Biological Subtypes Research Articles

Abstract ED5-2: Support for patients with MBC

Abstract ED5-2: Support for patients with MBC

Abstract PD11-02: PD11-02 A Phase II Randomized Window of Opportunity Trial Evaluating Cytotoxic and Immunomodulatory effects of Intratumoral INT230-6 in Early Stage Breast Cancer: the INVINCIBLE Trial

Abstract Background: The majority of breast cancers outside of the triple negative subtype are considered immunological quiescent and are therefore minimally responsive to immunotherapies. One potential method to combat this is through local therapies that induce cell death, thereby exposing tumor antigens, providing adjuvants for anti-tumor immune priming, and potentially increasing responsiveness to immunotherapies. We have conducted a randomized, Phase 2 presurgical Window-Of-Opportunity trial for intratumoral (IT) INT230-6 (comprising VINblastine (VIN) Cisplatin (VIN)) evaluating clinical and BioLogical Effects in patients with early-stage operable Breast Cancer (the INVINCIBLE trial- https://clinicaltrials.gov/ct2/show/NCT04781725). INT230-6 contains a dispersion enhancer molecule (SHAO) with the cytotoxic agents and is designed to cause tumor necrosis by dispersion throughout the tumor and diffusion into cancer cells. Previous in vitro studies have demonstrated that INT230-6 halts cancer cell replication and induces cell death recruiting dendritic cells and T-cells to the tumor microenvironment. In this trial, IT injections of INT230-6 are conducted to 1) exploit the potential of regional cytotoxic chemotherapy on breast cancer in vivo and 2) assess the immune response within the tumor, microenvironment and systemically in the host blood prior to surgical resection. Methods: Women with newly diagnosed and awaiting surgery for early-stage intermediate or high-grade T1-T2 invasive breast cancers were recruited to the trial. The study has two parts. Part I was a randomized (2:1) open label trial comparing 1-3 doses of INT230-6 injected weekly versus no treatment prior to surgery to evaluate safety, feasibility, and optimal drug dosing. Part II was a double-blinded randomized (2:1) trial where patients received one IT dose of INT230-6 vs saline injection. The primary objective was to estimate the proportion of patients with tumor necrosis and complete cell cycle arrest (CCCA) at the time of surgery compared to control. In addition, we performed targeted sequencing and proteomic profiling in tumour samples from the INT230-6 clinical trial. Results: The study recruited 90 patients with age ranges of 40-77 yrs (mean = 60 yrs) with tumors ranging from 1.5-4.3 cm (mean = 2.4cm). No surgeries were delayed or altered as a result of trial participation and the most common (>10%) AEs were injection site pain, injection site reaction and nausea/vomiting. Compared to the control group, up to 95% tumor necrosis was present in varying biologic subtypes and histologies, including invasive lobular carcinoma. Preliminary gene expression analysis showed significant differential gene expression between the baseline biopsy and surgical specimens. Pathway analysis identified genes associated with TCR signaling, B cells, T cells, chemokine signaling and NF-κB signaling were significantly changed in the post treatment samples. There was a relative increase in CD4 and CD8 T cells and B and NK cells within the tumor and in the tumour microenvironment. Conclusion: Preliminary evidence shows that a single dose of INT230-6 can cause substantial tumor necrosis and stimulate an immune response in breast cancers prior to surgery with minimal adverse effects and good tolerability. This window of opportunity clinical trial demonstrates that INT230-6 injection is a novel and simple method to convert traditionally immune quiescent breast cancers into immunogenic tumors. This can open the door to future potential immunotherapeutic options in early stage breast cancer. Citation Format: Angel Arnaout, Susan Robertson, Kianoosh Keyhanian, Megan Hopkins, Linda Liao, Vida Talebian, Arif Awan, John MS Bartlett, Gregory R. Pond, Lazlo Radvanyi, Lewis H. Bender, Ian B. Walters, Vanessa Lopez Ozuna, Melanie Spears. PD11-02 A Phase II Randomized Window of Opportunity Trial Evaluating Cytotoxic and Immunomodulatory effects of Intratumoral INT230-6 in Early Stage Breast Cancer: the INVINCIBLE Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-02.

Biologic Therapy Carries a Very Low Risk of Reactivation in Hepatitis B Surface Antigen-Negative Phase of Hepatitis B.

The risk of hepatitis B reactivation in hepatitis B surface antigen-negative phase of hepatitis B virus-infected patients exposed to biologic agents is not clear. We aimed to investigate the reactivation rate in hepatitis B surface antigen-negative phase of hepatitis B virus-infected patients after biologic therapy. Patients followed at gastroenterology, rheumatology, and dermatology clinics with a diagnosis of immune-mediated inflam matory diseases were screened. Immune-mediated inflammatory diseases patients exposed to biologic agents with a negative hepatitis B surface antigen and positive hepatitis B core immunoglobulin G antibody were included in the study. We screened 8266 immune-mediated inflammatory disease patients, and 2484 patients were identified as exposed to biologic agents. Two hundred twenty-one patients were included in the study. The mean age was 54.08 ± 11.69 years, and 115 (52.0%) patients were female. The median number of different biologic subtype use was 1 (range: 1-6). The mean biologic agent exposure time was 55 (range: 2-179) months. One hundred and fifty-two (68.8%) patients used a concomitant immunomodulatory agent, and 84 (38.0%) patients were exposed to corticosteroids during biologic use. No hepatitis B reactivation with a reverse seroconversion of hepatitis B surface antigen positivity was seen. Antiviral prophylaxis for hepatitis B was applied to 48 (21.7%) patients. Hepatitis B virus-DNA was screened in 56 (25.3%) patients prior to the biologic exposure. Two patients without antiviral prophylaxis had hepatitis B virus-DNA reactivation with a negative hepatitis B surface antigen during exposure to the biologic agent. We found 2 reactivations and no hepatitis B surface antigen seroconversion in our cohort. Antiviral prophylaxis for patients exposed to biologic agents may need to be discussed in more detail.

Biological subtyping of psychiatric syndromes as a pathway for advances in drug discovery and personalized medicine

Every common psychiatric syndrome is genetically, neurobiologically and clinically heterogeneous. This heterogeneity may reflect the dimensional variability of a single illness with common etiology, varying in severity. Alternatively, as in many areas of medicine, it may reflect different discrete types of illness leading to similar alterations of mood or behavior. Resolving uncertainty as to the nature of heterogeneity in psychiatric illness is crucial for advancing the development of novel therapeutics and improving the precision with which pharmacological interventions are chosen for specific patients. Recent work resolving illness heterogeneity has shown promise in identifying biologically distinct patient subgroups within common psychiatric syndromes. This progress offers hope for the longer-term aim of enhancing our understanding of biological alterations associated with psychiatric syndromes, so that drug development and pharmacological interventions can shift towards altering specific targeted biological processes, instead of working to change complex behavioral features that may represent the final common pathway of different biological illness mechanisms. Using approaches such as neuroimaging and peripheral immune markers, studies have identified subgroups with different patterns of biological features that provide translational targets for novel drug development programmes, and may, in the longer term, together with psychological and social perspectives, more closely link diagnostics and therapeutics in psychiatry. So far, multiple discrete subgroups have been identified, and these have been associated with clinical features. Work is now needed to improve the validity and reliability of biologically derived subtypes, and better characterize their clinical, developmental and psychosocial features. This is required to establish their clinical utility for predicting illness course and response to different therapies, and to determine how biologically distinct features of patient subgroups can guide the development of novel therapies targeting those alterations.

Amide proton transfer (APT) imaging of breast cancers and its correlation with biological status

PurposeTo assess the usefulness of amide proton transfer (APT) imaging to predict the biological status of breast cancers. MethodSixty-six patients (age range 31–85 years, mean 58.9 years) with histopathologically proven invasive ductal carcinomas of 2 cm or larger in diameter were included in this study. 3D APT weighted imaging was conducted on a 3 T scanner. Mean APT signal intensity (SI) was analyzed in relation to biological subtypes, Ki-67 labeling index, and nuclear grades (NGs). ResultsThe triple-negative (TN) cancers (n = 10; 2.75 ± 0.42%) showed significantly higher APT SI than the luminal type cancers (n = 48; 1.74 ± 0.83) and HER2 cancers (n = 8; 1.83 ± 0.21) (P = 0.0007, 0.03). APT SI had weakly positive correlation with the Ki-67 labeling index (r = 0.38, P = 0.002). The mean APT SIs were significantly higher for high-Ki-67 (>30%) (n = 31; 2.25 ± 0.70) than low-Ki-67 (≤30%) cancers (n = 35; 1.60 ± 0.79) (P = 0.0007). There was no significant difference in the APT SIs between NG 1–2 (n = 31; 1.71 ± 0.84) and NG 3 (n = 35; 2.08 ± 0.76%) cancers (P = 0.06). ConclusionsTN and high-Ki-67 breast cancers showed high APT SIs. APT imaging can help to predict the biological status of breast cancers.

Stem Cell Therapies in Movement Disorders: Lessons from Clinical Trials

Stem cell-based therapies (SCT) to treat neurodegenerative disorders have promise but clinical trials have only recently begun, and results are not expected for several years. While most SCTs largely lead to a symptomatic therapeutic effect by replacing lost cell types, there may also be disease-modifying therapeutic effects. In fact, SCT may complement a multi-drug, subtype-specific therapeutic approach, consistent with the idea of precision medicine, which matches molecular therapies to biological subtypes of disease. In this narrative review, we examine published and ongoing trials in SCT in Parkinson's Disease, atypical parkinsonian disorders, Huntington's disease, amyotrophic lateral sclerosis, and spinocerebellar ataxia in humans. We discuss the benefits and pitfalls of using this treatment approach within the spectrum of disease-modification efforts in neurodegenerative diseases. SCT may hold greater promise in the treatment of neurodegenerative disorders, but much research is required to determine the feasibility, safety, and efficacy of these complementary aims of therapeutic efforts.

Immunological characteristics of primary tumor and bone marrow in patients with breast cancer

Introduction. The Implementation of immunotherapy in cancer requires a thorough analysis of the biological characteristics of the tumor. Therefore, the study of tumor immunophenotype is the leading scientific direction. Molecules of the major histocompatibility complex are considered as promising markers for evaluating the possibility of using immunotherapy. Objective. To study the immunophenotype of the primary tumor in molecular subtypes of breast cancer and analyze it depending on the frequency of bone marrow damage. Materials and methods. The study included 99 patients with breast cancer. Tumor tissue and bone marrow samples were studied. Stages: T1 (51.5%), T2 (44.4%), T3 (2.0%). Metastatic involvement of lymph nodes (N+) was noted in 39.4% (n = 39) of cases. Immunophenotyping of the tumor was carried out on cryostat sections by immunofluorescence. Antibodies to HLA-I, HLA-II, KL1, FITC-labeled F(ab2) antiserum fragments (Becton Dickinson, USA) were used. The bone marrow was studied by morphological (Zeiss microscope, Axioskop, Germany) and immunological methods (flow cytometry, FACS Canto II, USA), data analysis – Kaluza Analysis v2.1 software. Used monoclonal antibodies: CD45, EPCAM (Becton Dickinson, USA). Statistical data processing was performed using the IBM-SPSS Statistics 21 package. Results . The HLA-I antigen is absent or expressed by single tumor cells in 50.8% of cases of luminal breast cancer. Pronounced or partial expression was noted in 36.9% of cases. With the Erb-B2 subtype, all samples had the expression of antigens of the HLA-I class. Loss of HLA-I antigen or weak expression was observed in 30% (3/10) of cases of the triple-negative subtype, in the same percentage of cases the expression of HLA-II molecules was noted. There were no significant differences in the expression of HLA molecules between subtypes. Using flow cytometry, bone marrow involvement was detected in 40% (26/65) of cases. There were no significant relationships between bone marrow damage and the size of the primary tumor, stage, grade of breast cancer, or expression of HLA molecules. Conclusions. The expression of HLA molecules does not differ in significant differences depending on the biological subtype. The frequency of bone marrow damage did not depend on the expression of HLA-I, class II molecules.

Features of gene polymorphism associations linked with sex hormone binding globulin level and breast cancer of various molecular biological subtypes

Aim: to identify specific associations between genes polymorphism associated with sex hormone-binding globulin (SHBG) level and breast cancer (BC) of various molecular biological subtypes.Materials and Methods. The retrospective comparative study was conducted using specimens collected from 261 patients with BC of two molecular biological subtypes – luminal A/B (n = 153) and triple negative (n = 108) as well as 1140 women in control group. All study participants (n = 1401) underwent a molecular genetic study of four single nucleotide polymorphism (SNP) loci, which showed a relationship with circulating SHBG level in previously conducted genome-wide association study (GWAS): rs12150660 SHBG, rs10454142 PPP1R21, rs780093 GCKR, rs17496332 PRMT6.Results. The analysis revealed an association between SHBG SNP candidate genes and a BC risk in patients with luminal A/B subtypes and lacked significant associations between the loci assessed and triple negative BC subtype. CC female genotype of rs10454142 PPP1R21 increased a risk of luminal A/B subtypes BC by more than 2-fold (recessive model [CC vs. TC+TT]; odds ratio = 2.07; 95 % confidence interval = 1.14–3.77; p = 0.017; pperm = 0.018). This SNP is localized in functionally "significant" regions of the genome (enhancers/active enhancers, promoters/active promoters) and affects methylation level in several hepatocyte DNA sites [cg15846641 (chr2:48541264)].Conclusion. The genetic variant rs10454142 PPP1R21 is associated with the risk of developing ВС luminal A/B subtypes, but not with ВС triple negative subtype.

A retrospective analysis of clinicopathological characteristics and risk factors for recurrence in young patients with breast cancer.

Younger and older patients with breast cancer often present with different clinicopathological characteristics and exhibit different risk factors for recurrence. This study sought to evaluate the biological characteristics and identify the recurrence risk factors in patients with operable breast cancer who were ≤40 years of age. This retrospective study investigated the biological characteristics and clinical outcomes of young patients (aged ≤40 years) with operable breast cancer who had been admitted to the Second Affiliated Hospital of Soochow University for treatment from January 2015 to December 2019. Clinicopathological and follow-up data were collected and statistically analyzed using IBM SPSS 27.0 software. The disease-free survival (DFS) rates were evaluated, and regression analyses were conducted to identify risk factors associated with adverse outcomes. A total of 154 young patients (aged ≤40 years) with operable breast cancer were included in this study, of whom 68 (44.2%) were aged ≤35 years. In terms of breast cancer subtypes, there were 19 (12.3%) patients with luminal A-like disease, 74 (48.1%) patients with luminal B-like disease, 17 (11.0%) patients with human epidermal growth factor receptor 2 (HER2)-positive (non-luminal) disease, and 44 (28.6%) patients with triple-negative breast cancer (TNBC). The 5-year DFS rate of all the patients was 88%; among those with TNBC, the rate was slightly lower at 76%. According to the results of the log-rank test, tumor (T) stage, node (N) status (N0 or N+), the biological subtype, and the Ki-67 index (with a 14% cut-off value between high and low expression levels) were risk factors for recurrence. The Cox regression analysis showed that the biological subtype was the only risk factor for recurrence. The multiple linear regression analysis demonstrated that the pathological type, tumor grade, estrogen receptor (ER) labeling intensity, and progesterone receptor (PR) expression level significantly affected the level of Ki-67 expression. This retrospective study showed that biological subtype was the most important risk factor for recurrence in operable breast cancer patients ≤40 years. The Ki-67 index is influenced by the pathological type, primary tumor grade, ER labeling intensity, and PR expression level. Fourteen percent is recommended as the cut-off value for the high and low expression of Ki-67 in clinical practice.

Chapter 2 - Models of precision medicine for neurodegeneration

The clinicopathologic model that defines neurodegenerative disorders has remained unchanged for over a century. According to it, clinical manifestations are defined and explained by a given pathology, that is, by the burden and distribution of selected proteins aggregated into insoluble amyloids. There are two logical consequences from this model: (1) a measurement of the disease-defining pathology represents a biomarker of that disease in everyone affected, and (2) the targeted elimination of that pathology should end that disease. But success in disease modification guided by this model has remained elusive. New technologies to probe living biology have been used to validate rather than question the clinicopathologic model, despite three important observations: (1) a disease-defining pathology in isolation (without other pathologies) is an exceptional autopsy finding; (2) many genetic and molecular pathways converge on the same pathology; (3) the presence of pathology without neurological disease is more common than expected by chance. We here discuss the rationale for abandoning the clinicopathologic model, review the competing biological model of neurodegeneration, and propose developmental pathways for biomarker development and disease-modifying efforts. Further, in justifying future disease-modifying trials testing putative neuroprotective molecules, a key inclusion criterion must be the deployment of a bioassay of the mechanism corrected by the therapy of interest. No improvements in trial design or execution can overcome the fundamental deficit created by testing experimental therapies in clinically defined recipients unselected for their biologically suitability. Biological subtyping is the key developmental milestone needed to launch precision medicine for patients living with neurodegenerative disorders.

Prediction of Residual Axillary Nodal Metastasis Following Neoadjuvant Chemotherapy for Breast Cancer: Radiomics Analysis Based on Chest Computed Tomography.

To evaluate the diagnostic performance of chest computed tomography (CT)-based qualitative and radiomics models for predicting residual axillary nodal metastasis after neoadjuvant chemotherapy (NAC) for patients with clinically node-positive breast cancer. This retrospective study included 226 women (mean age, 51.4 years) with clinically node-positive breast cancer treated with NAC followed by surgery between January 2015 and July 2021. Patients were randomly divided into the training and test sets (4:1 ratio). The following predictive models were built: a qualitative CT feature model using logistic regression based on qualitative imaging features of axillary nodes from the pooled data obtained using the visual interpretations of three radiologists; three radiomics models using radiomics features from three (intranodal, perinodal, and combined) different regions of interest (ROIs) delineated on pre-NAC CT and post-NAC CT using a gradient-boosting classifier; and fusion models integrating clinicopathologic factors with the qualitative CT feature model (referred to as clinical-qualitative CT feature models) or with the combined ROI radiomics model (referred to as clinical-radiomics models). The area under the curve (AUC) was used to assess and compare the model performance. Clinical N stage, biological subtype, and primary tumor response indicated by imaging were associated with residual nodal metastasis during the multivariable analysis (all P < 0.05). The AUCs of the qualitative CT feature model and radiomics models (intranodal, perinodal, and combined ROI models) according to post-NAC CT were 0.642, 0.812, 0.762, and 0.832, respectively. The AUCs of the clinical-qualitative CT feature model and clinical-radiomics model according to post-NAC CT were 0.740 and 0.866, respectively. CT-based predictive models showed good diagnostic performance for predicting residual nodal metastasis after NAC. Quantitative radiomics analysis may provide a higher level of performance than qualitative CT features models. Larger multicenter studies should be conducted to confirm their performance.

Updated CAP guidelines for determining molecular biological subtypes of breast cancer

Updated 2023 guidelines from the College of American Pathologists (CAP) on immunohistochemical detection of human epidermal growth factor receptor type 2 (HER2), receptors of estrogen (ER) and progesterone (PgR), and the cell proliferation marker Ki-67 in breast cancer are presented. Attention is drawn to the emergence of two new terms «ER Low Positive» and «HER2 Low» to characterize tumors with low expression of estrogen receptors and HER2.

Эффективность неоадъювантной терапии в лечении больных местнораспространенным раком молочных желез

Aim: to assess the severity of the pathomorphological response according to the classification of Residual Cancer Burden (RCB) in patients with breast malignancies depending on the surrogate molecular biological subtype after neoadjuvant drug therapy (chemotherapy ± anti- HER2 therapy). Design: Retrospective comparative study. Materials and methods. The retrospective study included 90 patients with breast cancer (T0-3, N0-1, M0) with luminal In HER2-negative, luminal In HER2-positive, HER2-positive non-luminal, thrice negative subtypes who were on complex treatment. The age of women ranged from 26 to 39 years (median age — 36 years). A retrospective analysis of the evaluation of residual tumor load in 85 patients according to the RGB system after neoadjuvant drug therapy and subsequent surgical treatment was performed. Results. In patients with luminal B HER2-negative breast cancer, a complete pathomorphological response was noted in 20% of cases, in 16% — RCB-I, in 36% — RCB-II, in 28% — RCB-III. Among women with luminal B HER2-positive breast cancer, a complete response was achieved in 26.67%, RCB-I was noted in 33.33%, RCB-II — in 13.33%, and RCB-III — in 26.67%. Among the patients with HER2-positive breast cancer, 46.16% had RCB-0, 23,08% had RCB-I, 15.38% each had RCB-II and RCB-III. In participants with thrice negative breast cancer, a complete response was achieved in 41.94% of cases, RCB-I was noted in 22.58%, RCB-II — in 19.35% and RCB-III — in 16.13%. The frequency of complete pathomorphological response (RCB-0) after neoadjuvant chemotherapy significantly differed among the more aggressive subtypes of breast cancer (thrice negative and HER2-positive), compared with HER2-negative (p &lt; 0.0001). Conclusion. The unified assessment of the residual tumor after neoadjuvant therapy makes it possible to clearly identify prognostic groups of patients with different treatment responses and plan additional drug therapy for them. Keywords: neoadjuvant chemotherapy, targeted therapy, breast cancer, HER2.

FEATURES OF PROLIFERATIVE PROCESSES IN CELL CULTURES FROM SAMPLES OF LUMINAL B (HER2- NEGATIVE) SUBTYPE BREAST CARCINOMA

Introduction. The Ki-67 cell proliferation marker is an indispensable point of the present morphological diagnosis of breast carcinoma, its association with the degree of malignancy and the recurrence risk for the disease has been substantiated. However dynamics of the Ki-67 index in cell culture from tumors of this subtype has not been studied enough. The aim of the study. To evaluate Ki-67 expression levels in cell cultures from samples of luminal B (HER2-negative) biological subtype tumors. Materials and methods. Tumor cells were extracted from BC samples by enzymatic method according to the standard protocol for obtaining a cell culture. A portion of cells from each passage was seeded on glasses in Petri dishes for immunocytochemical (ICC) analysis. ICC staining of the cells was conducted in autostainer Ventana (USA) using anti-Pan Keratin (AE1/AE3/PCK26) Primary Antibody (Roche diagnostics, the USA) and Ki-67 (clone of MIB-1, Dako, Denmark) antibodies. Results and discussion. Based on immunohistochemical (IHC) analysis of paraffin blocks the samples were determined as luminal B (Her2-negative) subtype. Cultures were obtained and the Ki-67 biomarker was determined at five passages. Significant differences in the values of the proliferation index between the examined passages were found. The epithelial phenotype of the tumor cells was saved as confirmed by the pancytoceratin staining data. Changes of proliferative activity showed the highest values of the biomarker at the first and third passages. The proliferation Ki-67 index value in the culture cells corresponded to the Ki-67 level in the tumor tissue of the luminal B (Her2-negative) subtype primary samples at the second, third and fourth passages. Conclusion. The high level of proliferative processes in the cell population maintaining the epithelial phenotype during cultivation allows the use of cell cultures as a comparative model for analyzing the expression of molecular biological markers and their compliance with primary cancer samples IHC data within a certain subtype.

Classification of HER2-negative breast cancers by ERBB2 copy number alteration status reveals molecular differences associated with chromosome 17 gene aberrations.

Recently, HER2-negative breast cancers have been reclassified by protein expression into 'HER2-low' and 'HER2-zero' subgroups, but the consideration of HER2-low breast cancer as a distinct biological subtype with differing prognoses remains controversial. By contrast, non-neutral ERBB2 copy number alteration (CNA) status is associated with inferior survival outcomes compared to ERBB2 CNA-neutral breast cancer, providing an alternative approach to classification. Here, we investigated the molecular landscape of non-metastatic HER2-negative BCs in relation to ERBB2 CNA status to elucidate biological differences. Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) TCGA-BRCA datasets (n = 1875) were analyzed. Nearly two-fifths of the cohort harbored ERBB2 CNAs (39.4%), which were significantly enriched within hormone receptor-negative (56.1%) than within hormone receptor-positive BCs (35.5%; p < 0.0001). Globally, CNAs across the genome were significantly higher in ERBB2 non-neutral compared to neutral cohorts (p < 0.0001). Notably, genetic aberrations on chromosome 17 - BRCA1, NF1, TP53, MAP2K4, and NCOR1 - were widespread in the ERBB2 non-neutral cases. While chromosome 17q arm-level alterations were largely in tandem with ERBB2 CNA status, arm-level loss in chromosome 17p was prevalent regardless of ERBB2 gain, amplification, or loss. Differential gene expression analysis demonstrated that pathways involved in the cell cycle, proteasome, and DNA replication were upregulated in ERBB2 non-neutral cases. Classification of HER2-negative BCs according to ERBB2 CNA status reveals differences in the genomic landscape. The implications of concurrent aberrations in other genes on chromosome 17 merit further research in ERBB2 non-neutral BCs.

Radionuclide imaging of breast cancer: experience of FSBI “N.N. Petrov National Medical Research Centre of Oncology” of the Ministry of Healthcare of Russian Federation

Abstract. Breast cancer is one of the most common malignant neoplasms among women nowadays. Timely diagnosis is the basis for effective and successful treatment of this disease. The existing classical methods of X-ray examination (MG, ultrasound, MRI) play a major role in the detection of breast cancer, but in some cases, the diagnosis of breast cancer can be difficult. Therefore, diagnostic performance of scintimammography with specialized gamma camera called molecular breast imaging (MBI) is now of particular clinical interest.Materials and methods. 312 patients with a preliminary clinical diagnosis of breast cancer were examined in the department of radionuclide diagnostics of N.N. Petrov Research Center of Oncology. They underwent scintimammography (MBI) with a specialized gamma camera manufactured by GE (Discovery 750b). Images of both breasts were obtained 15 min after intravenous injection of 500 MBq activity of 99mTc-MIBI. The foci of moderate and intensive radiopharmaceutical accumulation in breast were considered as a sign of a tumor. The diagnostic performance of MBI and the sensitivity in detection of various biological subtypes of cancer were calculated by comparing with the results of morphological and immunohistochemically studies.Results. The sensitivity, specificity and accuracy of the MBI in the diagnostics of breast cancer were 88, 75 and 87%, respectively. Sensitivity of this method in detection of different biological subtypes ranged from 89% to 95% with lowest performance found in luminal A subtype.Conclusion. Scintimammography (MBI) is an informative way of breast cancer diagnostics. The revealed differences in the sensitivity of the method in patients with different biological subtypes of breast cancer confirm the need for further study of this topic.

Immunohistochemical Study of Bladder Cancer Molecular Subtypes and Their Association with PD-L1 Expression.

The significant heterogeneity in clinical outcomes among patients with bladder cancer has highlighted the existence of different biological subtypes of muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). Meanwhile, immune checkpoint proteins and their interference with tumor-related immune-evasive strategies has led to the development of several immunotherapeutic drugs targeting programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1). However, the lack of any known biomarker that could predict responses to immunotherapy has led to a more agnostic therapeutic approach. Here, we present a study conducted in 77 bladder cancer (BC) patients (n = 77), ranging from stages pTa to pT2. Tumor specimens were resected via transurethral resection of bladder tumor (TURBT) and consistuted of 24 low-grade (LG) and 53 high-grade (HG) tumors. Patients' tumors were then categorized into molecular subtypes, via immunohistochemistry (CK5/6 and GATA3). Furthermore, all tumor specimens were stained with anti-PD-L1 and demonstrated significant correlations with basal immunophenotype, stage pT2 and HG tumors. As such, we attempted to stratify patients into groups of likely-responders and likely-not-responders to immunotherapy with anti-PD-L1, based on their molecular phenotype. Finally, in acknowledging the fact that there is a universal lack of biomarkers associated with predicting BC response to immunotherapeutic drugs, we tested all tumors for deficiency of mismatch repair proteins (MMR).

Meningioma classification by immunohistochemistry: A replicability study

IntroductionMeningiomas account for nearly 40% of intracranial tumors. Recently, the immunohistochemistry (IHC) markers S100B, SCGN, ACADL and MCM2 have been shown to be associated with underlying biological subtypes of meningioma (MG1-MG4). We aimed to evaluate these IHC markers in a clinical setting. Research questionAre the new proposed IHC markers clinically useful? MethodsIn total, 244 patients with meningiomas with tissue in TMAs were included and the IHC markers S100B, SCGN, ACADL and MCM2 were analyzed. Two sets of analyses were performed; the first included all samples with any staining considered positive, the second only samples with >10% immunopositivity. PFS and OS were analyzed in correlation to immunopositivity in the second analysis set. ResultsIn the first set of analyses only 26.2% of samples could be to allocate to one group. No further analyses were performed with this selection. In the second set of analyses 52.0% could be allocated to a group. There was an enrichment of WHO grade 2 and 3 tumors in MG3 and MG4 as compared to MG1 (24.1% and 25.7% vs. 12.1%). Both the molecular group (p ​= ​0.032) and WHO grade (p ​= ​0.005) had significant impact on PFS, but only WHO grade predicted OS (p ​= ​0.033). ConclusionWe studied the proposed new method of classifying meningiomas into groups MG1, MG2, MG3 and MG4 using IHC markers, but found difficulties applying the classification system in our material mainly due to lack of exclusivity of markers. Thus, in its present form the classification method lacks clinical applicability.

Loco-Regional Treatment of the Primary Tumor in De Novo Metastatic Breast Cancer Patients Undergoing Front-Line Chemotherapy.

Loco-regional therapy (LRT) in de novo metastatic breast cancer (MBC) has been investigated in several clinical trials, with heterogeneous and conflicting results. We conducted a retrospective study of de novo MBC patients treated with front-line chemotherapy (FLC) followed by LRT of the primary tumor. Our aims were to evaluate the characteristics, treatment, and oncological outcomes in terms of progression-free survival (PFS), distant progression-free survival (DPFS), and overall survival (OS) of de novo MBC. We also investigated possible subgroups of patients with better outcomes according to menopausal status, biological sub-type, location, number of metastases, and radiologic complete response after FLC. We included 61 patients in the study. After a median follow-up of 55 months, disease progression occurred in 60.7% of patients and 49.2% died. There were no significant differences in PFS, DPFS, and OS between different subgroups of de novo MBC patients. A trend toward better PFS and DPFS was observed in triple-positive tumors, without a statistically significant difference in OS. No specific subgroup of de novo MBC patients showed a statistically significant survival advantage after FLC followed by LRT of the primary tumor.

Expression of monomorphic HLA-determinants, transferrin receptor 1 (TfR1) in molecular subtypes of breast cancer

Background. Immunotropic drugs are widely used in the modern strategy of cancer treatment. Importance is given to immunological markers of the tumor, which determine the prognosis of the disease, the effectiveness of treatment. Therefore, the study of their expression is one of the leading scientific directions. Of particular interest is the study of monomorphic HLA determinants, transferrin receptor 1 (TfR1), depending on its biological subtype of breast cancer.Aim. To evaluate the frequency of expression of HLA class I, II, TfR1 molecules by breast cancer cells and determine their relationship with the molecular biological subtype of the tumor.Materials and methods. This study included 120 patients with breast cancer who received treatment at the N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia. Tumor stages II and III prevailed: 56.7 % and 33.4 %, respectively. A moderate degree of differentiation (G2) was more often noted. The luminal subtype was 58.3 % (n = 70), non-luminal – in 41.7 % (n = 50). Immunophenotyping of the primary tumor was performed by immunofluorescence on cryostat sections. The reaction was evaluated using a ZEISS Axioscope 5 luminescent microscope (Zeiss AG, Germany). The frequency of expression of HLA class I and II molecules were studied depending on the clinical and morphological characteristics of breast cancer. The frequency of expression of HLA class I, HLA-DR, TfR1, molecules, toumor infiltration of СD45+, CD38+, depending on the molecular subtype of breast cancer was studied.Results. It was found that the frequency of expression of monomorphic determinants of the HLA class I in luminal and non-luminal subtypes of breast cancer was comparable; HLA-DR was expressed significantly more often in the luminal subtype of breast cancer: 37.3 % and 18.0 %, respectively, p = 0.022. The frequency of TfR1 expression was significantly higher in the luminal subtype of cancer compared to non-luminal, p = 0.014. Predominantly monomorphic type of reaction was observed: in 76.5 % (n = 39) of cases. The mosaic type of the TfR1 reaction was noted in 7.8 % of the samples. TfR1 monomorphic expression was detected in 50.0 % (n = 30) of cases in non-luminal cancer, the mosaic expression – in 20.0 % (n = 12) of cases. A pronounced degree of lymphoid infiltration, in particular plasmacytic, was established in non-luminal subtype of breast cancer: 70.7 % (n = 29) and 35.0 % (n = 14), respectively, p = 0.001. An association was noted between the expression of HLA I class molecules and the severity of general leukocyte infiltration, p = 0.007.Conclusion. The frequency of expression of HLA class I monomorphic determinants did not differ in molecular subtypes of breast cancer. The expression of the HLA class II molecule was significantly more frequently observed in the luminal subtype of breast cancer. The expression of HLA class I monomorphic determinants is associated with the degree of lymphoid infiltration of the tumor. In the non-luminal subtype, plasmacytic infiltration is more pronounced. The expression of transferrin receptors is significantly more pronounced in the luminal subtype.