Resistance of breast cancer cells to paclitaxel is associated with low expressions of miRNA-186 and miRNA-7.

Aim: Neo-adjuvant chemotherapy is a common approach for the complex treatment of breast cancer (BC) and paclitaxel (PTX) is frequently included in the therapeutic regimen. However, the effect of PTX-based treatment is hard to predict precisely based on routinely used markers. As microRNAs are considered a new promising class of biomarkers, the link between miRNA expression and PTX resistance of BC cells needs to be well investigated. This study aimed at the identification of miRNAs associated with responses of BC cells to PTX. Methods: Intrinsic PTX sensitivity and miRNA profiling were assayed in five BC cell lines to identify candidate miRNAs. Selected miRNA (n. 15) expressions were analyzed by real-time-quantitative polymerase chain reaction (RT-qPCR) in BC tissue samples (n. 31) obtained from a diagnostic biopsy. Results were analyzed in the context of the effect of two cycles of PTX and the effect of the completed scheme of neoadjuvant therapy. The study's design facilitated the evaluation of the effect of PTX on cells and the identification of features of the microRNA expression profiles associated exclusively with sensitivity to this drug. Results: miR-186 and miR-7 expression in BC tissues was higher in patients with better outcomes of PTX-based neoadjuvant therapy. Conclusion: High expressions of miR-186 and miR-7 are associated with good response to PTX, whereas their low expressions may be associated with resistance to PTX in BC, indicating the possibility of developing innovative test systems for the prediction of the PTX response, which can be used before the start of neo-adjuvant chemotherapy for BC.

Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer.

BACKGROUND: AKT pathway activation is implicated in endocrine-therapy resistance. Data on the efficacy and safety of the AKT inhibitor capivasertib, as an addition to fulvestrant therapy, in patients with hormone receptor-positive advanced breast cancer are limited. METHODS: In a phase 3, randomized, double-blind trial, we enrolled eligible pre-, peri-, and postmenopausal women and men with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer who had had a relapse or disease progression during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy. Patients were randomly assigned in a 1:1 ratio to receive capivasertib plus fulvestrant or placebo plus fulvestrant. The dual primary end point was investigator-assessed progression-free survival assessed both in the overall population and among patients with AKT pathway-altered (PIK3CA, AKT1, or PTEN) tumors. Safety was assessed. RESULTS: Overall, 708 patients underwent randomization; 289 patients (40.8%) had AKT pathway alterations, and 489 (69.1%) had received a CDK4/6 inhibitor previously for advanced breast cancer. In the overall population, the median progression-free survival was 7.2 months in the capivasertib-fulvestrant group, as compared with 3.6 months in the placebo-fulvestrant group (hazard ratio for progression or death, 0.60; 95% confidence interval [CI], 0.51 to 0.71; P<0.001). In the AKT pathway-altered population, the median progression-free survival was 7.3 months in the capivasertib-fulvestrant group, as compared with 3.1 months in the placebo-fulvestrant group (hazard ratio, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The most frequent adverse events of grade 3 or higher in patients receiving capivasertib-fulvestrant were rash (in 12.1% of patients, vs. in 0.3% of those receiving placebo-fulvestrant) and diarrhea (in 9.3% vs. 0.3%). Adverse events leading to discontinuation were reported in 13.0% of the patients receiving capivasertib and in 2.3% of those receiving placebo. CONCLUSIONS: Capivasertib-fulvestrant therapy resulted in significantly longer progression-free survival than treatment with fulvestrant alone among patients with hormone receptor-positive advanced breast cancer whose disease had progressed during or after previous aromatase inhibitor therapy with or without a CDK4/6 inhibitor. (Funded by AstraZeneca and the National Cancer Institute; CAPItello-291 ClinicalTrials.gov number, NCT04305496.).

Intraoperative Assessment of Breast Cancer Tissues after Breast-Conserving Surgery Based on Mapping the Attenuation Coefficients in 3D Cross-Polarization Optical Coherence Tomography.

Intraoperative differentiation of tumorous from non-tumorous tissue can help in the assessment of resection margins in breast cancer and its response to therapy and, potentially, reduce the incidence of tumor recurrence. In this study, the calculation of the attenuation coefficient and its color-coded 2D distribution was performed for different breast cancer subtypes using spectral-domain CP OCT. A total of 68 freshly excised human breast specimens containing tumorous and surrounding non-tumorous tissues after BCS was studied. Immediately after obtaining structural 3D CP OCT images, en face color-coded attenuation coefficient maps were built in co-(Att(co)) and cross-(Att(cross)) polarization channels using a depth-resolved approach to calculating the values in each A-scan. We determined spatially localized signal attenuation in both channels and reported ranges of attenuation coefficients to five selected breast tissue regions (adipose tissue, non-tumorous fibrous connective tissue, hyalinized tumor stroma, low-density tumor cells in the fibrotic tumor stroma and high-density clusters of tumor cells). The Att(cross) coefficient exhibited a stronger gain contrast of studied tissues compared to the Att(co) coefficient (i.e., conventional attenuation coefficient) and, therefore, allowed improved differentiation of all breast tissue types. It has been shown that color-coded attenuation coefficient maps may be used to detect inter- and intra-tumor heterogeneity of various breast cancer subtypes as well as to assess the effectiveness of therapy. For the first time, the optimal threshold values of the attenuation coefficients to differentiate tumorous from non-tumorous breast tissues were determined. Diagnostic testing values for Att(cross) coefficient were higher for differentiation of tumor cell areas and tumor stroma from non-tumorous fibrous connective tissue: diagnostic accuracy was 91-99%, sensitivity-96-98%, and specificity-87-99%. Att(co) coefficient is more suitable for the differentiation of tumor cell areas from adipose tissue: diagnostic accuracy was 83%, sensitivity-84%, and specificity-84%. Therefore, the present study provides a new diagnostic approach to the differentiation of breast cancer tissue types based on the assessment of the attenuation coefficient from real-time CP OCT data and has the potential to be used for further rapid and accurate intraoperative assessment of the resection margins during BCS.

Different approaches to target volume definition and boost delivery in surgery de-escalation clinical trial in breast cancer patients with pathological complete response.

PURPOSE: We evaluate various approaches to target volume definition and boost delivery in patients with complete response to neoadjuvant systemic therapy (NST) who were treated by radiotherapy without a surgery. MATERIALS AND METHODS: A pathological complete response (pCR) was diagnosed in 21 of 27 patients included in "surgery de-escalation" prospective observation study. Clips were placed in the primary tumor volume (PrTV) before NST and during the vacuum aspiration biopsy. Twenty patients with pCR underwent the whole breast irradiation and a boost to the PrTV. High-dose rate brachytherapy (HDRB) was the basic technique for boost delivery. Finally, we identified the value of fused images (computed tomography [CT] before NST with simulation CT), clips and their combination for an accurate boost delivery. RESULTS: A complete overlap between PrTV on pre-treatment CT with the localization of the clips on simulation CT was mentioned in 10, partial mismatch in three patients. In 12 of these 13 women, HDRB was successfully used for the boost delivery. In five cases we mentioned a marked discrepancy between the PrTV on fused images and the topography of the clips. In other two women we did not find clips on simulation CT. The fused images in five of these seven patients showed anatomical landmarks (scar, fibrosis) used for identification of the gross tumor volume. In all 20 women with pCR (average follow-up of 16.6 months), there were no locoregional recurrences. CONCLUSION: Combination of the clips with fusion of pre-NST and simulation CTs is important for an accurate boost delivery.

Modern Breast Cancer Surgery 1st Central-Eastern European Professional Consensus Statement on Breast Cancer.

This text is based on the recommendations accepted by the 4th Hungarian Consensus Conference on Breast Cancer, modified on the basis of the international consultation and conference within the frames of the Central-Eastern European Academy of Oncology. The recommendations cover non-operative, intraoperative and postoperative diagnostics, determination of prognostic and predictive markers and the content of cytology and histology reports. Furthermore, they address some specific issues such as the current status of multigene molecular markers, the role of pathologists in clinical trials and prerequisites for their involvement, and some remarks about the future.

Immunology and immunotherapy in breast cancer.

Immuno-oncology is a rapidly developing field in medicine. Drug combination therapies have already been studied in many clinical trials on various tumor types. In recent years, a checkpoint inhibition therapy with monoclonal antibodies targeting PD-1 and its ligand PD-L1 has been developed. Breast cancer had been examined in the field of immune-oncology relatively recently. This review focuses on clinical evidence regarding immune checkpoint inhibition for curative treatment of various breast cancer subtypes. In addition, we present the results of studies demonstrating the prognostic and predictive value of levels of tumorinfiltrating lymphocytes (CD4 and CD8), their quantitative ratios, and their correlation with regulatory genes (PD-1, PD-L1, and FOX-P3).

TiLoop Bra Assisted Breast Reconstruction - Our Experience.

Additional covering of the lower pole with allomaterial or its synthetic analogues during immediate breast reconstruction is being perfomed at the N.N. Petrov National Medical Research Oncology Center, Ministry of Healthcare of Russian Federation for last 7 years. Initially, epidermal flap was the only option for lower pole coverage, later ADM was used as part of clinical approbation. Average complication rate ranges from 20-35% due to blood circulatory (supply) disorders. Since 2018, a titanized mesh (TiLoop Bra) been used as a additional coverage of the lower pole. Methods: From July 2018 to April 2019, 103 breast reconstructions were performed using TiLoop-BRA mesh. All operations were performed due to malignant tumors of breast, of which in 94 operations were performed for unilateral breast carcinoma, 9 for bilateral breast carcinoma.74 patients received neoadjuvant therapy, 31 received adjuvant therapy, 17 patients required radiation therapy. Results: Overall complications rates significally decreased. Complete loss of breast implant and mesh endoprosthesis 5.88%, Capsular contracture 17.65 %, Only mesh removal due to painful syndrome 5.88%,* Red breast * syndrome (by analogy with ADM) 5.88%.

Surgical Management of the Axilla in Clinically Node-Positive Breast Cancer Patients Converting to Clinical Node Negativity through Neoadjuvant Chemotherapy: Current Status, Knowledge Gaps, and Rationale for the EUBREAST-03 AXSANA Study.

In the last two decades, surgical methods for axillary staging in breast cancer patients have become less extensive, and full axillary lymph node dissection (ALND) is confined to selected patients. In initially node-positive patients undergoing neoadjuvant chemotherapy, however, the optimal management remains unclear. Current guidelines vary widely, endorsing different strategies. We performed a literature review on axillary staging strategies and their place in international recommendations. This overview defines knowledge gaps associated with specific procedures, summarizes currently ongoing clinical trials that address these unsolved issues, and provides the rationale for further research. While some guidelines have already implemented surgical de-escalation, replacing ALND with, e.g., sentinel lymph node biopsy (SLNB) or targeted axillary dissection (TAD) in cN+ patients converting to clinical node negativity, others recommend ALND. Numerous techniques are in use for tagging lymph node metastasis, but many questions regarding the marking technique, i.e., the optimal time for marker placement and the number of marked nodes, remain unanswered. The optimal number of SLNs to be excised also remains a matter of debate. Data on oncological safety and quality of life following different staging procedures are lacking. These results provide the rationale for the multinational prospective cohort study AXSANA initiated by EUBREAST, which started enrollment in June 2020 and aims at recruiting 3000 patients in 20 countries (NCT04373655; Funded by AGO-B, Claudia von Schilling Foundation for Breast Cancer Research, AWOgyn, EndoMag, Mammotome, and MeritMedical).

Frequency and spectrum of founder and non-founder BRCA1 and BRCA2 mutations in a large series of Russian breast cancer and ovarian cancer patients.

BACKGROUND: The spectrum of BRCA1 and BRCA2 mutations in Slavic countries is characterized by a high prevalence of founder alleles. METHODS: We analyzed a large data set of Russian breast cancer (BC) and ovarian cancer (OC) patients, who were subjected to founder mutation tests or full-length BRCA1 and BRCA2 analysis. RESULTS: The most commonly applied test, which included four founder mutations (BRCA1: 5382insC, 4153delA, 185delAG; BRCA2: 6174delT), identified BRCA1 or BRCA2 heterozygosity in 399/8533 (4.7%) consecutive BC patients, 230/2317 (9.9%) OC patients, and 30/118 (25.4%) women with a combination of BC and OC. The addition of another four recurrent BRCA1 mutations to the test (BRCA1 C61G, 2080delA, 3819del5, 3875del4) resulted in evident increase in the number of identified mutation carriers (BC: 16/993 (1.6%); OC: 34/1289 (2.6%); BC + OC: 2/39 (5.1%)). Full-length sequencing of the entire BRCA1 and BRCA2 coding region was applied to 785 women, very most of whom demonstrated clinical signs of BRCA-driven disease, but turned out negative for all described above founder alleles. This analysis revealed additional BRCA1 or BRCA2 mutation carriers in 54/282 (19.1%) BC, 50/472 (10.6%) OC, and 13/31 (42%) BC + OC patients. The analysis of frequencies of founder and "rare" BRCA1 and BRCA2 pathogenic alleles across various clinical subgroups (BC vs. OC vs. BC + OC; family history positive vs. negative; young vs. late-onset; none vs. single vs. multiple clinical indicators of BRCA1- or BRCA2-associated disease) revealed that comprehensive BRCA1 and BRCA2 analysis increased more than twice the number of identified mutation carriers in all categories of the examined women. CONCLUSION: Full-length BRCA1 and BRCA2 sequencing is strongly advised to Slavic subjects, who have medical indications for BRCA1 and BRCA2 testing but are negative for recurrent BRCA1 and BRCA2 mutations.

SPECT-CT localization of axillary sentinel lymph nodes for radiotherapy of early breast cancer.

PURPOSE: To evaluate the opportunities of single photon emission tomography/computerized tomography (SPECT-CT) for localization of axillary sentinel lymph nodes (ASLNs) and subsequent radiotherapy planning in women with early breast cancer. MATERIAL AND METHODS: Individual topography of ASLN was determined in 151 women with clinical T1-2N0M0 breast cancer. SPECT-CT visualization of ASLNs was initiated 120 min after intra-peritumoral injection of 99mTc-radiocolloids. Doses absorbed by virtual ASLNs after the whole breast irradiation with standard and extended tangential fields were calculated on a treatment planning station. RESULTS: SPECT-CT demonstrated a large variability of ASLN localization. They were detected in the central subgroup in 94 (61%) patients, in pectoral - in 77 (51%), and in interpectoral - in 4 (3%) patients. Sentinel lymph nodes "lying on the chest" were revealed in 35 (23%) cases.We found that with standard tangential fields coverage of ASLNs was obtained only in 20% of evaluated women. Extended tangential fields can effectively irradiate ASLNs localized in all axillary sub-regions with the exception of ASLNs "lying on the chest". CONCLUSION: SPECT-CT mapping of ASLNs in women with cT1-2N0M0 breast cancer reveals their variable localization. This information can be important for planning of radiation treatment in women that underwent breast conserving surgery without an axillary surgery.

99mTc-MIBI scintimammography and digital mammography in the diagnosis of multicentric breast cancer.

OBJECTIVE: To compare diagnostic accuracy of scintimammography (SMG) and digital mammography (DS) in the diagnosis of multicentric breast cancer. SUBJECTS AND METHODS: Three hundred and sixty seven women with histologically confirmed breast cancer were included in this analysis. All patients were candidates for conservative breast surgery and had cT1-3N0-1 stage of disease. Scintimammography was performed in prone position 5-10min after intravenous injection of 740MBq of technetium-99m-methoxy-isobtyl-isonitrile (99mTc-MIBI) with acquisition time of 10min for every lateral and anterior projection. Digital mammography was done in all women according to a standard clinical protocol. Final diagnosis was established by histopathology. Multicentric breast cancer was defined as 2 or more distinct invasive tumors located in more than one quadrant or additional lesions from the primary tumor of more than 4cm in size. RESULTS: According to histopathological examinations multicentric breast cancer was diagnosed in 47 of 367 (12.8%) patients. Scintimammography was more effective than mammography in detecting multicentric breast cancer: sensitivity: 83.0% vs 40.4% (P<0.001), specificity: 97.8% vs 95.3% (P=0.4), accuracy: 95.9% vs 88.3% (P<0.001), positive and negative predictive values: 84.8% vs 55.9% (P=0.004) and 97.5% vs 91.6% (P<0.001), respectively. Combination of DM and SMG was characterized by increased sensitivity (93.6%), worse specificity (93.4%), accuracy (93.4%) and worse predictive value (67.7%) as compared to only SMG. CONCLUSION: Scintimammography was significantly much better by all statistical parameters than DM in the detection of multicentric breast cancer. High positive predictive value of scintimammography (84.8%) advocates it as a tool for surgery and radiotherapy planning.

The use of single-photon emission computed tomography-computed tomography in detecting multiple metastatic lymph nodes in patients with breast cancer.

AIM: The aim of the present study was to determine the accuracy of single-photon emission computed tomography-computed tomography (SPECT-CT) with technetium-99m-sestamibi (Tc-MIBI) for detecting multiple (>2 nodes) axillary lymph node involvement in patients with breast cancer (BC). PATIENTS AND METHODS: A total of 184 women with BC were examined. Clinically, axillary lymph nodes were classified as N0 in all cases. Patients underwent SPECT-CT breast and axillary region imaging 10-15 min after a 740 mBq intravenous injection of Tc-MIBI. SPECT-CT data were then verified by definitive histopathological examination (sentinel-node biopsy and/or axillary lymph node dissection were used as reference standard). Diagnostic values of different CT and SPECT signs of multiple (>2) lymph node involvement were evaluated. RESULTS: Histological examination of excised lymph nodes showed metastatic involvement in 62 (33.7%) out of 184 patients. In fact, 25 (13.6%) patients had more than two lymph node involvements. In another 37 (20.1%) cases the metastasis was revealed in one or two sentinel lymph nodes only. The main SPECT-CT criteria of multiple (>2) lymph node involvement were as follows: the maximum size of the primary tumor (>20 mm), lymph node dimensions (>12 mm along the long axis and >10 mm along the short axis), nodal cortical thickness (>4 mm), round shape, solid structure, quantity of identified abnormal lymph nodes (>1), and intensity of tracer uptake. The developed integrated model offers the possibility to exclude multiple lymph node metastasis (>2) in BC patients with a probability of 99%. CONCLUSION: This single-center study showed that in patients with BC, a combination of functional and anatomical data that were obtained by using SPECT-CT with Tc-MIBI can significantly improve detectability of multiple (>2) axillary metastases.

PF-05280014 (a trastuzumab biosimilar) plus paclitaxel compared with reference trastuzumab plus paclitaxel for HER2-positive metastatic breast cancer: a randomised, double-blind study.

BACKGROUND: This randomised, double-blind study compared PF-05280014 (a trastuzumab biosimilar) with reference trastuzumab (Herceptin®) sourced from the European Union (trastuzumab-EU), when each was given with paclitaxel as first-line treatment for HER2-positive metastatic breast cancer. METHODS: Between 4 April 2014 and 22 January 2016, 707 participants were randomised 1:1 to receive intravenous PF-05280014 plus paclitaxel (PF-05280014 group; n = 352) or trastuzumab-EU plus paclitaxel (trastuzumab-EU group; n = 355). PF-05280014 or trastuzumab-EU was administered weekly (first dose 4 mg/kg, subsequent doses 2 mg/kg), with the option to change to a 3-weekly regimen (6 mg/kg) from Week 33. Treatment with PF-05280014 or trastuzumab-EU could continue until disease progression. Paclitaxel (starting dose 80 mg/m2) was administered on Days 1, 8 and 15 of 28-day cycles for at least six cycles or until maximal benefit of response. The primary endpoint was objective response rate (ORR), evaluating responses achieved by Week 25 and confirmed by Week 33, based on blinded central radiology review. RESULTS: The risk ratio for ORR was 0.940 (95% CI: 0.842-1.049). The 95% CI fell within the pre-specified equivalence margin of 0.80-1.25. ORR was 62.5% (95% CI: 57.2-67.6%) in the PF-05280014 group and 66.5% (95% CI: 61.3-71.4%) in the trastuzumab-EU group. As of data cut-off on 11 January 2017 (using data up to 378 days post-randomisation), there were no notable differences between groups in progression-free survival (median: 12.16 months in the PF-05280014 group vs. 12.06 months in the trastuzumab-EU group; 1-year rate: 54% vs. 51%) or overall survival (median: not reached in either group; 1-year rate: 89.31% vs. 87.36%). Safety outcomes and immunogenicity were similar between the treatment groups. CONCLUSION: When given as first-line treatment for HER2-positive metastatic breast cancer, PF-05280014 plus paclitaxel demonstrated equivalence to trastuzumab-EU plus paclitaxel in terms of ORR. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01989676.

Axillary lymph node staging in breast cancer: clinical value of single photon emission computed tomography-computed tomography (SPECT-CT) with 99mTc-methoxyisobutylisonitrile.

OBJECTIVE: To determine diagnostic accuracy of SPECT, CT and SPECT-CT in axillary lymph node (LN) staging in breast cancer (BC). METHODS: Sixty consecutive patients with primary operable T1-3NxM0 BC were included in this study. All patients underwent SPECT-CT examination on Symbia-T16 scanner which consists of dual-head gamma camera combined with 16 slices diagnostic CT. SPECT-CT acquisition started 10-15 min after i/v injection of 740-1,000 MBq of 99mTc-MIBI. On CT images of axillary LN we analyzed following diagnostic signs: size (short axis more or less than 10 mm), shape (round or oval), cortical thickness and fat content (solid or with fat gate). Intensity of tracer uptake in axillary LN was classified as follows: grade (Gr) I-background, Gr II-slightly above background, Gr III-intense but below uptake in muscles, Gr IV-as high as in muscles. Histological examination of dissected LN was used as gold standard. RESULTS: Various combinations of CT signs of axillary LN involvement demonstrated moderate diagnostic value with best results characterized by low (55 %) sensitivity (SEN), 97 % specificity (SP) and 83 % accuracy (AC). Intensive (Gr IV) uptake of 99mTc-MIBI in axillary LN characterized by low (55 %) SEN, high (100 %) SP and moderate (84 %) AC. Combination of CT and SPECT signs looks most promising especially when LN metastases were diagnosed in patients with enlarged solid LN or normal sized LN with Gr III-IV 99Tc-MIBI uptake. In these cases, SEN was equal to 75 %, SP-90 %, AC-85 %, only one of 5 patients with false negative results had metastases in more than 2 LN. CONCLUSIONS: By combination of SPECT and CT data we can more accurately diagnose axillary LN invasion by breast cancer.