combination; D: HR-positive/HER2-negative patients on chemotherapy). Patients (cohorts A-C) were randomized (2:1) to receive 6 or 8 doses of WT1-immunotherapeutic or placebo together with standard neoadjuvant treatment in a double-blind manner; cohort D patients received WT1-immunotherapeutic in an open manner. Safety was assessed throughout the study. WT1-specific antibodies were assessed pre- and post-vaccination. RESULTS: Sixty-two patients were randomized; 60 received ≥ one dose of WT1-immunotherapeutic. Two severe toxicities were reported: diarrhea (cohort C; also reported as a grade 3 serious adverse event) and decreased left ventricular ejection fraction (cohort B; also reported as a grade 2 adverse event). Post-dose 4 of WT1-immunotherapeutic, 10/10 patients from cohort A, 0/8 patients from cohort B, 6/11 patients from cohort C, and 2/3 patients from cohort D were humoral responders. The sponsor elected to close the trial prematurely. CONCLUSIONS: Concurrent administration of WT1-immunotherapeutic and standard neoadjuvant therapy was well tolerated and induced WT1-specific antibodies in patients receiving neoadjuvant aromatase inhibitors. In patients on neoadjuvant chemotherapy or trastuzumab-chemotherapy combination, the humoral response was impaired or blunted, likely due to either co-administration of corticosteroids and/or the chemotherapies themselves.

[The role of scintimammography with 99mTs-technetril to predict the pathologic status of regional lymph nodes in patients with locally advanced breast cancer after neoadjuvant chemotherapy].

The purpose of this study was to establish the role of scintimammography with 99mTs-technetril for predicting pathological status of regional lymph nodes after neoadjuvant chemotherapy. In 123 primary patients with locally advanced breast cancer stage cT1-4N0-3M0 there was performed scintimammography: before treatment and after 2-3 cycles of neoadjuvant chemotherapy 63 patients; after 2-3 cycles of neoadjuvant chemotherapy and before surgery--in 5 patients; after 4-6 cycles of neoadjuvant chemotherapy--55 women. All patients were divided into 2 groups: the first included 68 patients whom scintimammography was performed before and after 2-3 cycles of neoadjuvant chemotherapy; the second--60 women whom scintimammography was performed before treatment and before surgery. In patients of the first group positive results were obtained in 16 (23.5%), negative--26 (38.3%), false positive--16 (23.5%) and false negative--10 (14.7%) cases. Sensitivity, specificity, overall accuracy, positive predictive value and negative results were 61.5%, 61.9%, 61.7%, 50% and 72.2%, respectively. During the scintimammography after 4-6 cycles of neoadjuvant chemotherapy positive results were observed in 17 (28.3%) negative--18 (30%), false positive--19 (31.7%) and false negative--6 (10%) of patients. Thus, the sensitivity, specificity, overall accuracy, positive predictive value and negative results amounted to 73.9%, 48.6%, 58.3%, 47.2%, 75% respectively.

[Use of SPECT-CT for visualization of sentinel lymph nodes in breast cancer patients].

This study was performed in order to determine individual variability of axillary sentinel lymph nodes (SLN) localization in patient with breast cancer (BC). Individual topography of axillary SLN was determined in 182 patients with early BC. All women were candidates for conservative surgical treatment with postoperative radiotherapy. SPECT-CT visualization of SLN started 120-240 min after intratumoral injection of 74-150MBq of 99mTc-radiocolloids. Distribution of axillary SLN was allocated to following subregions: central (C), pectoral (P), apical (AP), lateral (L), subscapular (SSc). SLN visualization by SPECT-CT was successful in 153 cases (84%). AP nodes were detected in 7 patients (5%). SLN were localized on thoracic wall in 34 cases (22%), in the intrapectoral region--in 3 (2%) women. According to axillary levels they were detected on level I--in 149 (97%), level II--15 (10%), level III-- (7.5%) cases.

[METHODOLOGIC PROBLEMS OF SENTINEL LYMPH NODE BIOPSY IN PATIENTS WITH BREAST CANCER].

The study included data on 168 patients with breast cancer, surgical treatment of whom was supplemented by axillary dissection (133 patients or 79.2%) or biopsy of sentinel lymph nodes (35 patients or 20.8%). The examination included ultrasound, planar scintigraphy of the breast and zones of regional lymph drainage. In 122 patients with primary breast cancer stage cT1-2N0M0 retrospective analysis of radionuclide imaging sentinel lymph node was performed. In 89 patients the introduction of colloidal radiopharmaceutical was carried out using a particle diameter of not more than 80-100 nm, in 33 patients study was conducted after administration of radiocolloid with a particle diameter of 200 to 1000 nm. Based on the data obtained by scintigraphy and ultrasonography of zones of regional lymph drainage there were offered two diagnostics models: the first, in which the presence of metastatic axillary lymph nodes was established when there were changes according to at least one of the diagnostic methods--scintigraphy or ultrasound; the second, in which the defeat of lymph nodes was determined only in the case of simultaneous detection of ultrasound and scintigraphic evidence of axillary lymph nodes. Sensitivity, specificity, and overall accuracy of the combination of ultrasound and planar scintigraphy axillary lymph nodes using the first model accounted for 82.7%, 67.7% and 74.4%, respectively. In the second model, the specificity was 94.6%, sensitivity--56%. Rapid transport of radiopharmaceuticals from the injection site, a high gradient of radiopharmaceuticals accumulation in sentinel lymph nodes, effective their visualization, approaching to 100%, were undoubted advantages of radiocolloids having a particle diameter up to 100 nm.

Capivasertib and fulvestrant for patients with hormone receptor-positive advanced breast cancer: characterization, time course, and management of frequent adverse events from the phase III CAPItello-291 study.

BACKGROUND: Capivasertib is a potent, selective pan-AKT inhibitor. In CAPItello-291, the addition of capivasertib to fulvestrant resulted in a statistically significant (P < 0.001) improvement in progression-free survival over fulvestrant monotherapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer and disease progression on or after aromatase inhibitor-based therapy. Characterization of the capivasertib-fulvestrant adverse event (AE) profile as managed in CAPItello-291 can inform future management guidance and optimize clinical benefit. PATIENTS AND METHODS: Seven hundred and eight patients were randomized 1 : 1 to capivasertib (400 mg twice daily; 4 days on, 3 days off) or placebo, plus fulvestrant, on a 4-week cycle. Dose reductions/interruptions for capivasertib/placebo were permitted (up to two dose reductions). Safety analyses included exposure, AE, and clinical laboratory data and were conducted in patients who received at least one dose of capivasertib, fulvestrant, or placebo. Frequent AEs associated with phosphoinositide 3-kinase (PI3K)/protein kinase (AKT) pathway inhibition (diarrhea, rash, hyperglycemia) were characterized using group terms. AEs were summarized using descriptive statistics; time-to-event analyses were conducted. RESULTS: Safety analyses included 705 patients: capivasertib-fulvestrant (n = 355) and placebo-fulvestrant (n = 350). Frequent any-grade AEs with capivasertib-fulvestrant were diarrhea (72.4%), rash (38.0%), and nausea (34.6%); frequent grade ≥3 AEs were rash (12.1%), diarrhea (9.3%), and hyperglycemia (2.3%). Diarrhea, rash, and hyperglycemia occurred shortly after starting capivasertib-fulvestrant [median days to onset (interquartile range) of any grade: 8 (2-22), 12 (10-15), and 15 (1-51), respectively], and were managed with supportive medications, dose reductions, interruptions, and/or discontinuation. Discontinuation rates were 2.0%, 4.5%, and 0.3%, respectively. Overall, 13.0% discontinued capivasertib due to AEs. CONCLUSIONS: Frequent AEs associated with PI3K/AKT pathway inhibition occurred early and were manageable. The low rate of treatment discontinuations suggests that, when appropriately managed, these AEs do not pose a challenge to clinical benefit.