Heterochromatin-Encoded Satellite RNAs Induce Breast Cancer.

Heterochromatic repetitive satellite RNAs are extensively transcribed in a variety of human cancers, including BRCA1 mutant breast cancer. Aberrant expression of satellite RNAs in cultured cells induces the DNA damage response, activates cell cycle checkpoints, and causes defects in chromosome segregation. However, the mechanism by which satellite RNA expression leads to genomic instability is not well understood. Here we provide evidence that increased levels of satellite RNAs in mammary glands induce tumor formation in mice. Using mass spectrometry, we further show that genomic instability induced by satellite RNAs occurs through interactions with BRCA1-associated protein networks required for the stabilization of DNA replication forks. Additionally, de-stabilized replication forks likely promote the formation of RNA-DNA hybrids in cells expressing satellite RNAs. These studies lay the foundation for developing novel therapeutic strategies that block the effects of non-coding satellite RNAs in cancer cells.

Fast Ultrasound Scanning is a Rapid, Sensitive, Precise and Cost-Effective Method to Monitor Tumor Grafts in Mice.

In preclinical studies, accurate monitoring of tumor dynamics is crucial for understanding cancer biology and evaluating therapeutic interventions. Traditional methods like caliper measurements and bioluminescence imaging (BLI) have limitations, prompting the need for improved imaging techniques. This study introduces a fast-scan high-frequency ultrasound (HFUS) protocol for the longitudinal assessment of syngeneic breast tumor grafts in mice, comparing its performance with caliper, BLI measurements and with histological analysis. The E0771 mammary gland tumor cell line, engineered to express luciferase, was orthotopically grafted into immunocompetent C57BL/6 mice. Tumor growth was monitored longitudinally at multiple timepoints using caliper measurement, HFUS, and BLI, with the latter two modalities assessed against histopathological standards post-euthanasia. The HFUS protocol was designed for rapid, anesthesia-free scanning, focusing on volume estimation, echogenicity, and necrosis visualization. All mice developed tumors, only 20.6% were palpable at day 4. HFUS detected tumors as small as 2.2 mm in average diameter from day 4 post-implantation, with an average scanning duration of 47 s per mouse. It provided a more accurate volume assessment than caliper, with a lower average bias relative to reference tumor volume. HFUS also revealed tumor necrosis, correlating strongly with BLI in terms of tumor volume and cellularity. Notable discrepancies between HFUS and BLI growth rates were attributed to immune cell infiltration. The fast HFUS protocol enables precise and efficient tumor assessment in preclinical studies, offering significant advantages over traditional methods in terms of speed, accuracy, and animal welfare, aligning with the 3R principle in animal research.

Association of early menarche with breast tumor molecular features and recurrence.

BACKGROUND: Early menarche is an established risk factor for breast cancer but its molecular contribution to tumor biology and prognosis remains unclear. METHODS: We profiled transcriptome-wide gene expression in breast tumors (N = 846) and tumor-adjacent normal tissues (N = 666) from women in the Nurses' Health Studies (NHS) to investigate whether early menarche (age < 12) is associated with tumor molecular and prognostic features in women with breast cancer. Multivariable linear regression and pathway analyses using competitive gene set enrichment analysis were conducted in both tumor and adjacent-normal tissue and externally validated in TCGA (N = 116). Subgroup analyses stratified on ER-status based on the tumor were also performed. PAM50 signatures were used for tumor molecular subtyping and to generate proliferation and risk of recurrence scores. We created a gene expression score using LASSO regression to capture early menarche based on 28 genes from FDR-significant pathways in breast tumor tissue in NHS and tested its association with 10-year disease-free survival in both NHS (N = 836) and METABRIC (N = 952). RESULTS: Early menarche was significantly associated with 369 individual genes in adjacent-normal tissues implicated in extracellular matrix, cell adhesion, and invasion (FDR ≤ 0.1). Early menarche was associated with upregulation of cancer hallmark pathways (18 significant pathways in tumor, 23 in tumor-adjacent normal, FDR ≤ 0.1) related to proliferation (e.g. Myc, PI3K/AKT/mTOR, cell cycle), oxidative stress (e.g. oxidative phosphorylation, unfolded protein response), and inflammation (e.g. pro-inflammatory cytokines IFN α and IFN γ ). Replication in TCGA confirmed these trends. Early menarche was associated with significantly higher PAM50 proliferation scores (ß = 0.082 [0.02-0.14]), odds of aggressive molecular tumor subtypes (basal-like, OR = 1.84 [1.18-2.85] and HER2-enriched, OR = 2.32 [1.46-3.69]), and PAM50 risk of recurrence score (ß = 4.81 [1.71-7.92]). Our NHS-derived early menarche gene expression signature was significantly associated with worse 10-year disease-free survival in METABRIC (N = 952, HR = 1.58 [1.10-2.25]). CONCLUSIONS: Early menarche is associated with more aggressive molecular tumor characteristics and its gene expression signature within tumors is associated with worse 10-year disease-free survival among women with breast cancer. As the age of onset of menarche continues to decline, understanding its relationship to breast tumor characteristics and prognosis may lead to novel secondary prevention strategies.

Do we need reshape rTNM staging system for ipsilateral breast tumor recurrence of breast cancer? A population-based, propensity score matched cohort study.

BACKGROUND: The aim of the study was to explore the role of recurrent TNM (rTNM) staging in predicting prognosis for ipsilateral breast tumor recurrence (IBTR) and determine the optimal treatment strategy for IBTR. METHOD: IBTR cases were identified from the Surveillance, Epidemiology, and End Results (SEER) database spanning the years 2000-2018. Cox proportional hazards analysis was performed to examine factors associated with overall survival (OS) and breast cancer-specific survival (BCSS). Propensity score matching (PSM) was employed to match IBTR with primary early breast cancer (EBC) based on clinicopathological characteristics. Investigations into the impact of different therapies were also included. RESULTS: Of the 4375 IBTR cases included in the study, the 5-year OS was 87.1%, 71.6% and 58.7% in rTNM stages I, II and III, respectively. After PSM, while IBTR patients had worse survival to primary EBC patients, prognosis of IBTR for different rTNM stage always closely aligned with the corresponding stage of primary EBC. Repeat breast-conserving surgery (BCS) with radiation therapy was equivalent to mastectomy with respect to OS and BCSS. Chemotherapy was favorable for OS and BCSS in estrogen receptor (ER)-negative IBTR or IBTR occurring within a 60-month interval. CONCLUSIONS: rTNM staging system has an outstanding prognostic value for survival outcome of patients with IBTR, and IBTR and primary EBC may have potentially analogous features in the context of TNM staging. BCS plus radiation therapy may be an alternative. IBTR cases who have experienced recurrence with short intervals and with ER-negative tumors might benefit from chemotherapy.

An Integrated Nanoplatform via Dual Channel Excitation for Both Precise Fluorescence Imaging and Photodynamic Therapy of Orthotopic Breast Tumor in NIR-II Region.

Although research on photodynamic therapy (PDT) of malignant tumor has made considerable progress in recent years, it is a remaining challenge to extend PDT to the second near-infrared window (NIR-II) along with real-time and accurate NIR-II fluorescence imaging to determine drug enrichment status and achieve high treatment efficacy. In this work, lanthanide nanoparticles (Ln NPs)-based nanoplatform (LCR) equipped with photosensitizer Chlorin e6 (Ce6) and targeting molecular NH2-PEG1000-cRGDfK are developed, which can achieve NIR-II photodynamic therapy (PDT) and NIR-II fluorescence imaging by dual channel excitation. Under 808 nm excitation, Nd3+ in the outer layer can absorb the energy and transfer inward to emit strong NIR-II emissions (1064 and 1525 nm). Due to the low background noise of NIR-II light and the targeting effect of NH2-PEG1000-cRGDfK, LCR can recognize tiny tumor tissue (≈3 mm) and monitor drug distribution in vivo. Under 1530 nm excitation, internal Er3+ can be self-sensitized, generating intense upconversion emission (662 nm) that can effectively activate Ce6 for in vivo PDT due to the deep tissue penetration of NIR-II light. This study provides a paradigm of theranostic nanoplatform for both real-time fluorescence imaging and PDT of orthotopic breast tumor in NIR-II window.

SMALL MOLECULE INDUCES TIME-DEPENDENT INHIBITION OF STAT3 DIMERIZATION AND DNA-BINDING ACTIVITY AND REGRESSES HUMAN BREAST TUMOR XENOGRAFTS.

Aberrantly-active signal transducer and activator of transcription (Stat)3 has a causal role in many human cancers and represents a validated anticancer drug target, though it has posed significant challenge to drug development. A new small molecule, JKB887, was identified through virtual library screening and is predicted to interact with Lys591, Arg609 and Pro63 in the phospho-tyrosine (pTyr)-binding pocket of the Stat3 SH2 domain. JKB887 inhibited Stat3 DNA-binding activity in vitro in a time-dependent manner, with IC50 of 2.2-4.5 µM at 30-60-min incubation. It directly disrupted both the Stat3 binding to the cognate, high-affinity pTyr (pY) peptide, GpYLPQTV-NH2 in fluorescent polarization assay with IC50 of 3.5-5.5 µM at 60-90-min incubation, and to the IL-6 receptor/gp130 or Src in treated malignant cells. Treatment with JKB887 selectively blocked constitutive Stat3 phosphorylation, nuclear translocation and transcriptional activity, Stat3-regulated gene expression, and decreased viable cell numbers, cell growth, colony formation, migration, and survival in human or mouse tumor cells. By contrast, JKB887 had minimal effects on Stat1 activity, pErk1/2MAPK, pShc, pJAK2, pSrc induction, or cells that do not harbor aberrantly-active Stat3. Additionally, JKB887 inhibited growth of human breast cancer xenografts in mice. JKB887 is a Stat3-selective inhibitor with demonstrable antitumor effects against Stat3-dependent human cancers.

Management of Ipsilateral Breast Tumor Recurrence Following Breast Conservation Surgery for Ductal Carcinoma In Situ: A Data-Poor Zone.

BACKGROUND: Breast conserving surgery (BCS) is well established for the management of ductal carcinoma in situ (DCIS), but neither randomized trials nor guidelines address management of ipsilateral breast tumor recurrence (IBTR) after BCS for DCIS. PATIENTS AND METHODS: We identified women treated with BCS for DCIS who developed IBTR as a first event. Between those treated with mastectomy versus re-BCS, we compare the clinicopathologic characteristics, the use of adjuvant radiotherapy (RT) both upfront ("primary RT") and post IBTR ("secondary RT"), of tamoxifen, the rate of third events (local, regional, distant), and both breast cancer specific (BCSS) and overall survival (OS). RESULTS: Of 3001 women treated with BCS for DCIS (1978-2010), 383 developed an IBTR as a first event (1983-2023) and were treated by mastectomy (51%) versus re-BCS (49%). Compared with re-BCS, mastectomy patients at initial treatment were higher grade (74% versus 59%, p = 0.004), with more frequent primary RT (61% versus 21%, p < 0.001). Third local events were more frequent for re-BCS than mastectomy (16% versus 3%, p = 0.001), but there were no differences in breast cancer specific or overall survival. CONCLUSIONS: For isolated IBTR following BCS for DCIS and treated by mastectomy versus re-BCS (1) mastectomy was associated with less favorable initial pathology and more frequent use of primary RT, (2) re- recurrence was more frequent with re-BCS, and (3) BCSS and OS were comparable. Our data suggest a wider role for re-BCS and further study of the relationship between secondary RT and the rate of third breast events.

Patient Preference for Surgical Methods for Ipsilateral Breast Tumor Recurrence.

BACKGROUND: Mastectomy has been the standard surgical treatment for ipsilateral breast tumor recurrence (IBTR). Recently, there has been growing interest in repeat breast-conserving surgery (rBCS) for IBTR among breast surgeons; however, there is currently little information regarding patient preferences for surgical procedure for IBTR. The purpose of this study was to evaluate preference for surgical procedure (mastectomy vs. rBCS) among breast cancer patients who had undergone salvage surgery for IBTR. METHODS: Overall, 100 breast cancer patients who had undergone salvage surgery for IBTR were asked about their preferred surgical methods for IBTR and the reason. The association of patient preference and the reasons related to various clinical and pathological factors were assessed. RESULTS: Of the 100 respondents, only 11 patients (11%) preferred rBCS. Patients who had undergone rBCS and radiotherapy for IBTR were significantly more likely to prefer to undergo rBCS than other groups (p = 0.030). The most frequent reason for choosing rBCS was the patient's desire to minimize breast deformity and surgical wounds. CONCLUSIONS: Our study revealed that there is a low rate of patients who opt to undergo rBCS among patients who had undergone salvage surgery for IBTR. Discrepancies in perceptions regarding the surgical procedure for IBTR between patients and their surgeons may exist.

Indium(III) complexes with lapachol: cytotoxic effects against human breast tumor cells and interactions with DNA.

Lapachol (2-hydroxy-3-(3-methylbut-2-en-1-yl)naphthalene-1,4-dione) is a 1,4-naphthoquinone-derived natural product that presents numerous bioactivities and was shown to have cytotoxic effects against several human tumor cells. Indium(III) complexes with a variety of ligands also exhibit antineoplastic activity. Indium(III) complexes [In(lap)Cl2].4H2O (1), [In(lap)2Cl(Et3N)] (2), [In(lap)3]·2H2O (3) [In(lap)(bipy)Cl2] bipy = 2,2'-bipyridine (4) and [In(lap)(phen)Cl2] phen = 1,10-phenanthroline (5) were obtained with 2-hydroxy-3-(3-methylbut-2-en-1-yl)naphthalene-1,4-dione (lapachol). Crystal structure determinations for (4) and (5) revealed that the indium(III) center is coordinated to two O atoms from lapachol, two N atoms from 1,10-phenanthroline or 2,2'-bipyridine, and two chloride anions, in a distorted octahedral geometry. Although both complexes (4) and (5) interacted with CT-DNA in vitro by an intercalative mode, only 5 exhibited cytotoxicity against MCF-7 and MDA-MB breast tumor cells. 1,10-phenanthroline and complex (5) presented cytotoxic effects against MCF-7 and MDA-MB cells, with complex (5) being threefold more active than 1,10-phenanthroline on MCF-7 cells. In addition, complex (5) significantly reduced the formation of MDA-MB-231 colonies in a clonogenicity assay. The foregoing results suggest that further studies on the cytotoxic effects and cellular targets of complex (5) are of utmost relevance.

Successful Use of a Cadaver Model to Teach Ultrasound-Guided Breast Procedures to Surgical Trainees.

INTRODUCTION: In academic breast surgery, ultrasound use tends to be limited to radiology departments, thus formal surgical resident training in breast ultrasound is sparse. Building on residents' ultrasound skills in our general surgery training program, we developed a novel curriculum to teach ultrasound-guided breast procedures (UGBPs), including core needle biopsy (CNB) and wire localization (WL). We hypothesized that learning UGBPs on cadavers would be preferred to learning with a breast phantom model using chicken breasts. METHODS: Residents received a 1-h lecture on breast CNB and WL followed by a 1-h hands-on laboratory session. Olives stuffed with red pimentos were used to replicate breast masses and implanted in chicken breasts and the breasts of lightly embalmed and unembalmed female cadavers. All residents practiced UGBPs with a course instructor on both models. Residents completed anonymous prelaboratory and postlaboratory surveys utilizing five-point Likert scales. RESULTS: A total of 35 trainees participated in the didactics; all completed the prelaboratory survey and 28 completed the postlaboratory survey. Participant clinical year ranged from 1 to 6. Residents' confidence in describing and performing CNBs and WLs increased significantly on postlaboratory surveys, controlling for clinical year (P < 0.001). Eighty-point seven percent preferred learning UGBPs on cadavers over phantoms most commonly citing that the cadaver was more realistic. CONCLUSIONS: Following a novel 2-h UGBP training curriculum using phantom and cadaveric models, resident confidence in describing and performing UGBPs significantly improved. Most favored the cadaveric model and reported that the course prepared them for real-life procedures.

Design and one-pot synthesis of new substituted pyrrolo[1,2-a]thieno[3,2-e]pyrimidine as potential antitumor agents: in vitro and in vivo studies.

A new efficient and versatile one-pot three-component synthesis of substituted pyrrolo[1,2-a]thieno[3,2-e]pyrimidine derivatives has been developed. It is based on a multistep cascade reaction from 2-aminothiophenes and 2-hydroxy-4-oxobut-2-enoic acids, and derivatives of cyanoacetic acid catalyzed by diisopropylethylamine. As a result, novel pyrrolo[1,2-a]thieno[3,2-e]pyrimidine derivatives (21 compounds) were synthesized in a mild reaction conditions with a high yield. The structures of the developed compounds were confirmed by NMR and elemental analysis. The influence of electron-withdrawing or electron-donor substituents on the antitumor activity of the developed compounds has been identified. In vitro screening analysis of 21 compounds revealed six lead candidates (12aa, 12dc, 12hc, 12ic, 12lb, and 12mb) that demonstrated the most significant antitumor activity against B16-F10, 4T1 and CT26 cells. Necrosis/apoptosis assay showed that apoptosis was the predominant mechanism of cell death. Molecular docking analysis revealed several potential targets for tested compounds, i.e. phosphatidylinositol 5-phosphate 4-kinase (PI5P4K2C), proto-oncogene serine/threonine-protein kinase (Pim-1), nicotinamide phosphoribosyltransferase (NAMPT) and dihydrofolate reductase (DHFR). The lead compound (12aa) can effectively induce cell apoptosis, possesses a high yield (98 %) and requires low-cost starting chemicals for its synthesis. In vivo experiments with melanoma-bearing mice confirmed that 12aa compound resulted in the significant tumor inhibition on 15 d after the therapy. In particular, tumor volume was ∼0.19 cm3 for 50 mg/kg versus ∼2.39 cm3 in case of untreated mice and tumor weight was ∼71.6 mg for 50 mg/kg versus ∼452.4 mg when considered untreated mice. Thus, our results demonstrated the high potential of the 12aa compound in the treatment of melanoma and can be recommended for further preclinical studies.

Clinical effectiveness of transaxillary single-port endoscopic surgery in the treatment of breast benign tumor.

BACKGROUND: Benign breast lumps affect 10% of women in their lifetimes. Endoscopic surgery could be an alternative surgical technique for benign breast tumors because it is performed through small wounds hidden in inconspicuous areas. The aim of this study was to explore the safety and esthetic effects of endoscopic surgery in the treatment of benign breast disease. METHODS: This retrospective cohort study analyzed 363 patients with benign breast tumors from August 2021 to December 2023 in the Sixth Affiliated Hospital of Sun Yat-Sen University, of whom 118 underwent transaxillary single-port endoscopic surgery and 245 underwent traditional open surgery. Clinicopathologic characteristics, surgery type, hospital stay, and complications were analyzed to assess the effectiveness of the procedure for benign breast tumors. RESULTS: Breast tumor resection was successfully performed in 363 patients by endoscopic surgery or traditional open surgery. Endoscopic procedures demonstrated longer durations of surgery (98.54 ± 35.17 min vs. 70.28 ± 26.06 min, p < 0.01) and postoperative drainage (64.30 ± 34.92 mL vs.18.49 ± 19.86 mL, p < 0.01), but there was less blood loss. The nipple-areolar complex of the patients who underwent endoscopic resection was significantly more sensitive than the traditional open surgery group. Patients in the endoscopic group reported higher satisfaction with surgical outcome (13.10 ± 1.97 vs. 12.63 ± 1.90, p < 0.01). And there was a significant difference in the wound scar and cosmetic outcome total score between the two groups. CONCLUSION: Transaxillary single-port endoscopic surgery is effective and safe and improves postoperative nipple-areolar sensation and cosmetic outcome, as compared to the conventional technique.

Spatial and geometric learning for classification of breast tumors from multi-center ultrasound images: a hybrid learning approach.

BACKGROUND: Breast cancer is the most common cancer among women, and ultrasound is a usual tool for early screening. Nowadays, deep learning technique is applied as an auxiliary tool to provide the predictive results for doctors to decide whether to make further examinations or treatments. This study aimed to develop a hybrid learning approach for breast ultrasound classification by extracting more potential features from local and multi-center ultrasound data. METHODS: We proposed a hybrid learning approach to classify the breast tumors into benign and malignant. Three multi-center datasets (BUSI, BUS, OASBUD) were used to pretrain a model by federated learning, then every dataset was fine-tuned at local. The proposed model consisted of a convolutional neural network (CNN) and a graph neural network (GNN), aiming to extract features from images at a spatial level and from graphs at a geometric level. The input images are small-sized and free from pixel-level labels, and the input graphs are generated automatically in an unsupervised manner, which saves the costs of labor and memory space. RESULTS: The classification AUCROC of our proposed method is 0.911, 0.871 and 0.767 for BUSI, BUS and OASBUD. The balanced accuracy is 87.6%, 85.2% and 61.4% respectively. The results show that our method outperforms conventional methods. CONCLUSIONS: Our hybrid approach can learn the inter-feature among multi-center data and the intra-feature of local data. It shows potential in aiding doctors for breast tumor classification in ultrasound at an early stage.

Is repeat sentinel lymph node biopsy possible for surgical axillary staging among patients with ipsilateral breast tumor recurrence?

BACKGROUND: There is a lack of studies assessing the survival of repeat sentinel lymph node biopsy (rSLNB) versus axillary lymph node dissection (ALND) for surgical axillary staging among patients with ipsilateral breast tumor recurrence (IBTR). METHODS: We retrospectively identified patients with IBTR from the Surveillance, Epidemiology, and End Results database from 2000 to 2017. The primary outcome was overall survival (OS) between the rSLNB and ALND groups. RESULTS: Of the 2141 women with IBTR after lumpectomy and SLNB, 524 did not receive surgical axillary staging (nonsurgery group) and 1617 patients who did undergo axilla surgery received either rSLNB or ALND as axillary staging (1268 with rSLNB and 349 with ALND). The 10-year OS rates were 61.9% for the nonsurgery and 73.8% for axilla surgery groups (p = .001). In the 1:1 matched cohorts, the 10-year OS rates were 61.4% for the nonsurgery and 69.1% for axilla surgery groups (p = .072). After adjusting for other factors, axillary surgery treatment of IBTR was an independent favorable factor for OS (hazard ratio [HR], 0.71; 95% CI, 0.56-0.90; p = .004). Within the axilla surgery group, rSLNB presented a comparable 10-year OS to the ALND cohort (log-rank test p = .054). Multivariate Cox analysis, as well as subgroup analysis, showed that rSLNB had a similar benefit to ALND (10-year OS; HR, 1.18; 95% CI, 0.88-1.58; p = .268). CONCLUSIONS: The results of this cohort study suggested that receiving surgical axillary staging was associated with better survival of IBTR patients, and rSLNB had a similar long-term survival outcome as ALND. rSLNB might be considered for surgical axillary staging among patients with IBTR after lumpectomy and initial SLNB.

Ipsilateral breast tumor recurrence after breast-conserving surgery: insights into biology and treatment.

Despite modern surgical and irradiation techniques, ipsilateral breast tumor recurrence (IBTR) accounts for 5-15% of all cancer recurrence in women treated with breast conservative treatment. Historically, this event has been treated definitively with salvage mastectomy and completion axillary clearance. However, many local recurrences are small and without nodal involvement at presentation. Thus, there has been an interest in performing a surgical de-escalation procedure in the breast and the axilla. The current guidelines do not provide detailed descriptions and treatment suggestions for these selected patients, resulting in inconsistent treatment strategies. Moreover, the methods to define true recurrence (TR) and new primary tumor (NP) for IBTR remain controversial. Most developed classification methods mainly rely on clinical and pathological criteria, limiting the accuracy of the discerption and causing misclassification. In this editorial, we will discuss the current trends in surgical de-escalation for patients with IBTR. Moreover, we will focus on recent IBTR innovations, highlighting molecular-integrated classification and multimodal staging methods for clinical practice and postoperative surveillance strategies.

A prediction model for distant metastasis after isolated locoregional recurrence of breast cancer.

PURPOSE: The impact of progesterone receptor (PR) status on the prognosis of breast cancer after isolated locoregional recurrence (ILRR) remains unclear. This study evaluated the impact of clinicopathologic factors, including PR status of ILRR, on distant metastasis (DM) after ILRR. METHODS: We retrospectively identified 306 patients with ILRR diagnosed at the National Cancer Center Hospital between 1993 and 2021 from the database. Cox proportional hazards analysis was performed to examine factors associated with DM after ILRR. We developed a risk prediction model based on the number of detected risk factors and estimated survival curves using the Kaplan-Meier method. RESULTS: During a median follow-up time of 4.7 years after ILRR diagnosis, 86 patients developed DM, and 50 died. Multivariate analysis revealed that seven risk factors were associated with poor distant metastasis-free survival (DMFS): estrogen receptor-positive/PR-negative/human epidermal growth factor receptor 2-negative ILRR, short disease-free interval, recurrence site other than ipsilateral breast, no-resection of ILRR tumor, chemotherapy for the primary tumor, nodal stage in the primary tumor, and no endocrine therapy for ILRR. The predictive model classified patients into 4 groups based on the number of risk factors: low-, intermediate-, high-, and the highest-risk groups with 0 to 1, 2, 3 to 4, and 5 to 7 factors, respectively. This revealed significant variation in DMFS among the groups. A higher number of the risk factors was associated with poorer DMFS. CONCLUSION: Our prediction model, which considered the ILRR receptor status, may contribute to the development of a treatment strategy for ILRR.

Classification of breast tumors by using a novel approach based on deep learning methods and feature selection.

PURPOSE: Cancer is one of the most insidious diseases that the most important factor in overcoming the cancer is early diagnosis and detection. The histo-pathological images are used to determine whether the tissue is cancerous and the type of cancer. As the result of examination on tissue images by the expert personnel, the cancer type, and stage of the tissue can be determined. However, this situation can cause both time and energy loss as well as personnel-related inspection errors. By the increased usage of computer-based decision methods in the last decades, it would be more efficient and accurate to detect and classify the cancerous tissues with computer-aided systems. METHODS: As classical image processing methods were used for cancer-type detection in early studies, advanced deep learning methods based on recurrent neural networks and convolutional neural networks have been used more recently. In this paper, popular deep learning methods such as ResNet-50, GoogLeNet, InceptionV3, and MobilNetV2 are employed by implementing novel feature selection method in order to classify cancer type on a local binary class dataset and multi-class BACH dataset. RESULTS: The classification performance of the proposed feature selection implemented deep learning methods follows as for the local binary class dataset 98.89% and 92.17% for BACH dataset which is much better than most of the obtained results in literature. CONCLUSION: The obtained findings on both datasets indicates that the proposed methods can detect and classify the cancerous type of a tissue with high accuracy and efficiency.

Pan-cancer onco-signatures reveal a novel mitochondrial subtype of luminal breast cancer with specific regulators.

BACKGROUND: Somatic alterations in cancer cause dysregulation of signaling pathways that control cell-cycle progression, apoptosis, and cell growth. The effect of individual alterations in these pathways differs between individual tumors and tumor types. Recognizing driver events is a complex task requiring integrating multiple molecular data, including genomics, epigenomics, and functional genomics. A common hypothesis is that these driver events share similar effects on the hallmarks of cancer. The availability of large-scale multi-omics studies allows for inferring these common effects from data. Once these effects are known, one can then deconvolve in every individual patient whether a given genomics alteration is a driver event. METHODS: Here, we develop a novel data-driven approach to identify shared oncogenic expression signatures among tumors. We aim to identify gene onco-signature for classifying tumor patients in homogeneous subclasses with distinct prognoses and specific genomic alterations. We derive expression pan-cancer onco-signatures from TCGA gene expression data using a discovery set of 9107 primary pan-tumor samples together with respective matched mutational data and a list of known cancer-related genes from COSMIC database. RESULTS: We use the derived ono-signatures to state their prognostic significance and apply them to the TCGA breast cancer dataset as proof of principle of our approach. We uncover a "mitochondrial" sub-group of Luminal patients characterized by its biological features and regulated by specific genetic modulators. Collectively, our results demonstrate the effectiveness of onco-signatures-based methodologies, and they also contribute to a comprehensive understanding of the metabolic heterogeneity of Luminal tumors. CONCLUSIONS: These findings provide novel genomics evidence for developing personalized breast cancer patient treatments. The onco-signature approach, demonstrated here on breast cancer, is general and can be applied to other cancer types.

Clinical perspectives and outcomes of the giant breast phyllodes tumor and sarcoma: a real-world retrospective study.

BACKGROUND: Giant breast malignant phyllodes tumor or sarcoma (GBPS) are rare entities with diameter larger than 10 cm and variously histological pleomorphisms. This disease poses a significant threat to the quality of life of individuals, and its prognosis remains unclear. This study aimed to explore the differential diagnosis, treatment, and prognosis of GBPS in a real-world retrospective cohort. METHODS: We collected GBPS (diameter > 10 cm, n = 10) and BPS (diameter ≤ 10 cm, n = 126) from patients diagnosed with sarcoma or malignant phyllodes tumor between 2008 and 2022. We analyzed clinical characteristics, histological status, treatment, and local recurrence using the Fisher's exact test between GBPS (diameter > 10 cm) and BPS (diameter ≤ 10 cm) cohort. We described overall survival (OS) and disease-free survival (DFS) using Kaplan-Meier curves and identified risk factors for local recurrence using logistic regression. The tumor size, age at diagnosis, and differential immunohistochemistry markers of breast sarcoma or phyllodes tumor to determine the prognosis of GBPS. RESULTS: In our retrospective analysis of breast malignancies, we identified 10 cases of GBPS and 126 cases of BPS, corresponding to a GBPS prevalence of 0.17% (10/6000). The median age was 38.5 years (inter-quartile range, IQR: 28.25-48.5 years). During the follow-up of period (median: 80.5 months, IQR: 36.75-122 months), the local recurrence (LR) rate was 40% and 20.6%, respectively. Clinical characteristics of young age (HR:2.799, 95%CI -00.09276-0.017, p < 0.05) and cytological characteristics of marked stromal atypia (HR:0.88, 95% CI 0.39-1.40, p < 0.05) were risk factors for the poor prognosis of GBPS by COX regression model analysis. The Kaplan-Meier curves of GBPS 5-year disease-free survival (DFS) and overall survival (OS) were 31.5 months and 40 months, respectively, and were not associated with adjuvant radiation or chemotherapy. CONCLUSION: We recommend mastectomy with a clear surgical margin as the preferred treatment for GBPS. Age and stromal atypia are significantly associated with recurrence. Adjuvant radiation therapy is advised; however, there was no improvement in overall survival. There is no consensus on the effectiveness of adjuvant chemotherapy and genetic methods, highlighting the need for further research into this aggressive tumor. We recommend a multidisciplinary approach involving a dedicated team for the management of GBPS.

Suspension state and shear stress enhance breast tumor cells EMT through YAP by microRNA-29b.

Except for biochemical effects, suspension state (Sus) is proved to induce epithelial-mesenchymal transition (EMT) of circulating tumor cells (CTCs) mechanically. However, the difference between the effects of the mechanical microenvironment in capillaries (simplified as shear stress (SS) and Sus) and single Sus on EMT is unclear, nor the underlying mechanism. Here, breast tumor cells (BTCs) were loaded with Sus and SS to mimic the situation of CTCs stimulated by these two kinds of mechanics. It was demonstrated that the EMT of BTCs was enhanced by Sus and SS and the mechanotransductor yes-associated protein (YAP) was partially cytoplasmic stored with microRNA (miR)-29b decreased, which was detected by miR sequencing. Though it couldn't possess a feedback regulation, YAP promoted miR-29b expression and posttranscriptionally regulated BTCs EMT through miR-29b, where transforming growth factor ß involved. Analysis of clinical database showed that high miR-29b expression was beneficial to high survival rate stabilizing its role of tumor suppressor. This study discovers the mechanism that Sus and SS promote BTCs EMT by YAP through miR-29b posttranscriptionally and highlight the potential of YAP and miR-29b in tumor therapy. The combination of suspension state and shear stress promotes transforming growth factor ß involved epithelial-mesenchymal transition by yes-associated protein through microRNA-29b.