Subtypes Of Invasive Breast Cancer Research Articles

Multicenter study evaluating the utility of AI-aided HER2 scoring in the clinically relevant categories.

e15150 Background: The availability of multiple therapeutic options for breast cancer patients with varying levels of protein expression necessitates precise and standardized HER2 scoring. This study explored the clinical utility of AI-aided HER2 scoring of whole-slide digital images by pathologists in breast core needle biopsies and excisions. Methods: The study included patients (n=764) with multiple subtypes of invasive breast cancer from 3 US reference laboratories and 1 academic medical center. The non-interventional two-arm multi-reader study retrospectively compared manual digital vs. AI-aided HER2 scoring of 8 pathologists. The fully automated HER2 AI solution detects the invasive tumor area and then classifies the tumor cells based on staining pattern based and the 2023 ASCO/CAP guidelines to output slide-level HER2 score. Both study arms were compared to reference ground truth (GT) established by the consensus of two breast subspecialists, ground truthers (GTer), who reviewed the slides digitally. One site recorded the time taken for HER2 scoring of both arms to determine the efficacy of the HER2 AI solution. Results: The initial interobserver agreement among expert GT pathologists for each HER2 score, 0, 1+, 2+, 3+, were 83%, 63.8%, 46%, and 92.6, respectively. At the clinically meaningful cut-offs, the reader pathologists’ performance improved with the AI support. At the 0 vs. 1+/2+/3+ and 0/1+ vs 2+/3+ clinical cutoffs, the readers' accuracy was 86.3% vs 88.6% and 93.7%, 93.8% with and without AI support, respectively. The AI use contributed to approximately 12%-time savings for the readers at the medical center. The AI solution demonstrated high accuracy for HER2 scoring, with 89.2% agreement with GT for 0 vs 1+/2+/3+ scores and 93.1% for 0/1+ vs 2+/3+ cutoff. The results will be updated in the final submission with the additional site data. The reader feedback survey regarding the solution’s usability will also be presented. Conclusions: The pathologists demonstrated improvements in consistency, evidenced by inter-reader agreement and accuracy with the aid of the AI. The AI solution can improve efficiency toward accurate HER2 scoring. [Table: see text]

Retrospective cohort study on the bilateral occurrence of invasive lobular breast cancer

ObjectiveInvasive lobular carcinoma (ILC) is the second most common histological subtype of invasive breast cancer, following the no special type (NST) invasive carcinoma. It has historically been assumed that ILC occurs bilaterally in 20–29 % of cases, which has influenced the inclusion of MRI in the standard workup of ILC according to European guidelines. However, challenging this long-held belief regarding the bilateral occurrence of ILC opens up the possibility of revising the guidelines and using MRI only for more specific indications. This study aims to evaluate whether the previously reported high percentage of bilaterality still holds true and to question the added value of MRI in the standard workup of ILC. Study designA retrospective cohort study was conducted following approval from the institutional review board (EC 21/18/249) at Antwerp University Hospital (UZA). The cohort comprised female patients of all ages who had been diagnosed with either ILC or NST invasive carcinoma and had sought consultation at the UZA breast clinic. A comprehensive database was established to collect information on patient characteristics, imaging, and pathology. ResultsA total of 271 patients with ILC were included in the study, with incidence dates ranging from 01/01/2007 to 01/01/2023. Among these patients, a synchronous bilateral ILC lesion was observed in 1.85 % (5/271) of cases. This proportion is significantly lower than the reported percentage of patients with a bilateral lesion in the literature population, which stands at 4.95 %. The reference group consisted of 809 patients with NST invasive carcinoma, with incidence dates ranging from 01/01/2017 to 01/01/2023. In the control group, a synchronous bilateral NST lesion was observed in 3.96 % (32/809) of cases. There is no significant difference in the bilaterality rates between the group of ILC patients and the group of NST patients. Furthermore, MRI did not detect any histopathologically confirmed contralateral ILC lesion that had not already been detected by mammography or ultrasound. ConclusionsThe study results indicate a lower occurrence of bilateral ILC than previously assumed. Additionally, the incidence of synchronous bilateral lesions in ILC patients is not higher compared to patients with NST invasive carcinoma. Performing an MRI does not provide additional value in detecting bilateral carcinomas in ILC. Consequently, it is recommended that the current European guidelines be reassessed, and the indications for undergoing an MRI should be adjusted accordingly.

Overexpression of WT1 in all molecular subtypes of breast cancer and its impact on survival: exploring oncogenic and tumor suppressor roles of distinct WT1 isoforms.

Breast cancer is a highly heterogeneous solid tumor, posing challenges in developing targeted therapies effective for all mammary carcinoma subtypes. WT1 emerges as a promising target for breast cancer therapy due to its potential oncogenic role in various cancer types. Previous works have yielded inconsistent results. Therefore, further studies are needed to clarify the behavior of this complex gene in breast cancer. In this study, we examined WT1 expression in both Formalin Fixed Paraffin Embedded breast tumors (n = 41) and healthy adjacent tissues (n = 41) samples from newly diagnosed cases of ductal invasive breast cancer. The fold change in gene expression between the tumor and healthy tissue was determined by calculating 2-∆∆Ct. Disease-free survival analysis was computed using the Kaplan-Meier method. To identify the expression levels of different WT1 isoforms, we explored the ISOexpresso database. Relative quantification of the WT1 gene revealed an overexpression of WT1 in most cases. The percentage of patients surviving free of disease at 8years of follow-up was lower in the group overexpressing WT1 compared to the group with down-regulated WT1. Interestingly, this overexpression was observed in all molecular subtypes of invasive breast cancer, underscoring the significance of WT1 as a potential target in all these subtypes. The observed WT1 down-expression in a few cases of invasive breast cancer, associated with better survival outcomes, may correspond to the down-regulation of a particular WT1-KTS (-) isoform: the WT1 A isoform (EX5-/KTS-). The co-expression of this WT1 oncogenic isoform with a regulated WT1- tumor suppressor isoform, such as the major WT1 F isoform (EX5-/KTS +), could also explain such survival outcomes. Due to its capacity to adopt dual roles, it becomes imperative to conduct individual molecular expression profiling of the WT1 gene. Such an approach holds great promise in the development of personalized treatment strategies for breast cancer.

Triple-Negative Breast Cancer Treatment Advancements: A Review of Evolving Strategies

Women around the world are most frequently afflicted with breast cancer, and it is one of the most frequent causes of cancer death in females. Breast cancer is usually classified according to biomarker status, triple‐negative breast cancer (TNBC) represents a distinct subtype characterized by immunohistochemical findings that denote negativity for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (Her-2) on cancer tissue. It is more common in younger women than in other subtypes. As an invasive breast cancer subtype with a unique drug-resistant phenotype and metastatic burden, it has limited treatment options, and patients have a poor prognosis with high rates of local, distant recurrence and mortality, and there is still a lack of standardized treatment protocols for TNBC. In this review, we delve into the current treatment strategies for TNBC and explore the potential for new approaches and targets in the future. This trial is registered with NCT03997123.

Abstract NG01: Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity

Abstract NG01: Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity

Abstract 4652: Combined inhibition of MCL-1 and MEK reduces tumor growth in a triple-negative/inflammatory breast cancer, MEK-resistant xenograft mouse model

Abstract Background: Triple-negative breast cancer (TNBC) and inflammatory breast cancer (IBC) are highly aggressive subtypes of invasive breast cancer. Our previous work showed that the MEK inhibitor (MEKi) selumetinib (AZD6244) prevents lung metastasis in a xenograft model. However, clinical studies have shown that MEKi’s as single agents have only modest activity against solid tumors. Using a genome-wide synthetic lethal siRNA screening, we identified myeloid cell leukemia-1 (MCL1) as a potential contributor to selumetinib resistance. MCL-1 is an anti-apoptotic protein associated with cell immortalization, transformation, and chemoresistance in numerous cancers. We hypothesized that MCL-1 promotes MEKi resistance in TNBC/IBC and inhibition of MCL-1 in the presence of AZD6244 overcomes this MEKi resistance. Methods & Results: To understand MCL1’s role in MEKi resistance, we established two AZD6244 -resistant TNBC/IBC cell lines: MDA-MB-231-R and SUM149-R. These cells showed increased cell viability, colony formation, migration, cells in G1 phase, CD44+CD24low, mammosphere count, anchorage-independent growth and high MCL-1 expression. MCL-1’s biological role was evaluated by transient and stably knock down (KD) of MCL-1 in the resistant cells which showed decreased cell viability, colony formation, and increased apoptosis. To understand the mechanism mediating apoptosis, we examined the expression of MCL-1’s binding partners in the MCL-1-KD-R cells in the presence of AZD6244. These cells showed a high expression of the PUMA, NOXA, BAK, and BAX in the presence of AZD6244. Further, we treated resistant cells with MEKi AZD6244 and an MCL-1i (AZD5991) that confirmed restoration of MEK sensitivity in both resistant cell lines, resulting in decreased cell viability, colony formation and increased apoptosis. We compared tumor formation capability between SUM149 parental and SUM149 resistant cells by injecting them in nu/nu mice and observed a time-dependent increase (avg. 4-fold) in tumor growth with SUM149-R cells compared to parental cells (P≤0.0001). Moreover, IHC analysis showed high expression of MCL-1 (P≤0.01), Ki67 (ns), CD44 (P≤0.0001), and ALDHA1 (P≤0.0001) in the mammary gland tumor tissues of SUM149-R-injected mice compared to SUM149-P-injected mice. Next, we evaluated the therapeutic effect of AZD6244 in mice harboring SUM149-R - MCL-1-deficient tumors. AZD6244 treatment significantly reduced tumor development in mice harboring SUM149-R - MCL-1-KD tumors compared to control mice (P<0.0001), suggesting that MCL-1 mediates MEK resistance in triple-negative/inflammatory breast cancer. Conclusion: Our results suggest that MCL-1 is important for inducing acquired MEK resistance and combining an MCL-1i with a MEKi could improve treatment outcomes of patients with TNBC or IBC who have developed resistance to single-agent MEKi. Citation Format: Mohd Mughees, Alex Tan, Lakesla Iles, Michael White, Debu Tripathy, Savitri Krishnamurthy, Jian Wang, Wendy A. Woodward, Geoffrey Bartholomeusz, Chandra Bartholomeusz. Combined inhibition of MCL-1 and MEK reduces tumor growth in a triple-negative/inflammatory breast cancer, MEK-resistant xenograft mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4652.

Abstract 6115: Genetic ancestry specific meQTLs control immune function regulation in a breast cancer cohort of African and European patients

Abstract Black women with significant African ancestry experience a disproportionately higher incidence of the most aggressive and invasive breast cancer subtypes, along with worse clinical outcomes across all demographic groups within the United States. These health disparities arise from complex interactions between genetic, sociocultural, and environmental factors. Epigenetic mechanisms, such as DNA methylation (DNAm), which regulate gene expression have been proposed as a means to capture the molecular impact of adverse environments on tumor biology. While DNAm levels can be influenced by environmental stimuli, they are also regulated by individual genotypes at methylation quantitative trait loci (meQTLs), posing a challenge to modeling the impact of the environment on cancer molecular characteristics. We hypothesized that ancestry differential DNAm in breast cancer is a result of differential genotype frequencies of SNPs due to ancestry at meQTL loci that can result in phenotypic differences between breast cancer patients of African and European ancestry through differential gene expression regulation. To investigate this hypothesis, we leveraged multi-omic data from The Cancer Genome Atlas (TCGA) breast cancer cohort to perform integrative analysis in patients of European and African ancestry (n=578). 804 CpGs were significantly differentially methylated between European and African ancestry breast cancer patients. meQTL analysis at these sites identified 37 cis-meQTLs and 748 trans-meQTLs, regulating methylation at CpG sites enriched in CpG Islands, enhancers, and other open chromatin regions. 54% of the cis- and 69% of the trans-meQTLs show evidence of differential genotype frequencies by ancestry. Association analysis between methylation and local gene expression revealed that 683 of the 804 ancestry differentially methylated sites regulate the expression of 5,774 genes. We found a statistically significant enrichment for genes involved in immune-related functions such as MHC class II protein complex assembly and the regulation of leukocyte cell-cell adhesion. Intriguingly, 10.5% of these genes encode transcription factors (TFs), and out of these ~23% are linked to African-ancestry specific open chromatin regions in breast cancer cell lines derived from African-ancestry donors. Our findings show that ancestry specific DNAm differences display strong genetic associations via ancestry associated meQTLs, affecting fundamental immunological processes in breast cancer. Our findings suggest that the effects of ancestry-specific genetic regulation may be more profound than previously appreciated, while pointing to the potential for confounding due to genetic ancestry when using DNA methylation as a molecular readout of environmental exposures. Citation Format: Kyriaki Founta, Nyasha Chambwe. Genetic ancestry specific meQTLs control immune function regulation in a breast cancer cohort of African and European patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6115.

Rare Presentation of Papillary Carcinoma Within a Sentinel Lymph Node in a Patient With Ductal Carcinoma in Situ of the Breast: A Challenging but Useful Case Report Discussion Regarding Displacement or True Metastasis?

Papillary carcinoma of the breast is a rare histologic subtype of invasive breast cancer. In contrast, ductal carcinoma in situ (DCIS) is a noninvasive, nonobligate precursor to invasive mammary carcinoma, confined within the terminal duct lobular unit of the breast and surrounded by an intact myoepithelial cell layer at the stromal/epithelial interface. We present an unusual case in which a patient with only DCIS of the breast exhibited papillary carcinoma within a sentinel lymph node, leading to questions about the origin of the lymph node lesion-whether it represents a true metastasis or iatrogenic displacement during diagnostic procedures. This case underscores the diagnostic challenges and clinical implications associated with such rare presentations.

Metastatic profiles and survival differences between infiltrating ductal carcinoma and infiltrating lobular carcinoma in invasive breast cancer

BackgroundIn this study, we conducted a comprehensive evaluation of metastatic profiles and survival outcomes in patients with infiltrating ductal carcinoma (IDC) and infiltrating lobular carcinoma (ILC) treated at our university hospital center. MethodsWe collected and analyzed data from all patients diagnosed with invasive breast cancer at our center between January 1, 2007, and 31 December 2014. We specifically compared three subgroups: patients with IDC, patients with ILC and patients with mixed carcinoma, which is a combination of IDC and ILC. ResultsAmong the 1963 patients treated for invasive breast cancer in our center during the study period, 1435 had IDC, 466 had ILC, and 59 had mixed carcinoma. The incidence of patients with at least one positive axillary lymph node differed significantly: 40 % for IDC, 36 % for ILC, and 45 % for mixed carcinoma (p = 0.001). However, there was no significant difference in the mean number of positive nodes (p = 0.1633). The occurrence of distant metastases was lower in patients with ILC (p = 0.04), particularly in the case of brain metastases (p = 0.01), although there was no difference in bone or visceral metastatic sites. Patients with ILC exhibited a longer mean time to metastasis from the initial diagnosis of invasive breast carcinoma. Overall survival (p = 0.0525) and survival without locoregional recurrence (p = 0.026) were significantly different. Specifically, the 5-year overall survival rates for IDC, ILC, and mixed carcinoma were approximately 95 %. Distance metastatic-free survival at 5 years was 85 % for IDC, 91 % for ILC, and 87 % for mixed carcinoma (p = 0.00506). ConclusionOur findings indicate variations in the distribution of distant metastatic sites among patients with IDC, ILC, and mixed carcinoma, as well as differences in survival outcomes. This study sheds light on the unique characteristics and clinical implications associated with these two distinct subtypes of invasive breast cancer.

A Molecular Typing Method for Invasive Breast Cancer by Serum Raman Spectroscopy

BackgroundThe incidence of breast cancer ranks highest among cancers and is exceedingly heterogeneous. Immunohistochemical staining is commonly used clinically to identify the molecular subtype for subsequent treatment and prognosis. PurposeRaman spectroscopy and support vector machine (SVM) learning algorithm were utilized to identify blood samples from breast cancer patients in order to investigate a novel molecular typing approach. MethodTumor tissue coarse needle aspiration biopsy samples, and peripheral venous blood samples were gathered from 459 invasive breast cancer patients admitted to the breast department of Sichuan Cancer Hospital between June 2021 and September 2022. Immunohistochemical staining and in situ hybridization were performed on the coarse needle aspiration biopsy tissues to obtain their molecular typing pathological labels, including: 70 cases of Luminal A, 167 cases of Luminal B (HER2-positive), 57 cases of Luminal B (HER2-negative), 84 cases of HER2-positive, and 81 cases of triple-negative. Blood samples were processed to obtained Raman spectra taken for SVM classification models establishment with machine algorithms (using 80% of the sample data as the training set), and then the performance of the SVM classification models was evaluated by the independent validation set (20% of the sample data). ResultsThe AUC values of SVM classification models remained above 0.85, demonstrating outstanding model performance and excellent subtype discrimination of breast cancer molecular subtypes. ConclusionRaman spectroscopy of serum samples can promptly and precisely detect the molecular subtype of invasive breast cancer, which has the potential for clinical value.

Abstract C003: Analysis of genetic control of differential DNA methylation between breast cancer patients of African and European ancestry

Abstract Black women with significant African ancestry experience a disproportionately higher incidence of the most aggressive and invasive breast cancer subtypes, along with worse clinical outcomes across all population groups in the United States. These health disparities arise from complex interactions between genetic, sociocultural, and environmental factors. Although there is a critical need to understand how these non-genetic factors contribute to disease risk or etiology, they are difficult to measure reliably, and their long-term impacts are not well understood. Epigenetic mechanisms that regulate gene expression, such as DNA methylation (DNAm), have been proposed to capture the molecular impact of adverse environments on tumor biology. While DNAm levels can change in response to environmental cues, they are also regulated by individual genotypes at methylation quantitative trait loci (meQTLs), presenting a challenge for modeling environmental effects on cancer molecular phenotypes. We hypothesize that ancestry differential DNAm in breast cancer can be partially explained by ancestry differential genotype frequencies of SNPs at meQTL loci. We leveraged multi-omic data from The Cancer Genome Atlas (TCGA) breast cancer (BRCA) cohort to perform integrative analysis for patients of European and African ancestry (n=578), including ancestry-based differential methylation analysis, meQTL analysis and association testing of genotypes and ancestry. We identified 804 CpGs differentially methylated between European and African ancestry BRCA patients. meQTL analysis at these sites identified 130 cis-meQTLs and 1,019 trans-meQTLs. ~84% of the identified cis- and ~80% of the identified trans-meQTLs show evidence of differential genotype frequencies by ancestry. Gene set enrichment analysis of the meQTL target genes implicated genes involved in regulation of cell differentiation and developmental processes, phosphatase activity and phosphorylation processes. Our findings show that ancestry specific DNAm differences display strong genetic associations via ancestry associated meQTLs (a-meQTLs) affecting fundamental biological functions in breast cancer. This result points to the potential for confounding due to genetic ancestry in studies that use DNA methylation as a molecular readout of environmental exposures. Citation Format: Kyriaki Founta, Nyasha Chambwe. Analysis of genetic control of differential DNA methylation between breast cancer patients of African and European ancestry [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C003.

Pathological response in mucinous carcinoma of breast after neoadjuvant therapy - a multi-institutional study

Although mucinous carcinoma (MC) is considered a favorable histologic subtype of invasive breast cancer (BC), a subset of MC is managed with neoadjuvant therapy (NAT). The clinical and pathologic features of MC following NAT are not well characterized. The aim of this study is to characterize pathologic response in patients with MC treated with NAT, including neoadjuvant endocrine therapy (NET), neoadjuvant chemotherapy (NCT), and Herceptin-targeted NCT (H-NCT). We conducted a retrospective cohort study of 28 patients with MC who received preoperative adjuvant therapy followed by resection from three institutions between 2010 and 2020. Demographic and clinical information were retrieved from the medical records. Pathologic review of the post NAT resection specimens was performed including tumor grading, tumor size, staging, residual tumor cellularity, estrogen receptor (ER) and HER2 status. Nine (32 %) patients with ER+/HER2- MC received NET, 8 (29 %) ER+/HER2- MC were treated with NCT only and 11 (39 %) HER2+ MC received HER2-targeted NCT (H-NCT). The HER2+ MC patients were younger (45 vs. 64 years; p = 0.006). The HER2+ MC were of higher grade (p = 0.03) and more likely to be multifocal (p = 0.008). Only 2 of 28 (7 %) MC (both HER2+) showed complete pathologic response with residual acellular mucin pools. Persistent mass-forming mucin pools were present in 26 (93 %) cases. The residual tumor cellularity was markedly reduced (≤5 %) in H-NCT treated MC (11/11, 100 %), followed by NET group (6/9, 67 %) and NCT only group (4/8, 50 %) (p = 0.011). Similarly, a higher rate of pathologic response (pCR/RCB-I) was observed in H-NCT (7/11, 64 %), followed by NET group (5/9, 56 %), and NCT only group (1/7, 13 %) (p = 0.053). Post-therapy, all HER2+ MC were smaller than 2 cm and ypT size was significantly smaller in H-NCT group (11/11, 100 %) versus combined NET (5/9, 55 %) and NCT only groups (4/8, 50 %) (p = 0.029). We conclude that ER-/HER2+ and ER+/HER2-mucinous carcinomas of the breast show robust pathological response to neoadjuvant HER2 targeted and endocrine therapy, respectively. Our findings suggest that MC may show good response to endocrine therapy.

Secretory breast carcinoma: clinicopathological features and prognosis of 52 patients.

Secretory breast carcinoma is a rare histological subtype of invasive breast cancer and considered with an indolent clinical behavior. This study was conducted to analyze the clinicopathological features of patients with secretory breast carcinoma (SBC), explore the outcome, and compare the prognostic difference with invasive ductal breast carcinoma (IDC). METHODSAND MATERIALS: Patients with SBC diagnosed between 2006 and 2017 from Fudan University Shanghai Cancer Center were included in the study, excluding patients with previous malignant tumor history and incomplete clinical data or follow-up records. Peculiar clinicopathological and immunohistochemical features of the cases were fully described. Clinical data of 4979 cases of IDC were also evaluated during this period. After propensity score matching, prognostic analysis of SBCs and IDCs was calculated by Kaplan-Meier method and landmark analysis method. The data of 52 patients diagnosed with SBC were identified from the pathological files. Among them, 47 patients were women, and 5 were men. The median age of the 52 SBCs was 46years (mean, 48.1years; range, 10-80years). The tumor sizes ranged from 0.3 to 6.8cm, with a mean of 3.5cm. Eight patients (15.4%) had positive axillary lymph node involvement. The molecular classification was mostly triple-negative breast cancer (65.4%). Fluorescence in situ hybridization confirmed the presence of ETV6::NTRK3 rearrangement in 16 of 18 cases (88.9%). Furthermore, Kaplan-Meier survival analysis and landmark analysis demonstrated that there were no statistically significant differences in DFS and OS between SBC and IDC patients. Although SBCs are generally associated with a favorable prognosis, our work exhibited that the clinicopathological features of SBC were partly different from former understandings, indicating that therapeutic procedure should be prudent. Further studies are necessary to fully identify the clinical behavior and predictive markers to improvediagnosis and management in this unique subtype of breast cancer.

Synergistic effects of combined cisplatin and Clinacanthus nutans extract on triple negative breast cancer cells

ObjectiveTriple negative breast cancer (TNBC) is the most invasive breast cancer subtype enriched with cancer stem cells. TNBCs do not express estrogen, progesterone, or human epidermal growth factor receptor 2 (HER2) receptors, making them difficult to be targeted by existing chemotherapy treatments. In this study, we attempted to identify the effects of combined cisplatin and Clinacanthus nutans treatment on MDA-MD-231 and MDA-MB-468 breast cancer cells, which represent TNBC subtypes. MethodsThe phytochemical fingerprint of C. nutans ethanolic leaf extract was evaluated by LC–MS/MS analysis. We investigated the effects of cisplatin (0–15.23 μg/mL), C. nutans (0–50 μg/mL), and a combination of cisplatin (3.05 μg/mL) and C. nutans (0–50 μg/mL), on cell viability, proliferation, apoptosis, invasion, mRNA expression in cancer stem cells (CD49f, KLF4), and differentiation markers (TUBA1A, KRT18) in TNBC cells. In addition, we also studied the interaction between cisplatin and C. nutans. ResultsDerivatives of fatty acids, carboxylic acid ester, and glycosides, were identified as the major bioactive compounds with potential anticancer properties in C. nutans leaf extract. Reductions in cell viability (0–78%) and proliferation (2–77%), as well as a synergistic anticancer effect, were identified in TNBC cells when treated with a combination of cisplatin and C. nutans. Furthermore, apoptotic induction via increased caspase-3/7 activity (MDA-MB-231: 2.73-fold; MDA-MB-468: 3.53-fold), and a reduction in cell invasion capacity to 36%, were detected in TNBC cells when compared to single cisplatin and C. nutans treatments. At the mRNA level, cisplatin and C. nutans differentially regulated specific genes that are responsible for proliferation and differentiation. ConclusionOur findings demonstrate that the combination of cisplatin and C. nutans represents a potential treatment for TNBC.

The Response of Triple-Negative Breast Cancer to Neoadjuvant Chemotherapy and the Epithelial–Mesenchymal Transition

It would be highly desirable to find prognostic and predictive markers for triple-negative breast cancer (TNBC), a strongly heterogeneous and invasive breast cancer subtype often characterized by a high recurrence rate and a poor outcome. Here, we investigated the prognostic and predictive capabilities of ARIADNE, a recently developed transcriptomic test focusing on the epithelial-mesenchymal transition. We first compared the stratification of TNBC patients obtained by ARIADNE with that based on other common pathological indicators, such as grade, stage and nodal status, and found that ARIADNE was more effective than the other methods in dividing patients into groups with different disease-free survival statistics. Next, we considered the response to neoadjuvant chemotherapy and found that the classification provided by ARIADNE led to statistically significant differences in the rates of pathological complete response within the groups.

Neighborhood factors and triple negative breast cancer: The role of cumulative exposure to area-level risk factors.

Despite similar incidence rates among Black and White women, breast cancer mortality rates are 40% higher among Black women. More than half of the racial difference in breast cancer mortality can be attributed to triple negative breast cancer (TNBC), an aggressive subtype of invasive breast cancer that disproportionately affects Black women. Recent research has implicated neighborhood conditions in the etiology of TNBC. This study investigated the relationship between cumulative neighborhood-level exposures and TNBC risk. This single-institution retrospective study was conducted on a cohort of 3316 breast cancer cases from New Castle County, Delaware (from 2012 to 2020), an area of the country with elevated TNBC rates. Cases were stratified into TNBC and "Non-TNBC" diagnosis and geocoded by residential address. Neighborhood exposures included census tract-level measures of unhealthy alcohol use, metabolic dysfunction, breastfeeding, and environmental hazards. An overall cumulative risk score was calculated based on tract-level exposures. Univariate analyses showed each tract-level exposure was associated with greater TNBC odds. In multivariate analyses that controlled for patient-level race and age, tract-level exposures were not associated with TNBC odds. However, in a second multivariate model that included patient-level variables and considered tract-level risk factors as a cumulative exposure risk score, each one unit increase in cumulative exposure was significantly associated with a 10% increase in TNBC odds. Higher cumulative exposure risk scores were found in census tracts with relatively high proportions of Black residents. Cumulative exposure to neighborhood-level risk factors that disproportionately affect Black communities was associated with greater TNBC risk.

Artificial intelligence: opportunities and challenges in the clinical applications of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) accounts for 15-20% of all invasive breast cancer subtypes. Owing to its clinical characteristics, such as the lack of effective therapeutic targets, high invasiveness, and high recurrence rate, TNBC is difficult to treat and has a poor prognosis. Currently, with the accumulation of large amounts of medical data and the development of computing technology, artificial intelligence (AI), particularly machine learning, has been applied to various aspects of TNBC research, including early screening, diagnosis, identification of molecular subtypes, personalised treatment, and prediction of prognosis and treatment response. In this review, we discussed the general principles of artificial intelligence, summarised its main applications in the diagnosis and treatment of TNBC, and provided new ideas and theoretical basis for the clinical diagnosis and treatment of TNBC.

Multimodality imaging and histopathology of metaplastic breast cancer

Metaplastic breast cancer (MBC) is a rare subtype of invasive breast cancer characterized by mixed epithelial and mesenchymal differentiation. Commonly seen subtypes include squamous cell carcinoma, spindle cell carcinoma, and metaplastic carcinoma with heterologous mesenchymal differentiation. MBC tends to have a more aggressive clinical presentation, higher metastatic potential, higher rates of local recurrence, and a worse prognosis compared with invasive breast carcinoma of no special type. Most MBCs are triple-negative breast cancers, which explains their resistance to most systemic therapies. Therefore, accurately diagnosing MBC early is crucial for deciding the treatment strategy and predicting the prognosis. In this pictorial essay, the imaging findings of MBC in different modalities and the histopathologic features of its subtypes are reviewed.

Abstract C095: Deconstructing the link between neighborhood disadvantage and triple negative breast cancer: Preliminary evidence in support of cumulative exposure to area-level risk factors

Abstract Background: Triple negative breast cancer (TNBC) is an aggressive subtype of invasive breast cancer that disproportionately affects Black women and contributes to racial disparities in breast cancer mortality. Prior research has found evidence of a link between TNBC risk and neighborhood/area-level measures of disadvantage, including socioeconomic status and racial segregation. This study evaluated additional area-level exposures as potential mediators of the relationship between neighborhood disadvantage and TNBC risk in New Castle County, DE, a region with elevated rates of TNBC. Methods: The study population included 3,316 Black and White adult female residents of New Castle County who were diagnosed with invasive breast cancer at the Helen F. Graham Cancer Center & Research Institute (HFGCCRI) in Newark, DE from 2012-2020. Patient addresses were geocoded, and demographic and clinical measures were abstracted from the HFGCCRI cancer registry. Neighborhood and environmental exposure measures were generated from electronic health records (EHR), the US Census Bureau American Community Survey, and Environmental Protection Agency (EPA) Risk-Screening Environmental Indicator (RSEI) data; these measures were aggregated to the census tract and linked to patient geocodes. Included neighborhood exposure measures were factors that may influence patient-level exposure to well-known breast cancer risk factors, including alcohol use disorder (AUD) and diabetes prevalence, breastfeeding (assessed with the proxy measure ‘% single female-headed households with children’), and toxic environmental indicators (e.g., toxic release inventory sites). The relationships between these exposures and the odds of TNBC (relative to other subtypes of invasive breast cancer) were first evaluated on a univariate basis. Next, to estimate the relationship between cumulative exposure and TNBC odds, census tract risk scores were calculated by dichotomizing each exposure into low- and high-risk categories and summing the total of high-risk exposures. A multilevel logistic regression model was used to test the association between this risk score and TNBC odds while adjusting for patient-level age and race.Results: TNBC cases accounted for 14% (n = 453) of invasive breast cancer cases. Significantly higher odds of TNBC were observed for patients who reside in census tracts characterized by higher rates of AUD, diabetes, % single female-headed households with children, and RSEI scores. In the multilevel logistic regression model that adjusted for patient demographics, the cumulative exposure risk score was significantly associated with greater odds of TNBC. Conclusion: Results provide preliminary support for a link between TNBC odds and cumulative, area-level exposure to disordered alcohol use, metabolic disorders, lower breastfeeding rates, and toxic environmental indicators. Additional research evaluating the cumulative exposure risk score as a potentially modifiable mediator of the relationship between neighborhood disadvantage and TNBC risk will be presented. Citation Format: Scott D. Siegel, Madeline M. Brooks, Jesse D. Berman, Shannon M. Lynch, Jennifer Sims-Mourtada, Zachary T. Schug, Frank C. Curriero. Deconstructing the link between neighborhood disadvantage and triple negative breast cancer: Preliminary evidence in support of cumulative exposure to area-level risk factors [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C095.

Metaplastic Breast Carcinoma (MBC), Primary Squamous Cell Carcinoma Subtype in A 49-Year-Old Woman: A Case Report

Introduction: Metaplastic Breast Carcinoma (MBC) is quite a challenging case because metaplastic breast cancer is one of the rarest subtypes of invasive breast cancer. It is reported that MBC occurs only 0.2 to 1% throughout the world. The metaplastic changes can be squamous cells or other mesenchymal cell types. Clinically, MBC presents as a large palpable mass and may be associated with rapid growth. The size of MBC tends to be larger compared with other types of invasive breast cancer ranging from 1 to more than 10 cm. Although there are several main categories of MBC, some carcinoma can be difficult to classify due to their unusual histologic patterns. This case report study is to provide a clinicopathological overview and approach to MBC.Case Presentation: We reported a 49-year-old woman who suffered from a breast mass that rapidly grew for less than one year. The microscopic findings showed squamous cell carcinoma. While molecular studies revealed triple negative results for hormone receptors although Human Epidermal Growth Factor Receptor 2 (HER2) overexpression was unusual (< 5%). Then, we confirmed with chromogen in situ hybridization (CISH) and there was no gen amplification for HER2. Microscopically, we found ductal carcinoma in situ and this finding supported breast origin.Conclusions: Metaplastic carcinoma did not have any specific and distinctive signs clinically. Metaplastic carcinoma can be monophasic (with only a metaplastic component) or biphasic with two or more components. As treatment options, our patient received conventional chemotherapy. Metaplastic breast cancer is reported to have a lower response rate to conventional adjuvant chemotherapy and worse clinical outcome after chemotherapy than other forms of triple-negative breast cancer.