Estrogen Receptor Negative Research Articles

PATH-67. THE ROLE OF STATUS OF HER-2, ESTROGEN-RECEPTOR, BRCA 1, AND BRCA 2, IN THE INCIDENCE OF BRAIN METASTASIS IN BREAST CANCER

Abstract Breast cancer (BC) is the most diagnosed tumor in women and the second-leading cause of brain metastasis (BM), with a prevalence ranging from 10-36%. According to the Epidemiological Strategy and Medical Economics research program, advanced BC patients face an estimated 25% risk of developing BM within 2-3 years after the initial diagnosis. The frequency of BM is significantly increased by the primary tumor profile, including larger tumors, higher nuclear grade, HER-2 positivity, estrogen-receptor negativity, and triple-negative status. A gap remains in the classification of the BM site relative to primary tumor biomarkers, and the absence of multimodality treatment methodologies poses challenges to survival rates and quality of life in BC patients. This retrospective cross-sectional study at Aga Khan University Hospital identified 52 cases of brain metastasis secondary to breast cancer over a 10-year period. The median age of patients was 55 years, ranging from 32 to 78 years. Primary breast tumors were predominantly high-grade ductal carcinomas (65%), followed by lobular carcinomas (25%) and other rare histological types (10%). Secondary brain metastases were primarily located in the cerebrum (60%), cerebellum (25%), and brainstem (15%). Tumor profiles indicated a significant correlation between HER-2 positivity and the development of brain metastasis, with 70% of HER-2 positive patients presenting with extensive brain metastasis. Tumor progression varied, with a median time to brain metastasis of 2.5 years from the initial breast cancer diagnosis. Despite aggressive multimodality treatments, including surgery, radiation, and chemotherapy, the overall prognosis remained poor. The study found that early detection of HER-2 positive and triple-negative tumors could potentially delay the progression of brain metastasis through targeted therapies. Mortality rates in this cohort were high, with a median survival of 8 months following the diagnosis of brain metastasis. These findings underscore the need for improved diagnostic, preventive, and therapeutic strategies to manage brain metastasis in breast cancer patients.

Nomogram Predicting Axillary Lymph Node Dissection Omission After Neoadjuvant Chemotherapy for Node-positive Breast Cancer.

To develop an accurate method to predict nodal pathological complete response (ypN0) in patients after neoadjuvant chemotherapy (NAC) for clinically node-positive breast cancer. We included 128 patients with clinically node-positive primary breast cancer who underwent axillary lymph node dissection after NAC. Breast primary tumor clinical complete response (ycT0) was observed in 29.7% and nodal clinical complete response (ycN0) in 44.5% of cases. When ycN0 was predicted as ypN0, the negative predictive value was 77.2%, and the false-negative rate was 19.7%. Estrogen receptor status, ycT0, and ycN0 were independent predictive factors for ypN0 after NAC in patients with clinically node-positive breast cancer. These factors were used to develop a nomogram for ypN0 prediction. The following points were added: 82 in case of estrogen receptor-negative, 56 in case of ycT0, and 100 in case of ycN0. Score summation was used to prognosticate the manifestation of ypN0. Our nomogram predicted ypN0 with a negative predictive value of 92.9% and false-negative rate of 4.5%, demonstrating an approximate 15% improvement over ypN0 prediction using ycN0 alone. Estrogen receptor-negativity, ycT0, and ycN0 are independent predictive factors for ypN0 after NAC in clinically node-positive breast cancer. The nomogram may improve individualized axillary treatment.

Genes Related to Motility in an Ionizing Radiation and Estrogen Breast Cancer Model

Breast cancer is a major global health concern as it is the primary cause of cancer death for women. Environmental radiation exposure and endogenous factors such as hormones increase breast cancer risk, and its development and spread depend on cell motility and migration. The expression of genes associated with cell motility, such as ADAM12, CYR61, FLRT2, SLIT2, VNN1, MYLK, MAP1B, and TUBA1A, was analyzed in an experimental breast cancer model induced by radiation and estrogen. The results showed that TUBA1A, SLIT2, MAP1B, MYLK, and ADAM12 gene expression increased in the irradiated Alpha3 cell line but not in the control or the malignant Tumor2 cell line. Bioinformatic analysis indicated that FLERT2, SLIT2, VNN1, MAP1B, MYLK, and TUBA1A gene expressions were found to be higher in normal tissue than in tumor tissue of breast cancer patients. However, ADAM12 and CYR61 expressions were found to be higher in tumors than in normal tissues, and they had a negative correlation with ESR1 gene expression. Concerning ESR2 gene expression, there was a negative correlation with CYR61, but there was a positive correlation with FLRT2, MYLK, MAP1B, and VNN1. Finally, a decreased survival rate was observed in patients exhibiting high expression levels of TUBA1A and MAP1B. These genes also showed a negative ER status, an important parameter for endocrine therapy. The genes related to motility were affected by ionizing radiation, confirming its role in the initiation process of breast carcinogenesis. In conclusion, the relationship between the patient’s expression of hormone receptors and genes associated with cell motility presents a novel prospect for exploring therapeutic strategies.

The Great Mimicker: Goblet Cell Adenocarcinoma of the Appendix Mimicking Mammary Carcinoma in a Patient with a History of Metastatic Breast Cancer

Abstract Introduction/Objective Goblet cell adenocarcinoma of the appendix is a rare and aggressive malignancy with high- grade histological patterns that pose diagnostic challenges due to their resemblance to other tumors. Previous reports have indicated that high-grade goblet cell adenocarcinoma may exhibit similarities to well-differentiated neuroendocrine tumors, and metastatic high-grade goblet cell adenocarcinoma can manifest diverse histologic growth patterns within a single section. Methods/Case Report We present a case of an 82-year-old female with a known history of breast cancer with sacral metastasis, presenting with a left upper quadrant “pinching” sensation. Histopathological examination following colectomy showed features of metastatic mammary carcinoma with mixed lobular (pleomorphic and partial signet ring cell type) and ductal features (Figure 1); Notably, different histologic patterns were observed in two tumor deposits, highlighting the complexity of the diagnosis (Figure 2). However, further investigation of the tip of the appendix revealed goblet-like mucinous cells arranged in a tubular growth pattern (Figure 3). Immunohistochemical stains were performed with adequate controls, revealing positive staining for CK20, SATB2, and CDX2, while showing negativity for BRST2, SATB2, GATA3, CK7, PR, ER, and HER2 (Figure 4). These findings corroborate the diagnosis of goblet cell adenocarcinoma. Results (if a Case Study enter NA) NA Conclusion In our case, we observed morphological features of goblet cell adenocarcinoma that overlapped with those of established mammary carcinomas. This scenario underscores the diagnostic challenges posed by rare tumors and emphasizes the significance of identifying the low-grade component of goblet cell adenocarcinoma, particularly in patients with a history of metastatic breast cancer.

Clinicopathological correlation of three cases of metastatic carcinoma to uterine cervix: An institutional experience

Abstract Introduction/Objective Metastasis to the female genital tract presents a rare occurrence and poses significant diagnostic hurdles. The uterine cervix, although less frequently implicated, presents additional challenges for metastatic spread owing to its diminutive dimensions, limited vascular perfusion, and abundance of fibrous tissue. Clinical manifestations often include abnormal vaginal bleeding in 62–75% of cases, frequently accompanied by involvement in other anatomical sites. Accurate identification of cervical tumor activity and its primary origin holds paramount importance for precise diagnosis, therapeutic stratagem, and prognostic assessment. Methods/Case Report Here we are reporting three cases that were encountered in our institution over a 5-year period. The first patient, a 63-year-old female with a history of breast cancer, six years later exhibited metastatic breast cancer in a cervical polyp, confirmed by positivity for AE1/AE3, GATA3, ER, and negativity for TTF-1, chromogranin, synaptophysin, PAX8, inhibin, calretinin, CDX-2, CD10, desmin, smooth muscle actin, S100, and HMB-45. The second patient, diagnosed with pancreatic adenocarcinoma, two years later manifested cervical metastasis confirmed via positive staining for CK7, CDX2, and focal p63, and did not express PAX8, vimentin, ER, p16, synaptophysin, and chromogranin. The third patient, diagnosed with lung adenocarcinoma, one year later presented with a cervical mass, histologically confirmed as metastatic lung adenocarcinoma via positivity for CK7, Napsin A, and TTF1, and negativity for PAX8, p16, p40, p53, GATA3, and ER. Results (if a Case Study enter NA) N/A Conclusion Given the challenges of identifying metastasis to the cervix, thorough diagnostic evaluation should be undertaken to differentiate primary versus metastatic disease in women with a history of non-cervical malignancy.

Evaluation of Tumour-Associated Macrophages and Colony-Stimulating Factor-1 Expression in Invasive Breast Carcinoma and Their Association with Prognostic Parameters

INTRODUCTION: Recent breast cancer research has focused on tumour microenvironment (TME). Tumour-associated macrophages (TAMs) are the key players in TME as they provide pro-tumorigenic milieu for tumour progression and metastasis. These macrophages are primarily regulated by colony-stimulating factor-1 (CSF-1) secreted by breast cancer cells. This study investigated the association of localization of TAMs infiltration within breast carcinoma and CSF-1 expression by cancer cells with the pathological prognostic parameters. MATERIALS AND METHODS: TAMs were assessed in 128 cases of invasive breast carcinoma by CD163 immunohistochemical expression. The median TAM density in both the tumour nest and tumour stroma was utilized to classify TAMs into categories of low and high infiltration. The cancer cells were immunostained with anti-CSF-1 antibody and the staining intensity was evaluated as low or high expression. RESULTS: High nest and stromal TAMs were associated with higher tumour grades (p=0.005 and p=0.0001, respectively) whereas only high stromal TAMs showed significant association with negative oestrogen and progesterone receptors status (p=0.001 and 0.001, respectively); and triple-negative subtype (p=0.002). High CSF-1 expression was significantly associated with high stromal TAMs (p=0.031). High CSF-1 expression was associated with tumour grade and positive HER2 status (p=0.008 and 0.007, respectively). CONCLUSION: TAMs in tumour nest and stroma showed varying degrees of association with the clinicopathological parameters. High CSF-1 expression was associated with unfavourable prognostic parameters. Therefore, the evaluation of TAMs and CSF-1 expressions could potentially serve as prognostic markers and cellular targets for novel treatment modality in invasive breast cancers.

The Predictive Role of Mammography, Dynamic Contrast-Enhanced Breast Magnetic Resonance Imaging and Diffusion-Weighted Imaging in Hormone Receptor Status of Pure Ductal Carcinoma In Situ Lesions.

The aim of this retrospective study was to analyze the predictive capabilities of preoperative mammography, dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI), and diffusion-weighted imaging (DWI) in determining hormone receptor (HRc) status for pure ductal carcinoma in situ (DCIS) lesions. The study included a total of 79 patients who underwent preoperative mammography (MG) and MRI between December 2018 and December 2023 and were subsequently diagnosed with pure DCIS after surgery. The correlation between MG, DCE-MRI, and DWI features and estrogen receptor (ER) and progesterone receptor (PR) status was examined. Among the lesions, 44 were double HRc-positive (ER and PR-positive), 13 were single HRc-positive (ER-positive and PR-negative or ER-negative and PR-positive) and 22 were double HRc-negative (ER and PR-negative). The presence of symptom (p = 0.029), the presence of comedo necrosis (p = 0.005) and high histological grade (p<0.001) were found to be associated with ER and PR negativity. Amorphous microcalcifications were more commonly observed in the double HRc-negative group, while linear calcifications were more prevalent in both double and single HRc-positive groups (p = 0.020). Non-mass enhancement (NME) with a linear distribution was significantly more common in double HRc-negative lesions (38%), and NME with a segmental distribution in both double (43%) and single (50%) receptor-positive lesions (p = 0.042). Evaluation of DWI findings revealed that a higher lesion-to-normal breast parenchyma apparent diffusion coefficient (ADC) ratio statistically increased the probability of HRc positivity (p = 0.033). Certain clinicopathological, mammography, and MRI features, along with the lesion-to-normal breast parenchyma ADC ratio, can serve as predictors for HRc status in DCIS lesions.

Therapeutic response and outcomes with uncommon breast cancer subtypes in the I-SPY trial 2010-2022.

1 Background: Uncommon histologies are over-represented among high-risk breast cancer (BC) and denote an area with limited trial data and of significant unmet medical need. To better understand trial outcomes in this group and identify signals of tumor responsiveness, we report pathologic complete response (pCR) and early event-free survival (EFS) by disease subtype in the I-SPY2 trial. Additionally, the I-SPY2 trial currently utilizes a combination of tumor molecular signature and receptor status to determine response predictive subtype (RPS) first developed from 987 I-SPY2 patients [Wolf et al, Cancer Cell 2022]. We report disease response rates for those who received what is now known to be optimal RPS guided therapy. Methods: The I-SPY2 platform trial tests novel agents given neo-adjuvantly with a chemotherapy backbone in high-risk BC (HER2 positive, triple negative and high molecular risk estrogen receptor positive BC). Histologic images of research biopsies, local biopsy and surgical pathology reports were reviewed centrally by I-SPY pathologists. Receptor subtype distribution and pCR rates were summarized; and EFS was estimated using the Kaplan Meier method. Association between pCR and EFS was evaluated using the Cox proportional hazard model with significance assessed by the log rank test. Results: 144/2118 (7%) of I-SPY2 participants were identified with metaplastic (60), lobular (55), mucinous (9), micropapillary (8), neuroendocrine (4) and other (8) BCS. Tumor receptor status, pCR rate and EFS by tumor type are shown in the Table. For the full cohort, pCR was associated with better EFS (hazard ratio (95% CI): 0.12 (0.02 - 0.88), p = 0.01). Within metaplastic (metapBC) 11/32 (34%) and 5/28 (18%) patients had a pCR with or without checkpoint blockade, respectively. By RPS group, 9 of 18 (50%) (13 metapBC, 3 other, 2 lobular) in the HER2-Immune+ group who received RPS optimized therapy had a pCR. In this group 6/13 (46%) with metapBC had a pCR. In the HER2+ driven RPS groups, pCR rate in the HER+HER2orBasal was 88% (7/8) and 0% (0/3) in the HER2+Luminal. Conclusions: High pCR rates observed in metapBC and other among subsets of often difficult to treat BC subtypes support novel approaches and provide a roadmap for future study of uncommon BCs. Outcomes were improved when therapy matched RPS vulnerabilities. Participants presenting with uncommon BC subtypes will be prospectively identified in the I-SPY2.2 trial to further develop effective approaches for this group. Clinical trial information: NCT01042379 .[Table: see text]

Estrogen and progesterone receptor expression: Impacts on platinum sensitivity and survival outcomes in high‐grade serous ovarian cancer

AbstractBackgroundThis study aimed to explore the impact of patient‐specific factors on the effectiveness of platinum‐based chemotherapy in ovarian cancer patients. Specifically, we investigated the relationship between estrogen receptor (ER) and progesterone receptor (PR) expression levels and platinum sensitivity, and how this influenced treatment outcomes and prognosis. We conducted a survival analysis on patients who underwent surgical treatment for serous ovarian cancer and received platinum‐based adjuvant therapies.MethodsThis study was a retrospective observational analysis of 171 patients with high‐grade serous ovarian cancer. We extracted and analyzed the patients' clinical data, focusing on platinum sensitivity concerning hormone receptor expression. We also assessed survival outcomes based on receptor expression and platinum resistance.ResultsOur findings revealed that 78.4% (n = 134) of the patients were platinum‐sensitive, while 21.6% (n = 37) were platinum‐resistant. The expression of hormone receptors showed significant associations with platinum sensitivity, particularly among ER‐positive patients (p &lt; 0.05). Age, disease stage, preoperative carbohydrate antigen 125 (CA125) levels, and residual tumor size were identified as notable factors influencing both progression‐free survival (PFS) and overall survival (OS). In terms of PFS, 88.5% of patients remained free from disease progression after one year, but this percentage dropped to 21% after five years. The average duration of PFS was 35.3 months. As for OS, 93.5% of patients were still alive after one year, but this percentage decreased to 50.5% after five years. The average survival duration was 64 months. Furthermore, platinum resistance was found to be a significant risk factor for disease progression, with a more than fivefold increase in risk (p &lt; 0.001).ConclusionOur study identified disease stage progression, ER negativity, and platinum resistance as the primary factors influencing OS. We also found that ER and PR expression played a crucial role in determining the sensitivity to platinum‐based chemotherapy in patients with serous ovarian cancer.

Immune and Gene-expression Profiling in Estrogen Receptor Low and Negative Early Breast Cancer.

The cut-off of < 1% positive cells to define estrogen receptor (ER) negativity by immunohistochemistry (IHC) in breast cancer (BC) is debated. We explored the tumor immune microenvironment and gene-expression profile of patients with early-stage HER2-negative ER-low (ER 1-9%) BC, comparing them to ER-negative (ER < 1%) and ER-intermediate (ER 10-50%) tumors. Among 921 patients with early-stage I-III, ER ≤ 50%, HER2-negative BCs, tumors were classified as ER-negative (n = 712), ER-low (n = 128), or ER-intermediate (n = 81). Tumor-infiltrating lymphocytes (TILs) were evaluated. CD8+, FOXP3+ cells, and PD-L1 status were assessed by IHC and quantified by digital pathology. We analyzed 776 BC-related genes in 116 samples. All tests were 2-sided at < 0.05 significance level. ER-low and ER-negative tumors exhibited similar median TILs, significantly higher than ER-intermediate tumors. CD8/FOXP3 ratio and PD-L1 positivity rates were comparable between ER-low and ER-negative groups. These groups showed similar enrichment in Basal-like intrinsic subtypes and comparable expression of immune-related genes. ER-low and ER-intermediate tumors showed significant transcriptomic differences. High TILs (≥30%) were associated with improved relapse-free survival (RFS) in ER-low (5-year RFS 78.6% vs 66.2%, log-rank p = .033, hazard ratio (HR) 0.37 [95% CI 0.15-0.96]) and ER-negative patients (5-year RFS 85.2% vs 69.8%, log-rank p < .001, HR 0.41 [95% CI 0.27-0.60]). ER-low and ER-negative tumors are similar biological and molecular entities, supporting their comparable clinical outcomes and treatment responses, including to immunotherapy. Our findings contribute to the growing evidence calling for a reevaluation of ER-positive BC classification and management, aligning ER-low and ER-negative tumors more closely.

Asparaginase-like protein 1 as a prognostic tissue biomarker in clinicopathologically and molecularly characterized endometrial cancer

ObjectivePrognostic stratification of endometrial cancer involves the assessment of stage, uterine risk factors, and molecular classification. This process can be further refined through annotation of prognostic biomarkers, notably L1 cell adhesion molecule (L1CAM) and hormonal receptors. Loss of asparaginase-like protein 1 (ASRGL1) has been shown to correlate with poor outcome in endometrial cancer. Our objective was to assess prognostication of endometrial cancer by ASRGL1 in conjunction with other available methodologies. Study DesignThis was a retrospective study of patients who underwent primary treatment at a single tertiary center. Tumors were molecularly classified by the Proactive Molecular Risk Classifier for Endometrial Cancer. Expression of ASRGL1, L1CAM, estrogen receptor, and progesterone receptor was determined by immunohistochemistry. ASRGL1 expression intensity was scored into four classes. ResultsIn a cohort of 775 patients, monitored for a median time of 81 months, ASRGL1 expression intensity was related to improved disease-specific survival in a dose-dependent manner (P < 0.001). Low expression levels were associated with stage II–IV disease and presence of uterine factors, i.e. high grade, lymphovascular space invasion, and deep myometrial invasion (P < 0.001 for all). Among the molecular subgroups, low expression was most prevalent in p53 abnormal carcinomas (P < 0.001). Low ASRGL1 was associated with positive L1CAM expression and negative estrogen and progesterone receptor expression (P < 0.001 for all). After adjustment for stage and uterine factors, strong ASRGL1 staining intensity was associated with a lower risk for cancer-related deaths (hazard ratio 0.56, 95 % confidence interval 0.32–0.97; P = 0.038). ASRGL1 was not associated with the outcome when adjusted for stage, molecular subgroups, L1CAM, and hormonal receptors. When analyzed separately within the different molecular subgroups, ASRGL1 showed an association with disease-specific survival specifically in “no specific molecular profile” subtype carcinomas (P < 0.001). However, this association became nonsignificant upon controlling for confounders. ConclusionsLow ASRGL1 expression intensity correlates with poor survival in endometrial cancer. ASRGL1 contributes to more accurate prognostication when controlled for stage and uterine factors. However, when adjusted for stage and other biomarkers, including molecular subgroups, ASRGL1 does not improve prognostic stratification.

Immunohistochemical Expression of CD47 and CD68 in Breast Carcinoma and Their Prognostic Value.

Cluster of differentiation 47 (CD47) has been identified as a new immune checkpoint. The exact role of CD47 in prognosis of breast cancer remains unclear. This study aims to evaluate immunohistochemical (IHC) expression of CD47 in breast cancer, and to measure the density of tumor associated macrophages (TAMs) infiltration by CD68 IHC staining. Furthermore, assessing the relations of CD47 and CD68 expression to different clinicopathological variables and evaluating the prognostic role of CD47 and CD68 in breast cancer cases. This retrospective cohort study included 200 diagnosed primary breast cancer cases who underwent surgical resection at the Oncology Center of Mansoura University (OCMU), Faculty of Medicine, Egypt. Clinicopathological and survival data were collected. IHC for CD47 and CD68 was performed. Among 200 breast cancer cases, high CD47 expression was detected in 89 cases (44.5%). CD47 high expression was significantly associated with presence of distant metastasis (P=0.04), advanced TNM stage (P=0.02), ER & PR negativity (P=0.04 & 0.004 respectively), and molecular subtype (P=0.03). Their was a statistically significant association between CD47 and CD68 expression (P=0.002). CD47 high expression was found to predict poor overall survival, but it is not considered alone as independent poor prognostic factor by multivariate analysis. Multivariate analysis spotted combined high expression of CD47 and CD68 as an independent prognostic predictor for shorter OS in breast cancer patients (P=0.002). CD47 high expression is related to poor prognosis in breast cancer patients especially when associated with high CD68+TAMs infiltration. Therefore, CD47 is a promising prognostic and therapeutic target in breast carcinoma that may direct selection of patients for immunotherapy.

A Study on Stromal Expression of CD10 Marker in Breast Carcinoma and Its Role as a Prognostic Marker in a Tertiary Care Center in South Kerala

Abstract Background and Aims: Breast cancer is one of the leading causes of mortality among women. The aim of our study is to evaluate the stromal expression of CD10 in invasive breast carcinoma and to find its relationship with other prognostic markers such as age, histopathologic grade, estrogen receptor (ER), progesterone receptor (PR), and HER2Neu status. Materials and Methods: A total of 51 cases of breast cancer were included in the study. Representative sections were taken and hematoxylin and eosin staining was done. Immunohistochemistry was performed with ER, PR, Her2neu, and CD10. Stromal expression of CD10 is positive when &gt;10% of stromal cells show cytoplasmic and membranous positivity in invasive breast carcinoma. This will be noted and statistically analyzed with different known prognostic markers of breast carcinoma. Results: Stromal CD10 positivity was seen in 74.5% of cases (45% were strongly positive and 29.5% were weakly positive). 25.5% of cases were negative. Positivity for ER, PR, and HER2, was 58.8%, 35.3%, and 27.5%, respectively. Stromal expression of CD10 was found to be significantly associated with ER negativity (P = 0.001) and PR negativity (P = 0.001). Increasing intensity was noted with few parameters such as postmenopausal status and histologic grade but could not show statistical significance. No correlation was found between CD10 overexpression with respect to the age, tumor size, lymph node positivity status, tumor stage and HER2Neu status. Conclusions: CD10 expression correlated strongly with well-established negative prognostic markers, ER/PR negativity, and higher tumor grade, thus indicating that CD10 can be used as an independent marker indicating poor prognosis. This study highlights the role of stromal CD10 expression in predicting prognosis and the relationship with other prognostic markers. Keeping the role stroma plays in predicting prognosis and tumor response, CD10 can be included as a routine prechemotherapy marker in breast carcinoma. Further studies should be performed to see the role stroma plays in hormonal expression and the usefulness of CD10 to predict treatment failure in breast carcinomas receiving neoadjuvant therapy.

DDR2 expression in breast cancer is associated with blood vessel invasion, basal-like tumors, tumor associated macrophages, regulatory T cells, detection mode and prognosis

Discoidin Domain Receptor 2 (DDR2) is a receptor tyrosine kinase for collagen, stimulating epithelial-mesenchymal transition and stiffness in breast cancer. Here, we investigated levels of DDR2 in breast tumor cells in relation to vascular invasion, TIL subsets, macrophages, molecular tumor subtypes, modes of detection and prognosis. This retrospective, population-based series of invasive breast carcinomas from the Norwegian Screening Program in Vestfold County (Norway), period 2004–2009, included 200 screening patients and 82 cases detected in screening intervals. DDR2 was examined on core needle biopsies using a semi-quantitative, immunohistochemical staining index and dichotomized as low or high DDR2 expression. Counts of macrophages and TIL subsets were dichotomized based on immunohistochemistry using TMA. We also recorded blood or lymphatic vessel invasion (BVI or LVI) as present or absent by immunohistochemistry. High expression of DDR2 in tumor cells showed significant relation with high counts of CD163+ macrophages (p < 0.001) and FOXP3 TILs (p = 0.011), presence of BVI (p = 0.028), high tumor cell proliferation by Ki67 (p = 0.033), ER negativity (p = 0.001), triple-negative cases (p = 0.038), basal-like features (p < 0.001) as well as interval detection (p < 0.001). By multivariate analysis, high DDR2 expression was related to reduced recurrence-free survival (HR, 2.3, p = 0.017), when examined together with histologic grading, lymph node assessment, tumor diameter, BVI, and molecular tumor subtype. This study supports a link between high DDR2 expression, high counts of macrophages by CD163 (tumor associated) and regulatory T cells by FOXP3 together with the presence of BVI, possibly indicating increased tumor motility and intravasation in aggressive breast tumors.

Clinicopathological characteristics and prognostic significance of casting-type calcifications in patients with invasive breast cancer presenting with microcalcification

To explore the clinicopathological characteristics and prognostic significance of casting-type calcification (CC) in patients with breast cancer presenting with microcalcification on mammography. Data on patients with invasive breast cancer who had mammographic calcification was retrospectively analyzed. The chi-square test was utilized to assess the clinicopathological characteristics of two forms of CC-related breast cancer. The examination of prognostic variables was conducted using Kaplan–Meier and Cox regression analyses. A total of 427 eligible patients were included in this study. Chi-square analysis indicated that the presence of CC was associated with estrogen receptor (ER) negativity (P = 0.005), progesterone receptor (PR) negativity (P < 0.001), and epidermal growth factor receptor 2 (HER-2) positivity (P < 0.001); among these, the association was stronger with the CC-predominant type. After a median follow-up of 82 months, those with CC had a worse 5-year recurrence-free survival (RFS) (77.1% vs. 86.9%, p = 0.036; hazard ratio [HR], 1.86; 95% confidence interval [CI] 1.04–3.31) and overall survival (OS) (84.0% vs. 94.4%, p = 0.007; HR, 2.99; 95% CI 1.34–6.65) rates. In COX regression analysis, such differences were still observed in HER-2 positive subgroups (RFS: HR: 2.45, 95% CI 1–5.97, P = 0.049; OS: HR: 4.53, 95% CI 1.17–17.52, P = 0.029). In patients with invasive breast cancer exhibiting calcifications on mammography, the presence of CC, especially the CC-predominant type, is linked to a higher frequency of hormone receptor negativity and HER-2 positivity. The presence of CC is associated with an unfavorable 5-year RFS and OS rates.

Is overexpression of CD163 and CD47 in tumour cells of breast carcinoma implicated in the recruitment of tumour-associated macrophages (TAMs) in tumour microenvironment? immunohistochemical prognostic study

ABSTRACT Background Now, targeted therapy and immunotherapy are promoted. tumour -Associated Macrophages (TAMs) are an essential component of immune-response in breast cancer(BC) with prognostic controversy. Additionally, their recruiting factors are still obscure. Purpose:This study aimed to evaluate the prognostic significance of CD163 and CD47 in BC of No Special Type (BC-NST) and to explore their suggested role in recruiting TAMs. Material and methods This immunohistochemical study was conducted on 91 archival specimens of breast cases. Immunoreactivity scores were correlated with TAMs density, clinicopathological data, and survival. Results Revealed the highest CD163 expression was detected in the pure DCIS group (p = 0.016), while the highest CD47 expression and high TAMs density were reported in the invasive group (p = 0.008, and p = 0.002 respectively) followed by the DCIS group. In IC-NSTs the CD163 and CD47 scores were associated with poor prognostic parameters like(high grade, advanced stage, distant metastasis, ER negativity,Ki67 index, post-surgical chemotherapy, poor NPI group, high mitotic count, dense infiltration of TAMs, shorter OS). Also, CD47 was associated with the dens infiltration of TAMs in DCIS (p = 0.001). There was a significant correlation between tumour cell expression of CD163 and CD47 in IC-NSTs and DCIS (p = 0.002 and p = 0.009 respectively). Conclusions High CD163 and CD47 expressions in both DCIS andIBC are intimately associated, significantly associated with poor prognosis and are important provoking factors of TAMs.

Therapeutic response and outcomes with less common breast cancer subtypes in the I-SPY trial 2011-2022.

582 Background: Uncommon histologies are over-represented among high-risk breast cancer (BC) and denote an area with limited trial data and of significant unmet medical need. To better understand trial outcomes in this group and identify signals of tumor responsiveness, we report pathologic complete response (pCR) and early event-free survival (EFS) by disease subtype in the I-SPY2 trial. Additionally, the I-SPY2 trial currently utilizes a combination of tumor molecular signature and receptor status to determine response predictive subtype (RPS) first developed from 987 I-SPY2 patients (1). We report disease response rates for those who received what is now known to be optimal RPS guided therapy. Methods: The I-SPY2 platform trial tests novel agents given neo-adjuvantly with a chemotherapy backbone in high-risk BC (HER2 positive, triple negative and high molecular risk estrogen receptor positive BC). Histologic images of research biopsies, local biopsy and surgical pathology reports were reviewed centrally by I-SPY pathologists. Receptor subtype distribution and pCR rates were summarized. EFS was estimated using the Kaplan Meier method. Association between pCR and EFS was evaluated using the Cox proportional hazard model with significance assessed by the log rank test. Results: 144/2118 (7%) of I-SPY2 participants were identified with metaplastic (60), lobular (55), mucinous (9), micropapillary (8), neuroendocrine (4) and other (8) BCs. Tumor receptor status, pCR rate and EFS by tumor type are shown in the Table. For the full cohort, pCR was associated with better EFS (hazard ratio (95% CI): 0.12 (0.02 - 0.88), p = 0.01). Within metaplastic (metapBC) 11/32 (34%) and 5/28 (18%) patients had a pCR with or without checkpoint blockade, respectively. By RPS group, 9 of 18 (50%) (13 metapBC, 3 other, 2 lobular) in the HER2-Immune+ group who received RPS optimized therapy had a pCR. In this group 6/13 (46%) with metapBC had a pCR. In the HER2+ driven RPS groups, pCR rate in the HER+HER2orBasal was 88% (7/8) and 0% (0/3) in the HER2+Luminal. Conclusions: High pCR rates observed in metapBC and other among subsets of often difficult to treat BC subtypes support novel approaches and provide a roadmap for future study of uncommon BCs. Outcomes were improved when therapy matched RPS vulnerabilities. Participants presenting with uncommon BC subtypes will be prospectively identified in the I-SPY2.2 trial to further develop effective approaches for this group. 1. Wolf et al, Cancer Cell 2022. Clinical trial information: NCT01042379 . [Table: see text]

Postpartum breast cancer: Analysis of factors related to pregnancy and identification of differential prognostic markers.

557 Background: Postpartum breast cancer (PPBC) has an increasing incidence. It is associated with a worse prognosis compared to other breast cancers diagnosed outside of this stage. Objectives: To study clinical and histopathological differences between PPBC (diagnosed within 10 years after delivery) and non-postpartum breast cancer (NPBC, diagnosed more than 10 years after delivery or in nulliparous). Analyze whether reproductive factors such as parity or lactation influence these characteristics. Methods: An observational, analytical and retrospective case-control study is carried out. For the first part, we consider those women with PPBC as case; healthy mothers as control. For the second part, we consider PPBC women as case; NPBC women as control. The data have been analyzed with SPSS v.22. Results: 2698 women under 45 years were recruited. 264 (9.8%) have breast cancer and 2434 (90.2%) are healthy women. The percentage of ex-smokers is higher in PPBC compared to healthy mothers (30.6% vs. 19.7%) (X2=9.632; p=0.022; SS). The proportion of women with previous gynecological pathology is higher in PPBC group than in the group of healthy mothers (48.9% vs. 25.7%) (X2=33.767; p&lt;0.001; SS). The same occurs with previous breast pathology (51.9% vs. 21.7%) (X2=62.75; p&lt;0.001; SS). Women with early PPBC (diagnosed within 5 years after delivery) have higher percentage of previous mastitis compared to the rest of groups that develop tumor beyond 5 years postpartum (20.3% vs. 3.6%) (X2=17.76; p=0.023; SS). The percentage of female pregnancies is more frequent in early PPBC (58.6%) compared to non-postpartum or late PPBC (42.4%) (X2=4.039; p=0.044; SS). The percentage of women who abruptly discontinued breastfeeding is higher in those with PPBC with 27.5% compared to healthy mothers (12.6%) (X2=18.448; p&lt;0.001; SS) (Table). PPBC has higher percentage of stages II (63.9%), the other group of NPBC is mostly diagnosed in stage I (64.9%) (X2=9.808; p=0.002; SS). We found higher elevated expression of Ki67 in early PPBC (90.1%), compared to non-postpartum cancer or late PPBC (77%) (X2=6.252; p=0.012; SS). We observe higher proportion of negative estrogen receptors in early PPBC (36.6%) compared to late PPBC or non-postpartum cancer (13.6%) (X2=9.880; p=0.002; SS). Conclusions: Postpartum breast cancer presents different clinical and histopathological characteristics, highlighting differences in early postpartum period. PPBC has worse prognosis, it constitutes a different entity. Breastfeeding abrupt interruption is associated with development of PPBC. [Table: see text]

Molecular characterization of breast cancer cell lines in correlation with clinical markers

Cell lines are indispensable for biomedical research, offering a consistent platform for investigating cellular processes and disease mechanisms. Despite their value, cell lines possess limitations such as genetic drift and phenotypic alterations over successive passages, potentially compromising their relevance. Monoclonal derivation may not represent in vivo heterogeneity, particularly in cancer. Therefore, characterizing them becomes imperative. We aimed to identify breast cancer subtype-specific cell lines by assessing ER, PR, and HER-2 expression via immunohistochemistry and their concordance with molecular expression. We selected cell lines with consistent phenotypes that mimic primary cells and confirmed concordance in ER, PR, and HER-2 expression at protein and mRNA levels. Evaluation of ER, PR, and HER-2 was conducted using Immunocytochemistry (ICC), Immunofluorescence (IF), and real-time PCR across commonly used breast cancer cell lines. Results revealed differential expression patterns, with MCF-7 and T-47D cells showing positive ER and PR staining but negative HER-2 staining, while SK-BR-3 and HCC1954 cells exhibited positive HER-2 staining and negative ER and PR staining. Conversely, MDA-MB-231 and MDA-MB-468 cells displayed negative staining for all three markers. Real-time PCR analysis highlighted variations in HER-2 expression among the cell lines. Our investigation underscores MCF-7, SK-BR-3, MDA-MB-231, and MDA-MB-468 cell lines as pertinent models for studying major molecular subtypes of breast cancer.

Clinicopathological Significance of Cyclin-Dependent Kinase 2 (CDK2) in Ductal Carcinoma In Situ and Early-Stage Invasive Breast Cancers.

Cyclin-dependent kinase 2 (CDK2) is a key cell cycle regulator, with essential roles during G1/S transition. The clinicopathological significance of CDK2 in ductal carcinomas in situ (DCIS) and early-stage invasive breast cancers (BCs) remains largely unknown. Here, we evaluated CDK2's protein expression in 479 BC samples and 216 DCIS specimens. Analysis of CDK2 transcripts was completed in the METABRIC cohort (n = 1980) and TCGA cohort (n = 1090), respectively. A high nuclear CDK2 protein expression was significantly associated with aggressive phenotypes, including a high tumour grade, lymph vascular invasion, a poor Nottingham prognostic index (all p-values < 0.0001), and shorter survival (p = 0.006), especially in luminal BC (p = 0.009). In p53-mutant BC, high nuclear CDK2 remained linked with worse survival (p = 0.01). In DCIS, high nuclear/low cytoplasmic co-expression showed significant association with a high tumour grade (p = 0.043), triple-negative and HER2-enriched molecular subtypes (p = 0.01), Comedo necrosis (p = 0.024), negative ER status (p = 0.004), negative PR status (p < 0.0001), and a high proliferation index (p < 0.0001). Tumours with high CDK2 transcripts were more likely to have higher expressions of genes involved in the cell cycle, homologous recombination, and p53 signaling. We provide compelling evidence that high CDK2 is a feature of aggressive breast cancers. The clinical evaluation of CDK2 inhibitors in early-stage BC patients will have a clinical impact.