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Background: The lack of sensitivity and specificity of existing diagnostic markers like Carbohydrate Antigen 15-3(CA15-3) and Carcinoembryonic antigen (CEA) in breast cancer stimulates the search for new biomarkers to improve diagnostic sensitivity especially in differentiating benign and malignant breast tumors. Expression of Human epididymal protein 4 (HE4) has been demonstrated in ductal carcinoma of the breast tissue. So we tried to evaluate serum HE4 levels as diagnostic marker in breast cancer patients and to comparatively assess serum HE4, CEA and CA15-3 in breast tumor patients both benign and malignant. Methods: Total 90 female subjects were included in the study. We selected 30 breast cancer cases (Malignant group) and 30 benign breast lump cases (Benign group) based on histopathology report. And other 30 were age matched apparently healthy controls (Control group). HE4, CEA and CA15-3 were analysed in serum samples of all subjects by Electrochemiluminiscence immunoassay method. Results: A significant difference in the median (IQR) of HE4 (pmol/l) was identified among malignant, benign and control groups {62.4(52.6-73.7) vs 49.3(39.8-57.4) vs 52.3(50.6-63.3) P=0.0009} respectively. The cutoff value for prediction of breast cancer was determined at >54.5 pmol/l for HE4, with a sensitivity of 73.3%, specificity of 65.3%, whereas cutoff value of CA 15-3 was >21.24 (U/ml) with a sensitivity of 56.7%, specificity of 74.5%. For CEA at cutoff value >0.99 (ng/ml) the sensitivity and specificity were 96.7 % and 62.7% respectively. AUC for HE4, CA15-3 and CEA were 0.725, 0.644 and 0.857 respectively. Conclusion: Our study demonstrated that serum levels of HE4 were significantly higher in malignant group compared to benign and control groups. There is no significant difference between HE4 levels between benign and control groups. These results indicate that HE4 appears as a useful and highly specific biomarker for breast cancer, which can differentiate between malignant and benign tumors.

ObjectivesTo assess DWI for tumor visibility and breast cancer detection by the addition of different synthetic b-values.MethodsEighty-four consecutive women who underwent a breast-multiparametric-MRI (mpMRI) with enhancing lesions on DCE-MRI (BI-RADS 2–5) were included in this IRB-approved retrospective study from September 2018 to March 2019. Three readers evaluated DW acquired b-800 and synthetic b-1000, b-1200, b-1500, and b-1800 s/mm2images for lesion visibility and preferred b-value based on lesion conspicuity. Image quality (1–3 scores) and breast composition (BI-RADS) were also recorded. Diagnostic parameters for DWI were determined using a 1–5 malignancy score based on qualitative imaging parameters (acquired + preferred synthetic b-values) and ADC values. BI-RADS classification was used for DCE-MRI and quantitative ADC values + BI-RADS were used for mpMRI.ResultsSixty-four malignant (average = 23 mm) and 39 benign (average = 8 mm) lesions were found in 80 women. Although b-800 achieved the best image quality score, synthetic b-values 1200–1500 s/mm2were preferred for lesion conspicuity, especially in dense breast. b-800 and synthetic b-1000/b-1200 s/mm2values allowed the visualization of 84–90% of cancers visible with DCE-MRI performing better than b-1500/b-1800 s/mm2. DWI was more specific (86.3% vs 65.7%,p< 0.001) but less sensitive (62.8% vs 90%,p< 0.001) and accurate (71% vs 80.7%,p= 0.003) than DCE-MRI for breast cancer detection, where mpMRI was the most accurate modality accounting for less false positive cases.ConclusionThe addition of synthetic b-values enhances tumor conspicuity and could potentially improve tumor visualization particularly in dense breast. However, its supportive role for DWI breast cancer detection is still not definite.Key Points•The addition of synthetic b-values (1200–1500 s/mm2) to acquired DWI afforded a better lesion conspicuity without increasing acquisition time and was particularly useful in dense breasts.•Despite the use of synthetic b-values, DWI was less sensitive and accurate than DCE-MRI for breast cancer detection.•A multiparametric MRI modality still remains the best approach having the highest accuracy for breast cancer detection and thus reducing the number of unnecessary biopsies.

Beckwith-Wiedemann syndrome (BWS) is a human genomic imprinting disorder that presents with a wide spectrum of clinical features, including overgrowth, abdominal wall defects, macroglossia, neonatal hypoglycemia, and predisposition to embryonal tumors. Its diagnosis is based on molecular tests or clinical signs. However, in children with features of BWS who do not fulfill the clinical diagnostic criteria, the molecular tests may play an important role in the diagnosis. There is an increased risk of embryonal tumors in patients with BWS, but few case reports have been reported on benign breast tumors in female adolescents with this syndrome. To our knowledge, this is the first case report in the literature that describes the imaging findings of fibroepithelial breast tumors (phyllodes tumor and fibroadenomas) in a 13-year-old female with BWS, highlighting the need for lifelong tumor surveillance in this patient population.

Background and aim Benign breast diseases are one of the most common diseases in females. An important goal in its treatment should be cosmesis, so a new minimally invasive technique has advanced. One of these techniques is the transaxillary endoscopic resection. The aim of this study was to assess the feasibility, safety, operative time, postoperative pain, hospital stay, and cosmetic outcome of this transaxillary approach. Methods This study was carried out on 40 female patients presented with benign breast tumors in the surgical oncology unit at the General Surgery Department, Tanta University Hospital during the period from January 2018 to January 2019. The patients included in the study aged ≥18 years, had solitary or multiple benign breast tumors, located at any breast quadrant. The patients subjected to transaxillary endoscopic excision of the tumors. Results The age of the patients ranged from 20 to 49 years with a mean age of 32 years. 60% of the lesions located in the upper half of the breast. Fibroadenoma was the most common finding in 80% of the patients, 60% of the patients had solitary tumor. The operative time ranged from 42 to 105 minutes with a mean of 61.4 minutes. 88.8% of the patients considered the cosmetic outcome excellent. Conclusion Endoscopic transaxillary excision of benign breast tumors is safe, feasible and has excellent cosmetic outcomes with high patient's satisfaction.

Background Metastatic breast tumors from extramammary malignancies are quite rare. Characteristics of such tumors are unclear due to small number of reported cases. During 2012–2019, approximately 3,500 malignant breast tumors were diagnosed with needle biopsy at our hospital and we experienced three cases (0.09%) of metastatic extramammary malignancies. We herein report these cases focused on imaging and pathological findings. Case presentation The first case was a 59-year-old woman who underwent curative surgery for thyroid cancer. After developing lung and ovarian metastases, she visited our department with a mass in her right breast. Ultrasound revealed a 7 mm-sized oval mass. With high depth–width ratio and abundant blood flow, primary breast cancer was suspected. Core needle biopsy revealed atypical cells with nuclear grooves proliferating in papillary formation. With immunohistochemical examination, her final diagnosis was metastatic thyroid cancer. The second case was a 74-year-old woman with metastatic spinal tumors and referred to our department for searching primary tumor. She was diagnosed with gastric cancer at the age of 41. Ultrasound revealed a hypoechoic area including cysts and the internal echo level was uneven. Contrast-enhanced magnetic resonance imaging showed a non-mass lesion with heterogeneous internal enhancement pattern, suggesting ductal carcinoma in situ. Core needle biopsy showed alveolar lesion with predominant signet cell-like morphology. We histologically diagnosed her disease as metastatic gastric cancer. The last case was 33-year woman with Stage IV clear cell sarcoma of the left foot. She came to our department after she felt a lump on her right breast. Ultrasound revealed a 45 mm-sized mass. Her disease was confirmed as metastatic clear cell sarcoma by needle biopsy. Conclusions Imaging suggested malignancies, but it was difficult to distinguish them from primary breast cancer. Our cases indicate that metastatic tumors to the breast might have imaging patterns specific to primary organs, although more cases should be accumulated to establish such patterns on imaging. The first two cases shared some similar pathological findings with breast cancer, but also had some histological characteristics of the primary tumors. Hence, it was possible to diagnose these cases as metastatic tumors with careful observation.

To explore the value of amide proton transfer-weighted (APTw) magnetic resonance imaging (MRI) for differential diagnosis of fibroadenomas and malignant breast tumors.This prospective study enrolled 56 patients with suspected breast tumors and performed APTw imaging. Based on the histopathology results, patients were divided into group 1 with malignant breast tumors (n = 41) and group 2 with fibroadenomas (n = 15). The measured image parameters (APTw value, ADC value, type of Time of Intensity Curve, maximum tumor diameter in image) and the maximal diameter of the tumors measured from surgical resection were compared between the two groups, and the diagnostic performance based on these parameters was quantified with ROC curve. Spearman's correlation coefficient was used to analyze the association between APTw or ADC values and ER, PR, HER2, and Ki-67 expressions.The intraclass correlation coefficients (ICC = 0.87 and 0.91) indicated a good inter-observer agreement of the measured APTw values. APTw values of malignant lesions were significantly higher than those of fibroadenomas (3.21 ± 1.04% vs 1.50 ± 0.54%, p 0.001). Area under the curve (AUC) obtained from APTw imaging, DWI, DCE, APTw imaging+DWI, APTw imaging+DWI, and APTw imaging+DWI + DCE was 0.959, 0.897, 0.976, 0.997, and 1 respectively. The APTw value showed a negative correlation with ER expression (r = -0.357).APTw imaging yielded similar diagnosis performance in discriminating fibroadenomas and malignant breast tumors when compared to the DCE and better than DWI imaging, and provided supplement information on tumor cell activity to DWI images. The APTw value showed correlations with some prognostic factors for breast cancer.

Objective. To enhance the reliability of visual analysis of X-ray mammograms, by applying the mathematical models of neoplasms and a method for their processing based on the mathematical apparatus of contour analysis.Material and methods. Two data sets were generated from X-ray mammograms obtained from 38–82 year old patients at routine examinations in the Republican Oncology Dispensary. The first set contained 100 packages of X-ray mammographic images that failed to reveal abnormal malignant changes. The second set was represented by 168 packages of X-ray mammographic images showing morphologically verified breast cancer. All the packages of mammographic images are presented in the standard direct craniocaudal and mediolateral oblique projections. The images were obtained using an analog mammograph. Digital copies of images having a resolution of 600 dpi were obtained for subsequent computer processing. The latter of digital mammographic images involved segmentation of space-occupying lesions, determination of the linearity factor of their outlines, and differential diagnosis of space-occupying lesions based on the calculated value of the linearity factor of their outlines.Results. An algorithm was elaborated for identifying the outlines of space-occupying lesions on X-ray mammographic images. The sequence of complex-valued vectors approximating its curve was used as a mathematical model of the outline. The concept on the outline linearity factor, which quantitatively characterizes its shape, was introduced. A method was developed for the objective classification of malignant and benign space-occupying lesions based on the value of the introduced linearity factor. The outlines of benign space-occupying lesions in the breast were ascertained to be characterized by the higher linearity factor (in the region of 0.3–0.4) (BI-RADS category 2), while the outlines of malignant tumors had a much lower value of this factor (in the order of 0.05–0.1) (BI-RADS categories 4–5). The main quantitative measures (sensitivity, specificity, and accuracy) of the informative value of the proposed method were determined. The latter was shown to have a higher specificity than the traditional visual analysis carried out by a radiologist. This allows the proposed method to be used as an additional procedure in the visual analysis of mammograms to enhance the reliability of clinical findings.Conclusion. The practical value of the method is in quantitatively evaluating the shapes of malignant breast neoplasms, in reducing the performance of a mammographic examination, and in increasing its objectivity. The proposed method makes it possible to reduce the time of analyzing X-ray mammograms and to enhance the reliability of clinical findings.

Neurotensin receptor-1 (NTS1) is increasingly recognized as a potential target in diverse tumors including breast cancer, but factors associated with NTS1 expression have not been fully clarified. We studied NTS1 expression using the Tissue MicroArray (TMA) of primary breast tumors from Institut Bergonie. We also studied association between NTS1 expression and clinical, pathological, and biological parameters, as well as patient outcomes. Out of 1419 primary breast tumors, moderate to strong positivity for NTS1 (≥ 10% of tumoral cells stained) was seen in 459 samples (32.4%). NTS1 staining was cytoplasmic in 304 tumors and nuclear in 155 tumors, a distribution which appeared mutually exclusive. Cytoplasmic overexpression of NTS1 was present in 21.5% of all breast tumors. In multivariate analysis, factors associated with cytoplasmic overexpression of NTS1 in breast cancer samples were higher tumor grade, Ki67 ≥ 20%, and higher pT stage. Cytoplasmic NTS1 was more frequent in tumors other than luminal A (30% versus 17.3%; p

Objectives: The diagnostic performance of intravoxel incoherent motion diffusion–weighted imaging (IVIM-DWI) in the differential diagnosis of breast tumors remains debatable among published studies. Therefore, this meta-analysis aimed to pool relevant evidence regarding the diagnostic performance of IVIM-DWI in the differential diagnosis of breast tumors.Methods: Studies on the differential diagnosis of breast lesions using IVIM-DWI were systemically searched in the PubMed, Embase and Web of Science databases in recent 10 years. The standardized mean difference (SMD) and 95% confidence intervals of the apparent diffusion coefficient (ADC), tissue diffusivity (D), pseudodiffusivity (D*), and perfusion fraction (f) were calculated using Review Manager 5.3, and Stata 12.0 was used to pool the sensitivity, specificity, and area under the curve (AUC), as well as assess publication bias and heterogeneity. Fagan's nomogram was used to predict the posttest probabilities.Results: Sixteen studies comprising 1,355 malignant and 362 benign breast lesions were included. Most of these studies showed a low to unclear risk of bias and low concerns regarding applicability. Breast cancer had significant lower ADC (SMD = −1.38, P < 0.001) and D values (SMD = −1.50, P < 0.001), and higher f value (SMD = 0.89, P = 0.001) than benign lesions, except D* value (SMD = −0.30, P = 0.20). Invasive ductal carcinoma showed lower ADC (SMD = 1.34, P = 0.01) and D values (SMD = 1.04, P = 0.001) than ductal carcinoma in situ. D value demonstrated the best diagnostic performance (sensitivity = 86%, specificity = 86%, AUC = 0.91) and highest post-test probability (61, 48, 46, and 34% for D, ADC, f, and D* values) in the differential diagnosis of breast tumors, followed by ADC (sensitivity = 76%, specificity = 79%, AUC = 0.85), f (sensitivity = 80%, specificity = 76%, AUC = 0.85) and D* values (sensitivity = 84%, specificity = 59%, AUC = 0.71).Conclusion: IVIM-DWI parameters are adequate and superior to the ADC in the differentiation of breast tumors. ADC and D values can further differentiate invasive ductal carcinoma from ductal carcinoma in situ. IVIM-DWI is also superior in identifying lymph node metastasis, histologic grade, and hormone receptors, and HER2 and Ki-67 status.

Vacuum-assisted aspiration biopsy (VAB) has been in use for over 20 years. It is an accurate and safe procedure with a sensitivity of 97 %, specificity of 100 %, and accuracy of 99 %. VAB is used for the evaluation of nonpalpable tumors suspicious for breast cancer. Since 2000, VAB is widely used as a therapeutic method for total biopsy or resection of benign breast tumors (breast fibroadenoma, recurrent cysts, and intraductal or intracyctic hyperplasia). Many authors consider VAB as an alternative to standard surgery. VAB demonstrates good results in the minimally invasive treatment of nodular mastopathy. VAB technique is continuously being improved, which indicates the progress in medical science and successful implementation of minimally invasive treatments into clinical practice.

Objective: to investigate the possibility of enhancing the efficiency of complex magnetic resonance (MR) imaging, including MR mammography with dynamic contrast-enhanced MRI and MR spectroscopy for the differential diagnosis of breast tumors. Material and methods. The investigation enrolled 87 patients with breast tumors and 15 healthy volunteers. The mean age of the examinees was 55.7±3.5 years. MR mammography with dynamic contrast-enhanced MRI and subsequent morphological diagnosis verification were performed in 100% of cases. MR spectroscopy was carried out in 93.1% of the patients with breast tumors. Results. There were 189 breast tumors, including 154 (81.5%) and 35 (18.5%) hypervascular and avascular ones, respectively. MR mammography could reveal only 36% of the hypervascular masses. The sensitivity of contrast-enhanced MR mammography was 97.1%, and the specificity was variable. Its specificity was 96.9% for BIRADS 2 and BIRADS 5 and 45% and 55% for BIRADS 4 and BIRADS 3, respectively. MR spectroscopy in addition to MR mammography could increase the overall specificity of the technique up to 98.3%. Conclusion. Comprehensive MR examination that involves MR mammography with dynamic contrast-enhanced MRI and MR spectroscopy makes it possible to visualize breast tissues, to identify additional masses, to investigate not only the morphological, but also chemical structure of the identified tumors, which allows the most precise differential diagnosis between benign and malignant lesions.

Substantial progress in the use of chemo-photodynamic nano-drug delivery systems (nano-DDS) for the treatment of the malignant breast cancer has been achieved. The inability to customize precise nanostructures, however, has limited the therapeutic efficacy of the prepared nano-DDS to date. Here, we report a structurally defined tandem-responsive chemo-photosensitive co-nanoassembly to eliminate primary breast tumor and prevent lung metastasis. This both-in-one co-nanoassembly is prepared by assembling a biocompatible photosensitive derivative (pheophorbide-diphenylalanine peptide, PPA-DA) with a hypoxia-activated camptothecin (CPT) prodrug [(4-nitrophenyl) formate camptothecin, N-CPT]. According to computational simulations, the co-assembly nanostructure is not the classical core-shell type, but consists of many small microphase regions. Upon exposure to a 660 nm laser, PPA-DA induce high levels of ROS production to effectively achieve the apoptosis of normoxic cancer cells. Subsequently, the hypoxia-activated N-CPT and CPT spatially penetrate deep into the hypoxic region of the tumor and suppress hypoxia-induced tumor metastasis. Benefiting from the rational design of the chemo-photodynamic both-in-one nano-DDS, these nanomedicines exhibit a promising potential in the inhibition of difficult-to-treat breast tumor metastasis in patients with breast cancer.

The NanoString GeoMx digital spatial profiling is a new multiplexed platform that quantifies the abundance of tumor‐ and immune‐related proteins in a spatially resolved manner. We performed DSP for the simultaneous assessment of 52 analytes within spatially resolved tissue compartments defined by pan‐cytokeratin expression. We compared protein targets between 94 African American/Black and 65 European American/White cases, tumor and stromal tissue compartments, estrogen receptor alpha (ER)‐positive and ER‐negative cases, and explored potential biomarkers of survival. Of 33 analytes with robust signal for analysis, results were highly replicable. For a subset of markers, correlative analyses between DSP analytes and traditional immunohistochemistry scores revealed moderate to very strong associations between the two platforms. Similarly, DSP analytes and gene expression scores were concordant for 21 of 25 markers with overlap between the two datasets. Several analytes varied by ER status, and across the 25 immune markers surveyed, 14 had a significant inverse association with ER expression. B7 homolog 3 (B7‐H3; encoded by CD276) was the only analyte to show a significant difference by race, being lower in both the tumor and stromal compartments in Black women. DSP markers that were associated with survival included CD8, CD25, CD56, CD127, EpCAM, ER, Ki‐67, and STING. We conclude that DSP is an efficient tool for screening tumor‐ and immune‐related markers in a simultaneous fashion and yields results that are concordant with established immune profiling assays. DSP immune analytes were inversely associated with ER expression, in agreement with a substantial body of previous work that documents higher immune infiltration in ER‐negative breast cancers. This technology revealed that scores of the B7‐H3 protein were significantly lower in breast cancers from Black women compared with White women, an intriguing finding that requires replication in independent and racially diverse female populations., We evaluated the NanoString GeoMx digital spatial profiling platform for highly multiplexed immune profiling in a population of Black and White women with invasive breast cancer. Using DSP for discovery and conventional immunohistochemistry and gene expression data for validation, we found the DSP technology to be efficient, reproducible, and to yield results that are concordant with established immune profiling assays.

The category of papillary breast tumors includes a limited number of entities. Nonetheless, this relatively uncommon group of tumors seems to instigate a disproportionate degree of diagnostic disquiet. As a group, papillary breast tumors suffer from a relatively high rate of discordant interpretation. The latter is due to the inherent complexity of the lesions compounded by conflicting criteria as well as simmering controversies. For instance, “encapsulated” papillary carcinoma remains contentious with regards to whether these are noninvasive or not, and the assessment of the extent of the invasive versus noninvasive components in many solid papillary carcinomas can be problematic. The latest classification system of breast tumors enunciated by the World Health Organization (WHO), that is, Breast Tumors, which appeared in 2019, mainly sought to incorporate advances in basic and clinical sciences into diagnostic criteria for the entire spectrum of breast neoplasms—including papillary ones. The latter category of tumors is discussed at some length in Breast Tumors; however, it still appears to suffer from some lack of clarity in its subclassification. It is our intent in this communication to provide an overview of the controversies around papillary breast tumors, and offer comments on its coverage in Breast Tumors—so that any tangible or perceived ambiguities therein could be addressed in its next edition.

Background In silico deconvolution of invasive immune cell infiltration in bulk breast tumors helps characterize immunophenotype, expands treatment options, and influences survival endpoints. In this study, we identify the differential expression (DE) of the LM22 signature to classify immune‐rich and ‐poor breast tumors and evaluate immune infiltration by receptor subtype and lymph node metastasis. Methods Using publicly available data, we applied the CIBERSORT algorithm to estimate immune cells infiltrating the tumor into immune‐rich and immune‐poor groups. We then tested the association of receptor subtype and nodal status with immune‐rich/poor phenotype. We used DE to test individual signature genes and over‐representation analysis for related pathways. Results CCL19 and CXCL9 expression differed between rich/poor signature groups regardless of subtype. Overexpression of CHI3L2 and FES was observed in triple negative breast cancers (TNBCs) relative to other subtypes in immune‐rich tumors. Non‐signature genes, LYZ, C1QB, CORO1A, EVI2B, GBP1, PSMB9, and CD52 were consistently overexpressed in immune‐rich tumors, and SCUBE2 and GRIA2 were associated with immune‐poor tumors. Immune‐rich tumors had significant upregulation of genes/pathways while none were identified in immune‐poor tumors. Conclusions Overall, the proportion of immune‐rich/poor tumors differed by subtype; however, a subset of 10 LM22 genes that marked immune‐rich status remained the same across subtype. Non‐LM22 genes differentially expressed between the phenotypes suggest that the biologic processes responsible for immune‐poor phenotype are not yet well characterized., Our approach classified 2369 patients into two groups (immune‐rich, and immune‐poor) using an immune cell expression signature. The overall frequency of immune‐rich versus immune‐poor tumors differed by receptor subtype, however the specific signature genes remained the same, suggesting that signature expression is a stronger determinant of immune infiltration than receptor subtype.

BACKGROUND: Benign and malignant breast tumors are the most commonly diagnosed tumor in females. Early and accurate diagnosis of malignancy is essential for effective breast cancer treatment. Human anterior gradient 3 (AGR3) has been suggested as a potential biomarker for the early detection and prognostic determination of breast cancer. OBJECTIVE: This study profiles AGR3 mRNA expression and serum protein levels in patients with benign and malignant breast tumors. METHODS: A case-control study was conducted on 40 benign and 40 malignant breast tumor patients in Makassar, Indonesia. AGR3 mRNA and protein were detected using qRT-PCR and ELISA, respectively. RESULTS: This study found significantly higher AGR3 mRNA expression in benign than malignant breast tumors using qRT-PCR (p

Background: Since the recorded time, breast has been a symbol for motherhood, fiminity, and sexuality, it has been portrayed throughout history in works of art symbolizing to all those aspects of woman's life. So breasts in female life are described as “life giving and life destroying”. Breast cancer existed in ancient times and reference to this disease can be found dating back as 3000 BC, in an Egyptian papyrus. Aim of Study: The Aim of this study is to compare between batwing mammoplasty and inferiorly based wise pattern therapeutic mammoplasty in management of upper pole breast tumors regarding cosmetic results, oncological outcomes, rate of complications and degree of satisfaction of the patients. Patients and Methods: Design: Study group: This study was conducted in Department of General Surgery Ain Shams University Hospitals, this is a prospective comparative study. The study included 40 women diagnosed with upper pole breast cancer. This study was done in Breast Surgery Unit, General Surgery Department at Ain Shams from July 1 st 2019 to July 1 st 2020. Sampling Method: Random controlled sampling study,after approval of the Ethical Committee, and informed consents were obtained from these patients they were enrolled in the study. Results: Our study includes 40 female patients were randomly categorized into 2 groups. Group A included patients who had inferiority based wise pattern mammoplasty (20 patients), while Group B included patients who had batwing mammoplasty (20 patients). Conclusion: In this study, we concluded that: Both tech-niques batwing mammoplasty and wise pattern therapeutic mammoplasty are valid options for upper pole breast tumors. Wise pattern therapeutic mammoplasty remains aesthetically superior; however, batwing mammoplasty is an easy, simple technique with acceptable results to patients. Recommendations: From this study, we could recommend: The decision of which surgical approach to be used for the oncoplastic procedure is heavily based on patient and tumor characteristics; the pre-operative evaluation should include examination for degree of ptosis, overall skin quality, evidence of prior radiation, and overall breast size; successful oncoplastic procedure begins with selecting the appropriate operation for a given patient, which takes into account a patient's unique breast anatomy (e.g., breast shape and degree of ptosis) and good understanding of tumor location and extent, as well as appreciation of the patient's goals; Mastectomy with recon-struction may provide a more aesthetically pleasing result than breast conservation surgery in the small to moderate-breasted woman; larger breasted women have more options available for reconstruction, whether it is local tissue rear-rangement, local or regional flaps, or reduction mammo-plasty/mastopexy; Batwing mammoplasty procedure achieve optimal results (i.e., breast contour and nipple projection) in patients with larger breast volume and a mild to moderate degree of breast ptosis; more studies on a large scale should be performed to assess the results of batwing mammoplasty and wise pattern therapeutic mammoplasty regarding compli-cation and cosmetic outcome for management of upper pole breast tumours.

Breast cancer is a heterogenous disease with various histologic subtypes, molecular profiles, behaviors, and response to therapy. After the histologic assessment and diagnosis of an invasive breast carcinoma, the use of biomarkers, multigene expression assays and mutation profiling may be used. With improved molecular assays, the identification of somatic genetic alterations in key oncogenes and tumor suppressor genes are playing an increasingly important role in many areas of breast cancer care. This review summarizes the most clinically significant somatic alterations in breast tumors and how this information is used to facilitate diagnosis, provide potential treatment options, and identify mechanisms of resistance.

Overview Mesenchymal tumors of the breast are rare. Few epithelial tumors also have mesenchymal components. It is crucial to identify these as per histogenesis. This can be facilitated by markers of epithelial–mesenchymal transition (EMT). Objectives The aim of this study was to categorize the breast lesions with mesenchymal morphology and to study EMT on immunohistochemistry (IHC). Materials and Methods This is a retrospective study of 5-year duration from January 2015 to December 2019. Inclusion criteria: all breast lesions showing mesenchymal/nonepithelial morphology, complete or partial, on histology. Exclusion criteria: Mammary carcinomas without any mesenchymal/nonepithelial morphology, fibroadenomas, and lymphomas. Demographics, clinical, gross examination, histology, and IHC findings of selected cases were reviewed and recorded. Three additional markers p53, E-cadherin, and β-catenin were performed. Statistical Analysis Used Frequency calculation for each variable (IHC). Results Thirteen (2.5%) out of total 510 breast specimens showed mesenchymal histology. Of these, five (38.5%) were metaplastic breast carcinomas (MBC), four (31%) were phyllodes tumor (PT), and one (7.7%) case each of malignant peripheral nerve sheath tumor, primary stromal sarcoma of breast, pseudoangiomatous stromal hyperplasia, and myofibroblastoma. Loss of E-cadherin was seen in 4/5 (80%) MBCs and was retained in ductal component of PTs. p53 was not expressed in any of the tumors except 3/5 (60%) MBCs. β-Catenin was aberrant in all MBCs. Conclusions Primary breast tumors with mesenchymal morphology present a spectrum ranging from benign mesenchymal, fibroepithelial neoplasms to malignant tumors of mesenchymal and epithelial origin. Loss of E-cadherin, expression of p53, and aberrant expression of β-catenin are suggestive of EMT and molecular heterogeneity of MBCs.

Systemic breast cancer treatments often fail to achieve complete and sustained responses due to drug-persistent residual tumor foci, the “seed” for eventual relapse. Recent clinical studies have revealed that the chemo-persistent tumor cells undergo extensive transcriptional reprogramming in response to neo-adjuvant treatment; however, the impact of this acquired molecular signature on the ability of residual cancer cells to survive during therapy is not clear. To further study the molecular hallmarks of chemo-persistent cancer cells, we analyzed the transcriptional signatures of post-treatment residual tumors in a large number of breast cancer patients from several neoadjuvant clinical studies. We observed that the treatment-persistent tumor cells had a distinct cellular state which molecularly resembles that of the embryonic diapause, a dormant stage of transiently suspended development in undifferentiated epiblasts triggered by stress and induced by suppression of Myc activity and overall biosynthesis. Remarkably, the propensity for residual tumors with an embryonic diapause-like (EDL) molecular signature was significantly associated with worse outcome in breast cancer patients. To dissect this distinct cancer cell state, we developed novel in vitro models using 3D breast cancer organoids which responded to cytotoxic treatment by generating longitudinally-persistent residual organoid fractions that phenotypically and molecularly simulated the in vivo emergence of post-treatment residual tumors in preclinical and clinical settings. The treatment-persistent tumor fractions in cancer organoids and in the respective in vivo xenografts did not exhibit significant genetic changes compared to baseline tumor cells, but had reduced apoptotic priming and an EDL transcriptional reprograming similar to that of residual tumors in patients. Similarly to embryonic diapause, residual persistent fractions in cancer organoids, xenografts and patient tumors had markedly suppressed Myc transcriptional output and biosynthetic levels. Ectopic induction of MYC expression enhanced acute chemotherapeutic cytotoxicity in breast cancer organoids. Conversely, suppression of MYC or pharmacological inhibition of Myc transcriptional co-activators, BET bromodomains, abrogated chemotherapeutic cytotoxicity and induced in breast cancer cells an EDL molecular signature characterized by below-baseline redox stress levels which were maintained during drug exposure. High-throughput interrogation of residual persistent breast cancer organoids indicated broad refractoriness to specific anticancer drug classes thought to operate through induction of cellular stress (e.g. agents targeting DNA or DNA-repair). However, maintaining the residual cells in dormancy after completion of cytotoxic chemotherapy via inhibition of Brd4/Myc axis or pharmacologically interfering with the diapause-like transcriptional reprogramming of treatment-persistent cancer cells represent potential therapeutic strategies to target chemo-persistent tumor cells. Overall, our study shows that breast tumors dynamically co-opt the stress survival mechanism of embryonic diapause to persist during treatment, and reveals an unexpected role of Myc as regulator of cancer cell entry into transient drug-refractory dormancy. The diapause-like persister organoid cancer models provide ex vivo tractability for studying the otherwise elusive, dormant, drug-refractory residual tumors, with potential implications in personalized medicine and drug discovery. Citation Format: Eugen Dhimolea, Ricardo De Matos Simoes, Dhvanir Kansara, Juliette Bouyssou, Jennifer Roth, Michal Sheffer, Rinath Jeselsohn, Nathanael Gray, Ulrich Steidl, Boris Bartholdy, Myles Brown, Aedin Culhane, Constantine Mitsiades. Treatment persistence of residual breast tumors through an embryonic diapause-like cancer cell state with suppressed myc activity [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS1-07.

Metabolic dysregulation and carcinogenesis are strongly linked. Leptin signaling acts as a metabolic switch that maintains body weight and energy homeostasis and gets impacted during metabolic dysregulation. Leptin signaling mediates its effect on breast cancer cells through downstream effectors like JAK-STAT, MAPK and PI3K pathways. At the molecular level, leptin exerts its effects through its receptor, LEPR, encoded by LEPR gene. Leptin signaling has been shown to contribute towards progression of breast cancer. Obese post-menopausal women are considered to be a high-risk category for breast cancer and dysregulated leptin signaling contributes towards it. We in this study focused on comparative molecular analysis of Leptin high (LEPRhi) and low (LEPRlow) expressing breast tumors.Breast cancer data from METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) study was used through the cBioPortal (http://cbioportal.org) platform for cancer genomics. The METABRIC study includes clinical and molecular data from over 2500 breast cancer cases. The LEPRhi and LEPRlow expressing breast tumors in RNA-seq dataset were queried using cBioPortal embedded SQL feature as LEPR: EXP>1 and LEPR: EXP Citation Format: Sara Pacheco, Maria E. Juarez, Sushmita Nandy. Leptin receptor expression in breast tumors and chromatin modulators: A comparative study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-51.

Addition of HER2-targeted agents to neoadjuvant chemotherapy has dramatically improved pathological complete response (pCR) rates in early stage Human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Still, up to 50% of patients have residual disease following treatment and biomarkers predictive of response are urgently needed. We performed spatial proteomic characterization using NanoString GeoMX Digital Spatial Profiling (DSP) of 122 samples from 57 HER2-positive breast tumors from the neoadjuvant TRIO-US B07 clinical trial (discovery cohort, n=28; validation cohort, n=29) sampled pre-treatment, after 14-21 days of HER2-targeted therapy and at surgery. In situ quantification of 40 tumor and immune proteins across multiple pancytokeratin-enriched regions per sample revealed that treatment results in decreased HER2 signaling and increased immune infiltration after several weeks of therapy. These changes were more dramatic in tumors that ultimately undergo pCR, and a classifier trained to predict pCR using on-treatment and pre-treatment DSP protein levels had a cross-validation mean Area Under the Receiver Operating Characteristics (AUROC) of 0.733 in the discovery cohort and validated in an independent cohort (AUROC = 0.725). Thus, we demonstrate robust stratification of sensitive tumors early during neoadjuvant HER2-targeted therapy using a multiplex spatial proteomic biomarker with implications for tailoring subsequent therapy.

Considering the difficulty in detecting primary breast cancers using whole-body positron emission tomography (WBPET) owing to its limited spatial resolution, we aimed to evaluate the detectability of breast cancer by ring-type dedicated breast PET (DbPET) on the World Health Organization (WHO) histological classification in comparison with WBPET.A total of 938 patients with breast cancer underwent WBPET and ring-type DbPET, and 1021 lesions were histologically assessed based on the WHO classification of tumors of the breast. The findings of WBPET and DbPET were retrospectively evaluated and compared.The size-related sensitivity of DbPET was superior to that of WBPET for subcentimetric tumors (81.9% vs. 52.4%, P 0.001). The histological distribution was as follows: 11 lobular carcinoma in situ, 158 ductal carcinoma in situ, 738 infiltrating duct carcinoma not otherwise specified (NOS), 12 lobular carcinoma NOS, 40 mucinous adenocarcinoma, 13 tubular carcinoma, 36 invasive breast carcinoma others, and 13 papillary neoplasms. WBPET had low sensitivity for lobular carcinoma in situ, ductal carcinoma in situ, lobular carcinoma NOS, mucinous adenocarcinoma, and tubular carcinoma. DbPET showed improved sensitivity for all the above except lobular and tubular carcinoma. The maximum standardized uptake values (SUVmax) of DbPET were significantly higher than those of WBPET for histological types, excluding lobular carcinoma in situ. The SUVmax of papillary neoplasms was high regardless of low-grade histology and Ki-67 labeling index.DBPET was found to have high sensitivity and SUVmax values for all histologic types that showed low sensitivity of detection on WBPET, except lobular carcinoma in situ.

Breast cancer is one of the most common cancers among women worldwide. Ultrasound imaging has been widely used in the detection and diagnosis of breast tumors. However, due to factors such as limited spatial resolution and speckle noise, classification of benign and malignant breast tumors using conventional B-mode ultrasound still remains a challenging task. H-scan is a new ultrasound technique that images the relative size of acoustic scatterers. However, the feasibility of H-scan ultrasound imaging in the classification of benign and malignant breast tumors has not been investigated. In this paper, we proposed a new method based on H-scan ultrasound imaging to classify benign and malignant breast tumors. Backscattered ultrasound radiofrequency signals of 100 breast tumors were used (48 benign and 52 malignant cases). H-scan ultrasound images were constructed with the radiofrequency signals by matched filtering using Gaussian-weighted Hermite polynomials. Experimental results showed that benign breast tumors had more red components, while malignant breast tumors had more blue components in H-scan ultrasound images. There were significant differences between the RGB channels of H-scan ultrasound images of benign and malignant breast tumors. We conclude H-scan ultrasound imaging can be used as a new method for classifying benign and malignant breast tumors.

Introduction: One of the principal limiting factors to achieving cures in patients with cancer is drug resistance. Drug repositioning is the application of FDA-approved drug compounds for novel indications beyond the scope of the drug’s original intended use. This approach offers advantages over traditional drug development by reducing development costs and providing shorter paths to approval, as drug safety has already been established during the drug’s original regulatory process. One approach for computational drug repositioning involves generating a disease gene expression signature and then identifying a drug that can reverse this disease signature. In this study, we extracted drug resistance signatures from the I-SPY 2 TRIAL by comparing gene expression profiles of responder and non-responder patients stratified by treatment and molecular subtype. We then applied our drug repositioning pipeline to predict compounds that can reverse the gene expression profiles of these drug resistance signatures. We hypothesize that reversing these drug resistance signatures will resensitize tumors to treatment and improve patient outcome. Methods: We first generated the drug resistance signatures by performing differential expression between responders (RCB 0/I) and non-responders (RCB III) within treatment arms and molecular subtypes. An optimal log fold-change cutoff was selected for each signature by identifying the cutoff that best separates the responder and non-responder samples using k-means clustering. We then applied our drug repositioning pipeline to identify compounds that significantly reverse these signatures using the drug perturbation profiles generated in a breast cancer cell line in the Connectivity Map v2 dataset. Briefly, the pipeline uses a non- parametric, rank-based pattern-matching strategy based on the Kolmogorov-Smirnov (KS) statistic to assess the enrichment of resistance genes in a ranked drug gene expression list. Significance of each prediction is estimated from a null distribution of scores generated from random gene signatures. Results: We found that few individual genes are shared among the resistance signatures across the treatment arms and molecular subtypes, with the most common genes present in only 5/17 of the treatment arm and molecular subtype groups. At the pathway-level, however, we found that immune-related pathways are generally enriched among the responders and estrogen-response pathways are generally enriched among the non-responders. Although most of our drug predictions are unique to treatment arms and molecular subtypes, our drug repositioning pipeline identified the selective estrogen receptor degrader (SERD) fulvestrant as a compound that can potentially reverse resistance across a majority of the treatment arms and molecular subtypes. Conclusion: We applied our drug repositioning pipeline to identify novel agents to sensitize drug-resistant tumors in the I-SPY 2+ clinical trial and identified a SERD, fulvestrant, as a potential candidate for multiple molecular subtypes and treatment arms. Citation Format: Katharine Yu, Amrita Basu, Christina Yau, Denise Wolf, Gillian Hirst, Laura Sit, Nicholas O’Grady, Thelma Brown, I-SPY 2 TRIAL Investigators, Angela DeMichele, Don Berry, Nola Hylton, Doug Yee, Laura Esserman, Laura van 't Veer, Marina Sirota. Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatment arms and molecular subtypes [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-04.

Background: Triple-negative breast cancer (TNBC) remains the most aggressive molecular subtype of breast cancer, with worse survival outcomes compared to other breast cancer subtypes. TNBC prevalence is highest among women of African descent worldwide, and through our previous work we have established a connection between West African ancestry (WAa) and higher rates of TNBC. Specifically, we have shown that prevalence rates of TNBC among West African and African American women are similar and higher than that of East African and White American women. We have also shown that quantified African ancestry is higher among TNBC cases compared to non-TNBC cases. To determine the influence African ancestry on the TNBC tumor environment, we sought to determine any differences in gene expression profiles of Ghanaian (West African) compared to Ethiopian (East African) women. Methods: RNA was extracted and sequenced from a pilot cohort of archival FFPE tumor tissue among Ghanaian (n = 19) and Ethiopian (n = 20) women. RNAseq reads were aligned, and quality of alignments were assessed, where de-duplicated samples with counts above 10M reads were included in the final analysis. Genetic ancestry was quantified by obtaining SNVs called from the RNAseq alignments, using GATK best practices. Differentially expressed genes lists were determined comparing Ghanaian vs. Ethiopian TNBC tumors, and also by identifying genes that were associated with increasing African ancestry. These gene lists, and log-fold change between comparison groups, were used as input for Ingenuity Pathway Analysis (IPA), to identify canonical pathways and de novo networks that are specific to Ghanaian or Ethiopian TNBC tumors. Results: Using 1KG populations as our reference to quantify genetic ancestry, we show that Ghanaian samples have >94% AFR ancestry, specifically matching population groups representative of WAa. The Ethiopian samples showed between 37-48% AFR ancestry, primarily represented by East African groups. Interestingly, there seems to be a significant proportion of EUR ancestry among the Ethiopians samples (30-49%), primarily represented by Italian ancestry. We have conducted the differential gene expression analysis in two ways. First, we have compared gene expression profiles between Ghanaian and Ethiopian tumors. In our preliminary analysis, we identified >600 genes (p < 0.01) that were differentially expressed between Ghanaian and Ethiopian TNBC tumors. Second, we used AFR ancestry as a continuous variable, where we conducted a linear regression analysis to identify genes associated with AFR ancestry. We identified >900 genes associated with AFR ancestry (p < 0.01), and this gene signature distinguished Ghanaian from Ethiopian tumors in an unsupervised hierarchical clustering. In comparing the differentially expressed gene lists from these two approaches, approximately 200 genes were shared, indicating the distinct value of both analyses. Using these gene lists as input for IPA analysis, we have begun to identify canonical pathways that have been altered by our differentially expressed genes, alongside de novo networks that differ between our Ghanaian and Ethiopian tumors. In our overlapping gene list, we see predicted differences in functions such as quantity of T lymphocytes, where genes downregulated in Ethiopian tumors may indicated reduced presence of these immune cells. Using CIBERSORT and xCell deconvolution methods, validation of these findings are ongoing. Conclusions and Ongoing work: This work highlights how ancestry-specific gene regulation can delineate differences in the tumor microenvironment among a cohort of African tumors. We are currently evaluating distribution of TNBC subtypes and estimation of immune cell populations in these tumors, to determine ancestry-specific differences in tumor heterogeneity and immune response. Citation Format: Rachel Martini, Endale Gebregzabher, Princesca Dorsaint, Timothy Chu, Kanika Arora, Lee Gibbs, Zarko Manojlovic, Nicolas Robine, Andrea Sboner, Olivier Elemento, John Carpten, Lisa Newman, Melissa Davis. Gene expression profiles of Ghanaian and Ethiopian triple-negative breast tumors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SS1-07.

Breast cancer is a vastly heterogeneous disease encompassing a panoply of special histological subtypes. Although rare breast tumors have largely not been investigated systematically in large scale genomics series, recent studies have shed light on the genetic underpinnings of special histologic subtypes of breast cancer. Genomic analyses of estrogen receptor-positive special histologic types of breast cancer have not resulted in the identification of novel pathognomonic genetic alterations in addition to the confirmation of the presence of CDH1 loss-of-function mutations in invasive lobular carcinomas. By contrast, the analyses of triple-negative breast cancers have demonstrated that low-grade triple-negative breast cancers categorically differ from the common forms of high-grade triple-negative disease biologically and phenotypically and are underpinned by specific fusion genes or hotspot mutations. A subset of low-grade triple-negative disease has been shown to harbor highly recurrent if not pathognomonic genetic alterations, such as ETV6-NTRK3 fusion gene in secretory carcinomas, the MYB-NFIB fusion gene, MYBL1 rearrangements or MYB gene amplification in adenoid cystic carcinomas, and HRAS Q61 hotspot mutations coupled with mutations in PI3K pathway genes in estrogen receptor-negative adenomyoepitheliomas. A subset of these pathognomonic genetic alterations (e.g., NTRK1/2/3 fusion genes) now constitute an FDA approved indication for the use of TRK inhibitors in the advanced/metastatic setting. These studies have also corroborated that salivary gland-like tumors of the breast, other than acinic cell carcinomas, harbor the repertoire of somatic genetic alterations detected in their salivary gland counterparts. Reassuringly, the systematic study of special histologic types of breast cancer utilizing state-of-the-art sequencing approaches, rather than rendering pathology obsolete, has actually strengthened the importance of breast cancer histologic typing and is providing additional ancillary markers for the diagnosis of these rare but fascinating entities.

Accurate detection of breast tumors and discrimination of tumor from normal tissues during breast-conserving surgery are essential to reduce the risk of misdiagnosis or recurrence. However, existing probes show substantial background signals in normal breast tissues. In this study, we focus on glycosidase activities in breast tumors. We synthesized a series of 12 fluorescent probes and performed imaging-based evaluation on surgically resected human breast specimens. Among them, the α-mannosidase-reactive fluorescent probe HMRef-αMan detected breast cancer with 90% sensitivity and 100% specificity. We identified α-mannosidase 2C1 as the target enzyme and confirmed its overexpression in various breast tumors. We found that fibroadenoma, the most common benign breast lesion in young woman, tends to have higher α-mannosidase 2C1 activity than malignant cancer. Combined application of green-emitting HMRef-αMan and a red-emitting γ-glutamyltranspeptidase probe enabled efficient dual-color, dual-target optical discrimination of malignant and benign tumors., By means of the imaging-based evaluation of glycosidase activities, we identified α-mannosidase 2C1 as a biomarker for breast tumors and realized their rapid and accurate visualization.

Homologous recombination (HR)-deficient breast tumors may have genomic alterations that predict response to treatment with PARP inhibitors and other targeted therapies. Comprehensive molecular profiles of 4647 breast tumors performed at Caris Life Sciences using 592-gene NGS were reviewed to identify somatic pathogenic mutations in HR genes ARID1A, ATM, ATRX, BAP1, BARD1, BLM, BRCA1/2, BRIP1, CHEK1/2, FANCA/C/D2/E/F/G/L, KMT2D, MRE11, NBN, PALB2, RAD50/51/51B, and WRN, as well as 41 markers that may be associated with treatment response to targeted anticancer therapies. 17.9% of breast tumors had HR mutations (HR-MT, 831/4647) [ER/PR+ , HER2− 18.3%, n = 2183; TNBC 18.2%, n = 1568; ER/PR+ , HER2+ 15.6%, n = 237; ER/PR−, HER2+ 12.9%, n = 217; unknown n = 442]. Mean TMB was higher for HR-MT tumors across subtypes (9.2 mut/Mb vs 7.6 h-wild type (HR-WT), p ≤ 0.0001) and independent of microsatellite status. MSI-H/dMMR was more frequent among HR-MT tumors (2.1% HR-MT vs 0.2% HR-WT, p ≤ 0.0001), as was tumor PD-L1 overexpression (13.2% HR-MT vs 11.0% HR-WT, p = 0.08). Additional co-alterations were similar between HR-MT and HR-WT, with the exception of PIK3CA (30.3% HR-WT vs 26.4% HR-MT, p = 0.024) and AKT1 (3.7% HR-WT vs 2.1% HR-MT, p = 0.021). AR overexpression and PIK3CA mutations were more common among ER/PR+ tumors. ERBB2 mutations were seen in both HER2+ and HER2− tumors. HR-MT was common across breast cancer subtypes and co-occurred more frequently with markers of response to immunotherapy (MSI-H/dMMR, TMB) compared to HR-WT tumors. Mutations were identified in both HR-MT and HR-WT tumors that suggest other targets for treatment. Clinical trials combining HRD-targeted agents and immunotherapy are underway and could be enriched through comprehensive molecular profiling.

The histological classification of breast tumors by the General Rule Committee of the Japanese Breast Cancer Society has been revised in the General Rules for Clinical and Pathological Recording of Breast Cancer (18th edition). In this article, the contents of the General Rules 18th edition are presented, and its revised points are briefly described in comparison with the classification of the General Rules 17th edition. The present classification takes into consideration the classification of breast tumors by the World Health Organization 4th edition, however, some differences remain. These differences will be briefly mentioned.

In this paper, we propose a transfer learning-based dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) method for classifying fibroadenoma and invasive ductal carcinoma (IDC) in breast tumors. A total of 207 breast tumors from patients were collected and identified by pathologic diagnosis within 15 days after enhanced DCE-MRI examination; 119 patients (average age 50.52±10.33 years) had fibroadenomas, and 88 patients (average age 42.20±10.10 years) had IDCs. Two lesion-level models were built based on the InceptionV3 and VGG19 models, which were pretrained with the ImageNet dataset. The effects of different depths of transfer learning were examined. The network's performance was evaluated through five-fold cross validation. In the lesion-level models, the model based on Inception V3 obtained better results (area under the receiver operating characteristic curve (AUC) = 0.89) when the weights were frozen before layer-276. The other model based on VGG19 obtained better results (AUC = 0.87) when the weights were frozen before layer-13. Compared with the image-level models, both lesion-level models displayed better discrimination (accuracy increased by 13% and 14%) based on the VGG19 and Inception V3 models, respectively. Our research confirms that transfer learning can be utilized to classify fibroadenomas and IDCs in DCE-MRI images. Different depths of transfer learning result in different performances, and our proposed lesion-level model notably improves the classification accuracy.

Evidence suggests that tumor cells and tumor-infiltrating lymphocytes (TILs) compete for glucose in the tumor microenvironment and that tumor metabolic parameters correlate with localized immune markers in several solid tumors. We investigated the relationship of the standardized uptake value (SUV) of 18F-fluorodeoxyglucose positron emission tomography computed tomography (18F-FDG-PET-CT) with stromal TIL levels in breast cancer. We included 202 patients who underwent preoperative 18F-FDG-PET-CT and had a tumor measuring ≥ 1 cm. Maximum SUV (SUVmax) was determined using 18F-FDG-PET-CT. Multiple logistic regression was used to identify factors related to high TIL levels (≥ 40%). All tumors were treatment naïve. A significant and weak correlation existed between continuous SUVmax and continuous TIL levels (p = 0.002, R = 0.215). Tumors with high SUVmax (≥ 4) had higher mean TIL levels than those with low SUVmax (

Objective: Study the epidemiological and anatomopathological characteristics of breast tumors of young woman. Patients and Methods: This was a retrospective and evaluative cross-sectional study of patients treated for a breast tumor between January 1, 2015 and December 31, 2019 in two hospitals in Cotonou. All the complete files of patients under the age of 40 treated for breast tumors of whatever nature were listed. The patients were recalled for clinical and / or radiological evaluation. The epidemiological and histological characteristics of breast tumors were analyzed. Results: The study involved 231 breast tumors including 12 cancers (5.2%) and 219 benign tumors (94.8%). The mean age of the patients was 25.7 years±7.2. Self-examination was the most common discovery (81%). The average consultation time was 6.4 months. The right breast and the upper-external quadrant were the most affected in 53% and 31.1%, respectively. Fibroadenomas (70.7%) and invasive ductal carcinomas (9/12) were the most frequent. Obesity and a family history of breast cancer were associated with the occurrence of breast cancer in young women (p ≤ 5%). The relative risk of developing breast cancer was practically zero before the age of 30. Benign breast tumors spontaneously regressed in part or in whole in 35.3% of cases (n=55), they were stable in 44.8% of cases (n=70) and increased in volume in 19.8% of cases (n=31). The age of diagnosis strongly influenced the evolution of tumors in the young woman in Cotonou (p=0.02). In 56% of cases, breast tumors diagnosed before the age of 20 spontaneously resolved in part and in whole. The breast cancer case fatality in women under 40 was 11.1%. Conclusion: Breast tumors in young women are mostly benign. More than half of these tumors diagnosed before the age of 20 resolve spontaneously. The risk of breast cancer is virtually zero before the age of 30 in our series.

Background Amplification of chromosome 8q with locus 8q24 is the most common copy number aberration, and is associated with tumour progression and chemoresistance. Materials and methods The study used paired samples of biopsy and surgical material from 60 patients with breast cancer. The amplification status of 8q was determined using a CytoScan HD Array microarray; complete transcriptomic analysis was performed using a Human Clariom S Assays microarray (Affymetrix, USA). Results It was shown that in 65% of cases, amplification of 8q was preserved in the tumour after neoadjuvant chemotherapy (NAC). NAC significantly enhanced the heterogeneity of the transcriptome between tumours with and without amplification of 8q. Compared with a good response, a poor response to NAC also led to increased heterogeneity of the transcriptome of residual tumours. Eight differentially expressed genes of patients with different amplification status of 8q before and after NAC overlapped. Conclusion Amplification of 8q leads to a significant shift in the level of transcription of a large number of genes after exposure to chemotherapy.

The oxytocin receptor (OXTR) plays an important role in childbirth, breastfeeding, and social interactions. There is emerging evidence that OXTR is associated with the breast cancer (BC) initiation and progression. However, the mechanisms leading to a change in its expression, the diagnostic or prognostic value of the receptor in BC are currently poorly understood. Here, we have evaluated the relative level of OXTR expression in BC samples (n=107), and also investigated the effect of estradiol on its expression in MCF-7 and MDA-MB-231 cells. The level of OXTR expression was significantly lower in breast tumor tissue than in normal tissue obtained from the same patient. The expression of OXTR was dependent on the status and expression of the estrogen receptor (ER): the level of OXTR mRNA was significantly lower in ER-negative BC samples compared to ER-positive BC samples. Moreover, OXTR expression was also lower in samples from patients with luminal subtype with a low value of ER expression (0-5 score according to the IHC assay, Allred scoring) compared with samples with high ER expression (6-8 score). In luminal BC, OXTR expression was associated with the HER2 expression level: the OXTR mRNA level was higher in tumors with a HER2 IHC score of 1+ as compared to cases with the HER2 expression score of 2+, 3+. We also showed that estradiol increased the level of OXTR mRNA in MCF-7 cells, but not in ER-negative MDA-MB-231 cells. These data indicate that changes in OXTR expression in BC tissues can be caused by increased ER expression. We found no association between OXTR and T or N stages and progesterone receptor expression.Retseptor oksitotsina (OXTR) igraet vazhnuiu rol' v protsessakh detorozhdeniia, grudnogo vskarmlivaniia i sotsial'nykh vzaimodeĭstviĭ. V poslednie gody poiavilis' dannye v pol'zu togo, chto OXTR sviazan s razvitiem i progressirovaniem raka molochnoĭ zhelezy (RMZh). Odnako mekhanizmy, privodiashchie k izmeneniiu ego ékspressii, diagnosticheskaia ili prognosticheskaia tsennost' retseptora pri RMZh na dannyĭ moment maloizuchenny. Poétomu my postavili tsel' otsenit' uroven' ékspressii OXTR v obraztsakh RMZh (n=107), a takzhe issledovat' vliianie éstradiola na ego ékspressiiu v kletkakh liniĭ MCF-7 i MDA-MB-231. Uroven' ékspressii OXTR byl znachitel'no nizhe v opukholevoĭ tkani molochnoĭ zhelezy, chem v normal'noĭ tkani, vziatoĭ ot togo zhe patsienta. Ékspressiia OXTR zavisela ot statusa i ékspressii éstrogenovogo retseptora (ER): uroven' mRNK OXTR byl dostoverno nizhe v obraztsakh ER-negativnogo RMZh po sravneniiu s obraztsami ER-pozitivnogo RMZh. Ékspressiia OXTR byla nizhe v obraztsakh patsientov s liuminal'nym RMZh pri nizkom znachenii ékspressii ER (0-5 ballov soglasno immunogistokhimicheskomu (IGKh) issledovaniiu, shkala Allred) po sravneniiu s obraztsami s vysokoĭ ékspressieĭ ER. Uroven' mRNK OXTR byl assotsiirovan s urovnem ékspressii HER2: uroven' mRNK OXTR byl znachitel'no povyshen v obraztsakh liuminal'nogo RMZh s urovnem ékspressii HER2 1 ball, soglasno IGKh issledovaniiu, po sravneniiu s opukholiami s vysokoĭ ékspressieĭ HER2 (2-3 balla). My takzhe pokazali, chto pod deĭstviem éstradiola uvelichivalsia uroven' mRNK OXTR v kletkakh MCF-7, no ne v ER-negativnykh kletkakh MDA-MB-231. Poluchennye dannye ukazyvaiut na to, chto izmenenie ékspressii OXTR v tkaniakh RMZh mozhet byt' vyzvano usileniem ékspressii ER. Sviazi OXTR so statusom T ili N opukholi i ékspressieĭ progesteronovogo retseptora vyiavleno ne bylo.

Previous reports suggest that a complex microbiome exists within the female human breast that might contribute to breast cancer etiology. The purpose of this pilot study was to assess the variation in microbiota composition by breast side (left versus right) within individual women and compare the microbiota of normal and breast tumor tissue between women. We aimed to determine whether microbiota composition differs between these groups and whether certain bacterial taxa may be associated with breast tumors. Bilateral normal breast tissue samples (n = 36) were collected from ten women who received routine mammoplasty procedures. Archived breast tumor samples (n = 10) were obtained from a biorepository. DNA was extracted, amplified, and sequenced. Microbiota data were analyzed using QIIME and RStudio. The most abundant phyla in both tumor and normal tissues were Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria. There were statistically significant differences in the relative abundance of various bacterial taxa between groups. Alpha diversity (Simpson’s index) was significantly higher in normal compared to tumor samples (0.968 vs. 0.957, p = 0.022). Based on unweighted UniFrac measures, breast tumor samples clustered distinctly from normal samples (R2 = 0.130; p = 0.01). Microbiota composition in normal samples clustered within women (R2 = 0.394; p = 0.01) and by breast side (left or right) within a woman (R2 = 0.189; p = 0.03). Significant differences in diversity between tumor and normal tissue and in composition between women and between breasts of the same woman were identified. These results warrant further research to investigate the relationship between microbiota and breast cancer.

Introduction. In the current environmental situation in Russia, the organization of early detection of cancer in women of fertile age is of particular importance, which has medical, social and demographic consequences. Among malignant neoplasms in women - breast cancer takes the first place in the Russian Federation. 30% of the cases are women of working age. The increase in the incidence of breast cancer in the Chelyabinsk region from 2008 to 2018 was about 30%. In 2018, the proportion of stage I-II breast cancer is 67.5%. To improve the quality of specialized medical care for patients with suspected and/or established breast cancer on the basis of the state medical institution «Chelyabinsk regional clinical center of Oncology and nuclear medicine» in 2018, a center for diagnosis and treatment of breast tumors (hereinafter - the Center) was established. Purpose of work. Analysis of the first results of the Center’s work. Materials and methods. Patients referred for consultation to the Center from 01.11.2018 to 31.08.2019. Results. As a result of the work of the Center for 10 months, there was a reduction in the time of examination of patients with suspected breast cancer from 30 to 14 calendar days. The share of detected breast cancer in the region at localized stages for 10 months of 2019 was higher (69.5%) compared to the same period of 2018 (66.7%), which is based on an increase in active detection of pathology in the established Center. Discussion. The creation of the Center has increased the availability of specialized care for patients with breast pathology. Reduced time for examination and conduct of trepan-biopsy of the tumor to confirm the diagnosis. Patients with breast cancer have a personalized approach to the treatment program. Conclusion. The establishment of the Center allows to improve the quality of specialized medical care for patients with suspected and/or established breast cancer.

Background: Among women with invasive breast cancer, the clinical significance of BRCA1 and BRCA2 variants of unknown significance (VUS) remain uncertain. A closer analysis of the somatic mutational profiles of women with invasive breast cancer and BRCA1 or 2 VUS could provide a better understanding of the pathogenesis of the disease and potentially allow for the development of targeted treatment regimens. We hypothesized that breast cancers with BRCA1/2 VUS will have different somatic genomic profiling patterns and tumor mutational burden (TMB) compared with BRCA1/2 wildtype (WT). Methods: We compared the tumor molecular profiling patterns for breast cancer with somatic BRCA1/2 VUS to BRCA1/2 WT using a multiplatform profiling service (Caris Life Sciences) consisting of next generation sequencing (NGS), protein expression (immunohistochemistry [IHC]) and gene amplification (fluorescence or chromogenic in situ hybridization [FISH or CISH]). We also determined the differences in TMB between VUS and WT. We defined ER/PR/Her2 status based on IHC and/or CISH results. DNA or mutation results with >1% frequency were analyzed using Chi Square test; p Citation Format: Hadeel Assad, Isabel Hart, Kristen Purrington, Joanne Xiu, Paula R Pohlmann, Sandra Swain, Gregory Vidal, Michael Simon. Somatic genomic profiles of breast tumors differ by BRCA1 and BRCA2 variants of unknown significance status [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-09-05.

Background: It has become increasingly clear that effective treatment of metastatic breast cancer (MBC) requires an in-depth understanding of the molecular differences between primary tumors and metastases. The AURORA US Network was established to collect primary breast cancer-metastasis pairs for multi-platform genomic profiling in order to identify the molecular drivers of metastatic disease. AURORA US has both a retrospective and prospective phase. This is the first report of the retrospective phase. Methods: Archived tissue samples from the primary tumor and at least one distant metastasis were retrospectively collected from 83 MBC patients. Following internal quality assessment, samples from 55 pts, including 105 distinct metastatic lesions, were subject to DNA low pass whole genome and exome sequencing, DNA methylation arrays, and RNA sequencing. Early analyses of these multi-platform data include: DNA methylation, tumor gene expression and microenvironmental signatures, somatic and germline variants, DNA copy number changes, and structural variants between breast primaries and matched metastases. Results: Median age at diagnosis was 49 years (25-76); 32 (58%) were Stage I or II at presentation, 27 (49%) had a family history of breast cancer, and 20 (36%) had a second breast primary. Median disease-free interval before developing MBC was 2 years (range 0-36, 5 patients presented with Stage IV). Median overall survival from initial presentation was 4 years (range 0-37). Median survival after developing MBC was 1 year (range 0-13), with a median of three treatments. Primary tissue samples were banked from 1977-2017 and metastases were banked from 1999-2017. Clinical phenotypes of the primaries included 27 HR+ (49%), 15 triple negative (TNBC, 27%), and 11 HER2+ (20%, 12 missing HER2 status). Intrinsic subtype distribution of the primaries included 17 Basal-like (31%), 17 Luminal A (31%), 7 Normal-like (13%), 5 HER2-enriched (9%), and 1 Luminal B, with 8 pending. All metastases from the Basal-like cases remained Basal-like, while metastases from luminal primaries tended to gain HER2-Enriched subtype features (5/18, p = 0.01). Overall, we identified significant metastasis-enriched alterations in metabolism pathways, an increase in proliferation, and the loss of differentiation signatures and immune infiltrates with progression; the latter being the most pronounced in brain metastases. The most frequent somatic mutations in this cohort were in TP53, NCOR1, and RUNX1. Interestingly, ERBB2, EGFR, and ATM were also mutated in ≥10% of the tumors sequenced. In almost all cases, CpG island hypermethylation was clonally present in the primary tumor and persisted stably in the majority of metastatic lesions. Promoter CpG island hypermethylation was also identified in some metastatic lesions at JAM3, an important cellular adhesion molecule,and this was accompanied by reduced mRNA expression. CONCLUSIONS: Collection of banked primary and metastatic tissue pairs identified a young MBC cohort with a high frequency of breast cancer family history and second breast primaries. Molecular characterization of luminal tumor pairs highlighted acquisition of aggressive traits including increased proliferation and loss of differentiation in the metastases. In contrast, basal-like pairs remained relatively unchanged, except for the loss of immune activation. Ongoing analyses to be presented include clonal heterogeneity and phylogeny, novel metastasis signature discovery, gene fusion, and endogenous retrovirus detection. Citation Format: Tari A King, Minetta C Liu, Marni B McClure, Toshinori Hinoue, Benjamin J Kelly, Chad J Creighton, Jay Bowen, Kristen Leraas, Robyn T Burns, Sara Coppens, Salma Rezk, Amy L Garrett, Justin M Balko, Joel S Parker, Ben H Park, Ian Krop, Carey Anders, Katherine A Hoadley, Julie Gastier-Foster, Mothaffar F Rimawi, Rita Nanda, Nancy U Lin, Claudine Isaacs, P. Kelly Marcom, Anna Maria Storniolo, Fergus J Couch, Elaine R Mardis, Adrian V Lee, Uma Chandran, Peter W Laird, Susan G Hilsenbeck, Larry Norton, Andrea L Richardson, W. Fraser Symmans, Lisa A Carey, Antonio C Wolff, Nancy E Davidson, Charles M Perou, the AURORA US Network. Multiplatform analysis of matched primary and metastatic breast tumors from the AURORA US Network [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS3-08.

Background: Racial disparities in breast cancer outcome continues to be a major health care challenge. The reasons underlying this disparity are multifactorial with a recent focus on the tumor microenvironment. The characterization of infiltrating immune cell populations in the tumor microenvironment are lacking in Black breast cancer patients. To address this research gap, we employed immunohistochemical (IHC) staining and quantitative digital imaging to assess CD8+ T-cells in breast tumor samples from the Women’s Circle of Health Study (WCHS), a population-based case-control study of breast cancer in Black and White women. Our aim was to characterize and compare the density, localization and distribution of CD8+ T cells, and explore their prognostic value in each racial group. Methods: Tumor-infiltrating CD8+ lymphocytes were assessed by IHC staining of tissue microarray (TMA) cores from 736 breast cancer patients, including 597 Blacks and 139 Whites. The Aperio platform was used for quantitative image analysis of TMA cores. Racial differences in demographic and clinical characteristics were evaluated using the Mann-Whitney U and Fisher’s exact tests. Overall (OS) and breast cancer-specific (DSS) survival were summarized by race using the Kaplan-Meier method and compared using the log-rank test. The associations between demographic/clinical factors and CD8 expression were evaluated using a general linear model (GLM). Multivariable Cox regression models were used to evaluate associations between survival outcomes and both race and CD8 expression, while adjusting for age. Results: Black women had a higher percentage of high-grade tumors in addition to higher prevalence of ER-negative and triple negative tumors than white women. There was a statistically significant difference in OS (p=0.043), showing worse outcomes among Black patients. Black patients had significantly higher CD8+ expression compared to White patients, with mean values of 756.2/mm2 and 292.4/mm2 respectively (p Conclusions: We observed a stronger presence of CD8+ T cells in tumor microenvironment from Black breast patients, suggesting the existence of distinct tumor immune responses in this population. Our current data do not support that CD8+ T cells contribute to breast cancer survival disparities given the lack of prognostic significance of CD8 expression in this sample. CD8+ T cells may become less cytotoxic towards tumor cells as a result of immunosuppression or exhaustion; therefore, in-depth immuno-profiling of the versatile immune cell subsets and their qualities of breast tumor microenvironment in Black patients is warranted to understand their roles in breast cancer racial disparities. Citation Format: Yara Abdou, Song Yao, Kristopher Attwood, Gary Zirpoli, Wiam Bshara, Christine Ambrosone, Angela Omilian. Racial differences in infiltration of CD8+ T-cells in breast tumors of Black and White women [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-10-02.

Background Some studies suggest that Human Papilloma Virus (HPV) infection is important factor in carcinogenesis of breast tumors. This study’ objective was to analyze HPV prevalence in breast cancers of patients from south-central Poland. Materials and methods The study was performed based on archival paraffin embebbed and formalin fixed blocks in the group of 383 patients with breast cancer. HPV prevalence and its genotype were assessed, respectively by: nested PCR (with two groups of primers: PGMY09/PGMY11 and GP5+/GP6+), quantitative PCR (qPCR). Tumors were classified as HPV positive in case of at least one positive result in nested PCR and positive results in genotyping procedure. For all HPV positive tissues P16 immunostaining was applied in order to confirm active viral infection. Results In the group of 383 breast cancers, HPV positivity was found in 17 samples (4.4%) in nested PCR. All these samples were subjected to HPV genotyping. This analysis revealed presence of HPV type 16 into two tumors (0.5%). In these two cancers, P16 overexpression was reported. Conclusion In breast tumors of patients from south-central Poland in Poland, HPV positivity is demonstrated in very low percentage of cases.

Background. One of the main reasons of the ineffectiveness of chemotherapy is still considered to be the formation of the multidrug resistance phenotype of the tumor due to the expression of energy-dependent proteins of ABC transporters. Our previous studies for some ABC genes have established that the expression of these genes correlates with the effectiveness of neoadjuvant chemotherapy (NAC). Some of the clinical studies indicate that ABC transporters can influence not only the formation of chemoresistance in the tumor, but also the progression, invasion and metastasis of the tumor node. Objective: to evaluate the level of transcription of all 49 known ABC genes in a breast tumor before and after treatment and their prognostic significance. Materials and methods. The study included 31 patients with a diagnosis of stage IIA – IIIB breast cancer. RNA was isolated from paired samples of tumor tissue before and after NAC. A microarray study of all tumor samples was performed on ClariomТМ S Assay, human microarrays. Using microarray studies, the expression of 49 genes of the ABC transporter family was studied. Analysis of the microchip data was carried out using the program Transcriptome Analysis Console (TAC) software 4.0. Results. It was found that changes in the expression (increase/decrease during NAC) of the ABCA5, ABCA7, ABCB1, ABCB4, ABCB11, ABCC1, ABCC10, ABCC11, ABCG1, ABCG2, ABCG4, ABCG5, ABCG8 genes are statistically significantly associated with the response to NAC. In addition, the prognostic significance of ABCB1 and ABCB4 gene expression was established. Survival analysis showed that 5-year survival rates in patients with high gene expression of ABCB1 and ABCB4 are lower compared to patients with low expression of these genes (log-rank-test p = 0.001 and 0.04 respectively). Conclusion. Data were obtained on the relationship of gene expression of the ABC transporter family with the effect of NAC in patients with breast cancer and the outcome of the disease. The prognostic potential of the ABCB1 and ABCB4 genes in patients with breast cancer has been established.

We studied the association between the presence of 2 or more stemness gene amplifications as well as copy number aberrations (CNAs) of WNT signaling genes in residual breast tumor and metastasis. WNT pathway genes associated with metastasis were identified.Material and Methods. The study included 30 patients with breast cancer, who had 2 or more stemness gene amplifications in the residual tumor after neoadjuvant chemotherapy. Fifteen of the thirty patients developed hematogenous metastases; they constituted a group with metastases, the remaining 15 patients entered the second group without metastases. The tumor DNA was examined using a CytoScanHD Array microarray (Affymetrix, USA).Results. By subtracting amplification and deletion frequencies in 852 cytobands between groups with metastases and without metastases, 21 cytobands were identified with the largest difference in deletion and amplification frequencies. They contain 19/150 of WNT genes (12 activators: SKP1, WNT8A, MAPK9, CCND3, FZD9, WNT8B, CCND1, PLCB2, PRKCB, FZD2, WNT3, WNT9B and 7 negative regulators: GSK3B, APC, CSNK2B, SFRP5, BTRC, TCF7L2, CSNK2A2). A point system was developed: when amplifying WNT-signaling activators or deletion of negative regulators, one point was added to the total score, and vice versa when deleting WNT-signaling activators or amplification of negative regulators, one point was taken from the total amount. It was shown that 93% (14/15) of patients with metastases had a total score higher than 0, while 93% (14/15) of patients without metastases had a total score of zero or less than zero. The differences between the groups were statistically significant according to the two-sided Fisher test with a high level of confidence probability (p=0.000003) and the log-rank test (p=0.00004) when assessing non-metastatic survival by the Kaplan-Mayer method.Conclusion. Nineteen WNT signaling genes were identified. Copy number aberrations of these genes in combination with stemness gene amplifications in residual tumors were associated with metastasis. A new highly effective prognostic factor for breast cancer was identified.

TP53 gene mutations are very common in human cancer. While such mutations abrogate the tumor suppressive activities of the wild‐type (wt) p53 protein, some of them also endow the mutant (mut) protein with oncogenic gain of function (GOF), facilitating cancer progression. Yet, p53 may acquire altered functionality even without being mutated; in particular, experiments with cultured cells revealed that wtp53 can be rewired to adopt mut‐like features in response to growth factors or cancer‐mimicking genetic manipulations. To assess whether such rewiring also occurs in human tumors, we interrogated gene expression profiles and pathway deregulation patterns in the METABRIC breast cancer (BC) dataset as a function of TP53 gene mutation status. Harnessing the power of machine learning, we optimized a gene expression classifier for ER+Her2‐ patients that distinguishes tumors carrying TP53 mutations from those retaining wt TP53. Interestingly, a small subset of wt TP53 tumors displayed gene expression and pathway deregulation patterns markedly similar to those of TP53‐mutated tumors. Moreover, similar to TP53‐mutated tumors, these ‘pseudomutant’ cases displayed a signature for enhanced proliferation and had worse prognosis than typical wtp53 tumors. Notably, these tumors revealed upregulation of genes which, in BC cell lines, were reported to be positively regulated by p53 GOF mutants. Thus, such tumors may benefit from mut p53‐associated activities without having to accrue TP53 mutations., In ER+Her2‐ breast cancer (BC), p53 tumor suppressor gene mutations are associated with bad prognosis, relative to tumors that retain wild‐type (wt) p53. Applying machine learning to a large BC dataset reveals a subset of ER+Her2‐ tumors (pseudomutant p53 tumors) which, despite retaining wt p53, display gene expression and pathway deregulation profiles typical of p53‐mutated tumors, correlating with bad prognosis.

As a primary risk factor and modifier of breast cancer incidence and prognosis, obesity may contribute to race disparities in breast cancer outcomes. This study examined association between obesity and DNA methylation in non-Hispanic Black and White women diagnosed with breast cancer. Genome-wide DNA methylation was measured in the breast cancer tumor tissue of 96 women using the EPIC array. To examine the association between obesity and tumor methylation, linear regression models were used—regressing methylation β value for each cytosine and guanine (CpG) site on body mass index adjusting for covariates. Significance was set at false discovery rate (FDR)

Background: Despite the assumption of breast cancer (BC) as a cold, non-immunogenic tumor, immune checkpoint inhibitor (ICI) therapy is favorable for a subgroup of patients. Immunohistochemical assessment of the programmed cell death ligand 1 (PD-L1) is the only approved companion diagnostic for anti-PD-L1 therapy in metastatic triple-negative BC; however, challenges regarding the standardization of PD-L1 scoring in tumor tissue still remain. Consequently, to select patients most likely to respond to ICI, blood-based biomarkers are urgently needed. Summary and Key Messages: Liquid biopsy, comprising circulating immune cells, circulating tumor cells and extracellular vesicles, as well as their surface proteins, is of high potential, and these analytes were already shown to be molecular correlates or regulators of the evasion from antitumoral immune reaction. Liquid biopsy, also enabling the evaluation of tumor mutational burden (TMB), microsatellite instability, and the T-cell receptor repertoire, allows serial sampling for monitoring purposes and reflects intra-tumoral heterogeneity which qualifies as marker for immunogenicity. Only a very few studies have already elucidated the potential of these analytes as biomarkers under ICI therapy. Nonetheless, the topic is of growing interest and has high relevance for the future. However, for clinical implementation, these multifarious analytes first need to pass robust standardization and validation procedures.

Background Breast cancer intrinsic molecular subtype (IMS) as classified by the expression-based PAM50 assay is considered a strong prognostic feature, even when controlled for by standard clinicopathological features such as age, grade, and nodal status, yet the molecular testing required to elucidate these subtypes is not routinely performed. Furthermore, when such bulk assays as RNA sequencing are performed, intratumoral heterogeneity that may affect prognosis and therapeutic decision-making can be missed. Methods As a more facile and readily available method for determining IMS in breast cancer, we developed a deep learning approach for approximating PAM50 intrinsic subtyping using only whole-slide images of H&E-stained breast biopsy tissue sections. This algorithm was trained on images from 443 tumors that had previously undergone PAM50 subtyping to classify small patches of the images into four major molecular subtypes—Basal-like, HER2-enriched, Luminal A, and Luminal B—as well as Basal vs. non-Basal. The algorithm was subsequently used for subtype classification of a held-out set of 222 tumors. Results This deep learning image-based classifier correctly subtyped the majority of samples in the held-out set of tumors. However, in many cases, significant heterogeneity was observed in assigned subtypes across patches from within a single whole-slide image. We performed further analysis of heterogeneity, focusing on contrasting Luminal A and Basal-like subtypes because classifications from our deep learning algorithm—similar to PAM50—are associated with significant differences in survival between these two subtypes. Patients with tumors classified as heterogeneous were found to have survival intermediate between Luminal A and Basal patients, as well as more varied levels of hormone receptor expression patterns. Conclusions Here, we present a method for minimizing manual work required to identify cancer-rich patches among all multiscale patches in H&E-stained WSIs that can be generalized to any indication. These results suggest that advanced deep machine learning methods that use only routinely collected whole-slide images can approximate RNA-seq-based molecular tests such as PAM50 and, importantly, may increase detection of heterogeneous tumors that may require more detailed subtype analysis.

Objective Breast cancer is the most common type of cancer in women worldwide. Our aim is to evaluate the importance of immunotherapy in breast cancer cases by using PD-L1 expression and to determine the effect of Maspin expression and lymphocytic density on predicting the prognosis. Methods A total of 200 breast cancer cases with different histological types were included in the study. The expression of PD-L1 and Maspin in these tumors were evaluated, and the lymphocytic infiltration density was examined. Results Expression of PD-L1 in tumor cells was significantly higher in "medullary carcinoma" and grade 3 tumors. Expression of PD-L1 in inflammatory cells was increased in the group of "other types" and grade 3 tumors. Maspin expression was observed in 93 cases and was higher in "lobular carcinoma" and high grade tumors. In our study, a significant correlation was found between lymphocytic density score and histological grade and PD-L1 expression. Conclusion In our study, PD-L1 expression was detected in breast cancer, and was associated with triple negativity and high grade. Our results show that the Maspin expression and lymphocyte density are associated with the prognosis (Tab. 5, Fig. 4, Ref. 44).