Prognostic Factor In Breast Cancer Research Articles

Electrical lymph node scanning (ELS) system for real-time intra-operative detection of involved axillary lymph nodes in adjuvant breast cancer patients

Lymph node (LN) status is an essential prognostic factor in breast cancer (BC) patients, with an important role in the surgical and therapeutic plan. Recently, we have been developed a novel system for real-time intra-operative electrical LN scanning in BC patients. The ELS scores were calibrated by pathological evaluation of the LNs. Herein, we evaluated the efficacy of ELS in a prospective study for non-chemo-treated breast cancer patients. This is a prospective study in which ELS scores are blind for pathologists who declare the clearance or involvement of LNs based on permanent pathology as the gold standard. ELS and frozen-section (FS) pathology results were achieved intra-operatively, and samples were sent for the permanent pathology. The score of ELS did not affect the surgeons’ decision, and the treatment approach was carried out based on FS pathology and pre-surgical data, such as imaging and probable biopsies. Patients were recruited from October 2021 through November 2022, and 381 lymph nodes of 97 patients were included in the study. In this study we recruited 38 patients (39.2%) with sentinel lymph node biopsy (SLNB) and 59 patients (60.8%) with ALND. Of the 381 LNs scored by ELS, 329 sentinel LNs underwent routine pathology, while others (n = 52) underwent both FS and permanent pathology. ELS showed a sensitivity of 91.4% for node-positive patients, decreasing to 84.8% when considering all LNs. Using ROC analysis, ELS diagnosis showed a significant AUC of 0.878 in relation to the permanent pathology gold standard. Comparison of ELS diagnosis for different tumor types and LN sizes demonstrated no significant differences, while increasing LN size correlated with enhanced ELS sensitivity. This study confirmed ELS’s efficacy in real-time lymph node detection among non-chemo-treated breast cancer patients. The use of ELS’s pathological scoring for intra-operative LN diagnosis, especially in the absence of FS pathology or for non-sentinel LN involvement, could improve prognosis and reduce complications by minimizing unnecessary dissection.

The specific shapes of capillaries are associated with worse prognosis in patients with invasive breast cancer.

Angiogenesis is considered essential for tumor progression; however, whether histological counting of blood vessel numbers, expressed as microvessel density (MVD), can be a prognostic factor in breast cancer remains controversial. It has been suggested that the specific morphology of blood vessels such as glomeruloid microvascular proliferation (GMP) is associated with clinical parameters. Here, we aimed to clarify the significance of MVD with revised immunohistochemistry and to identify new blood vessel shapes that predict prognosis in breast cancer. Four hundred and eleven primary breast cancer specimens were collected, and the sections were immunohistochemically stained with CD31 (single staining) and CD31 and Collagen IV (double staining). The prognosis of patients was examined based on the MVD value, and the presence of GMP and other blood vessels with other specific shapes. As a result, high MVD value and the presence of GMP were not associated with worse prognosis. By contrast, patients with deep-curved capillaries surrounding tumor cell nests (C-shaped) or excessively branched capillaries near tumor cell nests showed a significantly poor prognosis. The presence of these capillaries was also correlated with clinicopathological parameters such as Ki-67 index. Thus, the morphology of capillaries rather than MVD can be a better indicator of tumor aggressiveness.

Identification of SMC2 and SMC4 as prognostic markers in breast cancer through bioinformatics analysis.

Breast cancer (BRCA) is one of the most common malignant tumors. The structural maintenance of chromosome (SMC) gene family has been shown to play an important role in human cancers. However, the role of SMC families in BRCA is unclear. This study aimed to explore the role and potential clinical value of whole SMCs in BRCA. TIMER and UALCAN database were used to analysis the expression level. Genetic variations were analyzed by cBioPortal. Promoter methylation and protein level were analyzed by UCLCAN. GO and KEGG were analyzed by Metascape database. Prognostic value of SMCs was analyzed by Kaplan-Meier and multivariate cox regression analyses. Immune infiltration analysis was conducted by CIBERSORT. Immunotherapy outcome prediction was conducted by Cancer Immunome Atlas. Targeted drug therapy outcome prediction was taken by GDSC and R language. The cell viability was tested by CCK8 and migration was tested by wound healing assay. Xenograft model was used to investigate the in vivo role of SMC2. Expression levels of SMC1A, SMC2, SMC4, SMC5 and SMC6 mRNA were increased in BRCA tissues, and negatively correlated with promoter methylation. Overexpression of SMC2 and SMC4 was negatively correlated with survival. Function of SMCs family regulatory genes was mainly related to ATPase activity. Expression of most SMCs was negatively correlated with immunotherapy and drug therapy outcomes. Interfere SMC2 and SMC4 decreased IC50 values of 5-fluorouracil and oxaliplatin and inhibited the migration of MCF7 cells. Tumor growth and weights were significantly decreased in si-SMC2 groups. Combined bioinformatics and clinical specimen analysis verified SMC2 and SMC4 as independent prognostic factors in BRCA, suggesting their significance for the diagnosis and treatment of BRCA.

Association between lymphovascular invasion (LVI) and prognostic factors in breast cancer.

Association between lymphovascular invasion (LVI) and prognostic factors in breast cancer.

Abstract PO1-13-12: Mechanistic Analysis and Potential Therapeutic Implications in Breast Cancer with Fibrotic Focus

Abstract A fibrotic focus (FF) is a scar-like region that forms in the center of carcinoma due to excessive tumor stroma formation. In our earlier studies, we found FF as an independent poor prognostic factor for breast cancers. However, the underlying mechanisms of how the presence of FF contributed to a poor prognosis are still unknown. To improve our understanding of FF in breast cancer, we have investigated genes associated with FF and their impacts on breast cancer prognosis. Analysis of data from The Cancer Genome Atlas Program (TCGA) indicated that Bone Morphogenetic Protein 8A (BMP8A) was significantly upregulated in breast cancers with FF. To further validate this finding, immunohistochemistry (IHC) on BMP8A was performed on a local cohort of breast cancers (N= 900). Of these samples, 147 (16.3%) were found to be BMP8A positive, and there was a significant association between the presence of FF and high expression of BMP8A (p-value=0.026). We also found that high expression of BMP8A was positively correlated with apocrine phenotype, necrosis, increased Ki67 expression, and triple-negative breast cancer subtype; and most of these are poor prognostic factors for breast cancer. Kaplan-Meier survival estimate analysis revealed that high expression of BMP8A was significantly associated with poor overall survival (p-value=0.035). Gene ontology (GO) analysis showed that "Extracellular matrix organization" was the prominent biological process associated with BMP8A. KEGG pathway analysis suggested that BMP8A was significantly related to "Protein digestion and absorption", "ECM-receptor interaction", and "Focal adhesion" pathways, further validating its correlation with stromal FF. In cellular studies using MCF7 and MDA-MB-231 cell lines, overexpression of BMP8A was found to enhance breast cancer cell proliferation, invasion, and migration. Similar tumor-promoting phenotypes were exhibited when stimulating the cell lines with recombinant human BMP8A. In conclusion, our findings suggested that BMP8A was associated with FF in breast cancer, contributing at least partly to the aggressive features of these cancers. Our findings also provided new insights into the precision treatment and diagnosis of breast cancer. Further exploration of BMP8A as a therapeutic target and prognostic factor may contribute to improved management of breast cancer patients. Citation Format: Canbin Fang, Julia Y. S. Tsang, Gary M.K. Tse. Mechanistic Analysis and Potential Therapeutic Implications in Breast Cancer with Fibrotic Focus [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-13-12.

Abstract PO4-20-05: An open label phase III randomized trial to evaluate the efficacy of Post-chemotherapy Axillary Conservation Surgery in breast cancer (PACS)

Abstract Background- Axillary lymph nodes (ALN) status is the most important prognostic factor in breast cancer. Traditionally, a complete axillary lymph node dissection (ALND) has been standard of care for those patients who have a positive node pre-chemotherapy. However, lately axillary conservation is paving its way in the post-chemotherapy setting as well to avoid significant morbidity of ALND. Most sentinel node biopsy studies have failed to achieve the desired false negative rate(FNR). (Boughey JC et al, JAMA. 2013 Oct; Kuehn T et al, Lancet Oncol. 2013; Boileau JF et al, J Clin Oncol. 2015 Jan).We previously reported a low FNR of low axillary sampling (LAS) in the post-chemotherapy setting. (Parmar et al, JCO-GO, 2021) We are conducting a phase III, randomised controlled trial of LAS versus complete ALND in post-chemotherapy negative (ypN0) axilla. Aims and objectives- The primary objective is to assess the non-inferiority of LAS in patients who are rendered ypN0 by pre-operative chemotherapy with disease-free survival as primary end point. The secondary objectives are comparing the morbidity of ALND (lymphedema, paraesthesia, and shoulder dysfunction) in the LAS and ALND arms, and to evaluate the impact on overall survival, local, regional, and distant recurrence free survival and quality of life. Trial design- This is a prospective, open label, randomised, phase III trial where histologically proven, non-metastatic, cT1-4,N0-2 breast cancer patients who are rendered ycN0 after pre-operative systemic chemotherapy are being accrued. Patients with prechemo N3 disease, inflammatory breast cancer, recurrent disease, pregnancy associated breast cancer are being excluded from the study. The chemotherapy regimens and surgical assessment is as per standard institutional protocols. After obtaining informed consent, patients undergo LAS during surgery and lymph nodes(LN) are sent for frozen section analysis. If any LN is found to be involved, a complete ALND is carried out. If the staging procedure is negative, then patients are randomised into 2 groups- observation v/s complete ALND. Stratification factors are T stage, N stage, Hormone receptor status, Her2 receptor status and number of chemotherapy cycles taken. Morbidity assessment is done with- Constans shoulder score, arm volumetry, paraesthesia assessment, and a QOL questionnaire- Self-reported Breast cancer Lymphedema Symptom Experience Index (BCLSEI). A baseline assessment pre-surgery is followed by 6 monthly morbidity assessments and regular oncologically relevant follow-up up to 5 years. A two-sided log-rank test with an overall sample size of 2316 with a 10% dropout rate (1158 in ALND and 1158 in LAS group) achieves 80% power at a 0.05 significance level to detect a hazard ratio of 1.16 (upper limit of non-inferiority) when the proportion surviving in the control group is 0.71. An interim analysis will be carried out at 25% events and conditional power will be calculated. If the conditional power is below 20%, then the study will be discontinued for futility. The study has been approved by Institutional Ethics Committee (CTRI/2022/07/044461) Expected Study and Results- We started accrual in February 2023 and have screened 63 and randomized 45 patients until now. Ours is a first large randomised prospective study in the post-chemotherapy axillary management setting which will help us understand the efficacy of axillary conservation surgery in patients who are node negative post neoadjuvant chemotherapy. In future, lesser morbid procedures than LAS like targeted axillary dissection can be tested in the same trial. However, LAS as a technique of axillary conservation suits resource constraints and high volume setting such as ours. Citation Format: Shalaka Joshi, Jessicka Shah, Pallavi Daphale, Rohini Hawaldar, Anuradha Daptardar, Ayushi Sahay, Tanuja Shet, Palak Popat, Tabassum Wadasadawala, Nita Nair, Vani Parmar, Bipin Bandre, Shabina Siddique, Vaibhav Vanmali, Sudeep Gupta, Rajendra Badwe. An open label phase III randomized trial to evaluate the efficacy of Post-chemotherapy Axillary Conservation Surgery in breast cancer (PACS) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-20-05.

Influence of breast cancer prognostic factors on ovarian reserve and response to ovarian stimulation in fertility preservation

Research questionDo breast cancer (BC) prognostic factors influence ovarian reserve and response to controlled ovarian hyperstimulation (COH) in the context of fertility preservation (FP)? DesignObservational, bicentric retrospective study including all BC patients who had vitrified oocytes after COH using a random start GnRH antagonist protocol after measurement of serum AMH levels and antral follicle count (AFC) between November 2015 and August 2022. Three-hundred-fifty-two BC patients having undergone one cycle of COH were analyzed. Number of oocytes recovered (OOR), maturation rate (number of mature oocytes/number of oocytes recovered), and Follicular Output Rate (FORT) were studied according to the patients’ general characteristics, ovarian reserve markers, as well as BC diagnostic and prognostic factors: histological type, uni/multifocal character, TNM or UICC stage, hormonal receptors expression, HER2 status, Ki67, Grade, presence of vascular emboli, lymph node. ResultsOverall, mean patients’ age was 33.6 ± 4.1 years. Mean AFC and serum AMH level were 20.5 ± 13.0 follicles and 2.7 ± 4.6 ng/mL, respectively. After ovarian stimulation, 12.5 ± 8.5 oocytes were recovered and 9.3 ± 6.9 were mature and further vitrified. Mean oocyte maturation rate was 74 ± 23%. Patient's age was significantly related to the number of mature oocytes recovered: the risk of yielding less than 8 oocytes increased significantly after the age of 35 years. Follicular responsiveness to FSH, assessed by the follicular output rate (FORT index) as well as OOR were 30 ± 24% and 12.5 ± 8.5%, respectively. FORT index was not influenced by tumor characteristics and COH outcome was not influenced by breast cancer prognostic factors. ConclusionOur findings indicate that BC prognostic factors do not influence ovarian reserve markers nor the response to ovarian stimulation in the context of FP. Therefore, tumor grade, triple-negative status, overexpression of HER2, and high Ki67 should not modify the FP strategy when COH for oocyte vitrification is considered.

Systematic Review of Survival Outcomes of Pregnancy-Associated Breast Cancer in Asian Countries.

Pregnancy-associated breast cancer (PABC) is a rare type of gestational cancer. It poses a significant challenge in diagnosis and management, especially in Asian countries with limited resources. We carried out a systematic literature review and narrative synthesis to identify survival outcomes for women with PABC in Asia. We searched MEDLINE, PubMed, Cochrane Library and the reference lists of the included English language articles for those conducted between January 2010 and August 2022. The search terms were pregnancy-associated breast cancer, breast cancer AND pregnancy, survival of PABC and prognosis of PABC patients. PABC is defined as breast cancer diagnosed either during pregnancy or 1 year-5 years postpartum. This review included observational studies conducted in Asian countries. The final 11 articles met the selection criteria and were analysed. Five of the studies had high quality methods as assessed using the Joanna Briggs Institute (JBI) checklist. We reported study design, year of diagnosis, country, definition of PABC, control group, age of participants, median follow-up time, survival outcomes and pregnancy as prognostic factors. Only five studies reported that PABC patients had a poor overall or disease-free survival rate compared to the control. Pregnancy was a significant independent prognostic factor of breast cancer in only two studies. This review highlights that pregnancy has an unconfirmed association with breast cancer survival in Asia. Most studies that found a non-significant association had small samples, thus there is a need for large-scale multinational epidemiological studies in Asia to establish the survival outcomes in PABC patients.

The Relationship between Breast Cancer Subtypes, Prognostic Factors, and Apparent Diffusion Coefficient Histogram Analysis.

Diffusion Magnetic Resonance Imaging (MRI) is a useful method to evaluate tumor biology and tumor microstructure. The apparent diffusion coefficient (ADC) value correlates negatively with the cellular density of the tumor. This study aimed to investigate the effectiveness of the ADC histogram analysis in showing the relationship between breast cancer prognostic factors and ADC parameters. This study is a retrospective observational descriptive study. ADC histogram parameters were evaluated in all tumor volumes of 67 breast cancer patients. Minimum, 5, 10, 25, 50, 75, 90, 95 percentiles, maximum, mean, median ADC values, kurtosis, and skewness were calculated. Breast MRI examinations were performed on a 3T MR scanner. We evaluated the fibroglandular tissue density of bilateral breasts, background enhancement, localization of masses, multifocality-multicentricity, shape, rim, internal contrast enhancement, and kinetic curve on breast MRI. BIRADS scoring was performed according to breast MRI. Pathologically, histologic type, histologic grade, HER 2, Ki 67, ER-, and PR status were evaluated. A significant correlation was found between tumor volume and ADC scores. There is a significant correlation between min ADC values (p< 0.031), max ADC (p< 0.001), and skewness (p< 0.019). A significant correlation was found between tumor kurtosis and lymph nodes (p< 0.029). There was a significant difference in ADC <sub<mean</sub<, ADC<sub<10%</sub<, ADC<sub<25%</sub<, ADC<sub<50%</sub<, ADC<sub<75%</sub<, ADC<sub<90%</sub<, ADC <sub<95%</sub< and ADC<sub<max</sub> values depending on ER-and PRstatus. (for ER p = 0.004, p = 0.018, p = 0.010, p = 0.008, p = 0.004, p = 0.004, p = 0.02, p = 0.02 and p = 0.038, for PR p &#60; 0.001, p = 0.028, p = 0.011, p = 0.001, p < 0.001, p =<0.001, p < 0.001, and p < 0.001, respectively; p < 0.05). These values were lower in ER-and PR-positive status than in ER-and PR-negative receptor status. According to HER2 status, there was a statistically significant difference in ADC<sub<5%</sub< and measurements of the lesions (p = 0.041; p < 0.05). Our study found no significant correlation between other prognostic factors, such as histological grade, Ki-67 indices, and ADC values. Our study found a significant difference between tumor volume, ER- and, PR status, HER2, and lymph node involvement, and some ADC values among prognostic factors for breast cancer. Furthermore, ADC histogram analysis can provide additional value in predicting some prognostic factors.

Association between estrogen receptor alpha and aryl hydrocarbon receptor gene polymorphisms in the prognosis of breast cancer in Egypt

Breast cancer is the most malignant tumor among women in the world. Single nucleotide polymorphisms (SNPs) might better predict breast cancer prognosis. PvuII (T/C substitution), XbaI (A/G substitution), and aryl hydrocarbon (AhR) (G/A substitution) were evaluated as possible genetic prognostic factors for breast cancer. The aim of the current study was to assess the relation between PvuII (rs2234693), XbaI (rs9340799), and aryl hydrocarbon receptor gene polymorphisms AhR (rs2066853) in breast cancer prognosis. This was a case-control study that included 120 breast cancer patients classified into two groups. The first group included 60 patients with good prognostic factors, and the second group included 60 patients with poor prognostic factors. Blood samples were taken from all study participants to perform the genotyping assay. We found that positive genotypes of PvuII, XbaI, and AhR polymorphisms were strongly associated with better prognostic factors for breast cancer patients, while negative genotypes of PvuII and XbaI were more and significantly prevalent in poor prognostic breast cancer patients. We conclude that PvuII T/C, XbaI G/A, and AhR G/A alleles may be prognostic for breast cancer progression. ‎

Abstract 106: Selective elimination of CD169+ macrophages in lymph nodes invaded by breast cancers

Abstract Background: Lymph node metastasis is known as one of the strongest prognostic factors in breast cancer. The invasion mechanism of metastasized cancer cells in such immune cell-rich organs remains clear. Here, we aimed to elucidate the impact of metastasized cancer cells on the lymph node immune cell landscape. Methods: Multiscale transcriptomic analyses were performed on both metastatic and nonmetastatic lymph node samples from breast cancer patients with lymph node metastasis. As cancer cells interact with lymphocytes in lymph nodes in direct, proximal, and distant manners, we tried to capture the direct and proximal impact on immune cells in invaded lymph nodes by comparing paired metastatic and non-metastatic lymph node samples. Laser-micro-dissected sections were obtained from 17 lymph nodes across six breast cancer patients at stages II‒III, with each patient contributing both types of lymph nodes for direct comparison. We performed bulk transcriptome, spatial transcriptome, and imaging mass cytometry to analyze the obtained lymph nodes. Furthermore, we conducted immunohistochemistry analyses against a larger patient cohort (574 lymph nodes from 58 patients). Results: Comparing the transcriptomes of paired lymph nodes with and without metastasis from the same patients revealed selective downregulation of CD169+ macrophage-related genes in metastatic lymph nodes. The spatial transcriptome indicated a potential depletion of CD169+macrophages, initiators of anticancer immunity, from their residence in metastatic lymph nodes, while other principal immune cell types were unaltered. Mass cytometry imaging revealed that the numbers of CD169+ macrophages were smaller in the metastatic lymph nodes than in the nonmetastatic lymph nodes. Conversely, the number of B cells, CD4+ T cells, CD8+T cells, Treg cells, and CD11c+ cells remained comparable in both lymph node types. Additional immunohistochemistry analysis of 315 nonmetastatic lymph nodes and 159 metastatic lymph nodes from 58 patients with breast cancer showed that a reduced CD169+ macrophage population was prevalent in all breast cancer subtypes. CD169+ macrophages gradually decreased in correlation with pathological lymph node metastasis status, while no correlation was identified with pathological tumor size classification or metastasized cancer volume in invaded lymph nodes. Discussion: CD169+ macrophages are a unique type of resident macrophages in the lymphoid organs that present cancer-derived antigens to CD8+ T cells. The antigen-presenting role of CD169+ macrophages to T cells is a pivotal step in adaptive immunity. The elimination of CD169+ macrophage implies the disruption of the first step of the initial immune response. This study uncovered CD169+ macrophage suppression as a pronounced pathological phenotype in lymph nodes with breast cancer metastasis, thereby establishing it as a critical future therapeutic target. Citation Format: Yurina Maeshima, Tatsuki R. Kataoka, Alexis Vandenbon, Masahiro Hirata, Yasuhide Takeuchi, Yutaka Suzuki, Yukiko Fukui, Yumiko Ibi, Hironori Haga, Satoshi Morita, Masakazu Toi, Shinpei Kawaoka, Kosuke Kawaguchi. Selective elimination of CD169+ macrophages in lymph nodes invaded by breast cancers [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 106.

Abstract 7644: Prognostication of genomic characteristics of residual breast cancer after neoadjuvant chemotherapy

Abstract Residual cancer burden (RCB) based on pathologic characteristics is the most powerful prognostic factor in breast cancer (BC) which received neoadjuvant chemotherapy (NAC) followed by surgery. According to RCB classification, class III predicted short survival duration regardless of BC subtypes according to hormone receptor (HR) and human epidermal growth factor receptor-2 (HER-2) state. However, up to 20-40% of BCs with RCB class III did not experience BC recurrence and had long term survival without disease recurrence. In our study, we evaluated genomic characteristics of BC which had high RCB class. We collected 96 fresh frozen BC specimens which had undergone surgery after NAC between 2010 and 2018 from Samsung Medical Center Biobank. We performed whole genome or exome sequencing, RNA sequencing and high-plex single-cell spatial transcriptomics. Of 96 BCs, 65 BCs had experienced BC recurrence and 31 BCs have not been BC recurrence. Of 65 BCs with dismal prognosis, 12 were HR+HER2-, four in HR+HER2+, 39 in triple negative breast cancer (TNBC) and 10 in HR-HER2+ BC. Of 31 BCs without recurrence, 11 were HR+HER2-, two in HR+HER2+, 14 in TNBC and four in HR-HER2+ BC. In HR+HER2- BC, ten of 12 BCs with dismal prognosis were categorized into basal like intrinsic subtype and two were into luminal B subtype compared that six of luminal A and five of luminal B subtype categorization in good prognosis BC group. Age associated mutation signature were enriched in HR+HER2- BC with good prognosis (p=0.027). Tumor microenvironment (TME) analysis using Kassandra suggested that high monocytes were associated with BC with dismal prognosis (p=0.00031). In single-cell spatial transcriptome analysis, T-cell abundance in the tumoral niche is associated with dismal prognosis in HR+HER2- BC (p=0.039). In TNBC, almost BCs (88.7%) were categorized into basal-like intrinsic subtype regardless of their prognosis. TME analysis presented that immune cells including macrophages and lymphocytes with CD4 and CD8 T cells were significantly enriched in TNBC with good prognosis (ps &amp;lt;0.05, respectively). In HER2+ BC, intrinsic subtypes were heterogeneous in both groups. Focal amplification in HER2+BC patient harbored DNA segments from different chromosomes more frequently than in those with good prognosis (p=0.00091), which was prominent in oncogenic extrachromosomal DNA amplifications compared to other oncogenic amplifications. In TME analysis, there were no specific cell enrichments according to BC prognosis but sing-cell spatial transcriptome analysis revealed that higher T-cell abundance in the tumoral niche was associated with HR+HER2+ BC with good prognosis (p=0.047). In conclusion, each BC subtype had their own genomic characteristics to determine their prognosis. Our study also suggested that TME characteristics was common prognostic factor for survival outcome of BC with residual tumor after NAC. Citation Format: Ji-Yeon Kim, Sabin Park, Sepil Ahn, Eun Seop Seo, Soyeon Kim, Mark Gregory, Emily Killingbeck, Eun Yoon Cho, Jeong Eon Lee, Jin Seok Ahn, Yeon Hee Park, Woong-Yang Park, Hoon Kim, Semin Lee, Young-Hyuck Im. Prognostication of genomic characteristics of residual breast cancer after neoadjuvant chemotherapy [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 7644.

Analyses of hypoxia-related risk factors and clinical relevance in breast cancer.

Hypoxia plays an important role in the heterogeneity, relapse, metastasis, and drug resistance of breast cancer. In this study, we explored the hypoxia-related biological signatures in different subtypes of breast cancer and identified the key prognostic factors by bioinformatics methods. Based on The Cancer Genome Atlas (TCGA) Breast Cancer datasets, we divided the samples into immune-activated/suppressed populations by single-sample gene set enrichment analysis (ssGSEA) and then used hierarchical clustering to further identify hypoxic/non-hypoxic populations from the immune-suppressed samples. A hypoxia related risk model of breast cancer was constructed. Nuclear factor interleukin-3 regulated (NFIL3), serpin family E member 1 (SERPINE1), FOS, biglycan (BGN), epidermal growth factor receptor (EGFR), and sushi-repeat-containing protein, X-linked (SRPX) were identified as key hypoxia-related genes. Margin status, American Joint Committee on Cancer (AJCC) stage, hypoxia status, estrogen receptor/progesterone receptor (ER/PR) status, NFIL3, SERPINE1, EGFR, and risk score were identified as independent prognostic indicators for breast cancer patients. The 3- and 5-year survival curves of the model and immunohistochemical staining on the breast cancer microarray verified the statistical significance and feasibility of our model. Among the different molecular types of breast cancer, ER/PR+ and HER2+ patients might have higher hypoxia-related risk scores. ER/PR-negative samples demonstrated more activated immune-related pathways and better response to most anticancer agents. Our study revealed a novel risk model and potential feasible prognostic factors for breast cancer and might provide new perspectives for individual breast cancer treatment.

RANK and RANKL Expression in Tumors of Patients with Early Breast Cancer

AbstractThe receptor activator of nuclear factor-κB (RANK) pathway was associated with the pathogenesis of breast cancer. Several studies attempted to link the RANK/RANKL pathway to prognosis; however, with inconsistent outcomes. We aimed to further contribute to the knowledge about RANK/RANKL as prognostic factors in breast cancer. Within this study, protein expression of RANK and its ligand, RANKL, in the tumor tissue was analyzed in association with disease-free survival (DFS) and overall survival (OS) in a study cohort of patients with early breast cancer.607 samples of female primary and early breast cancer patients from the Bavarian Breast Cancer Cases and Controls Study were analyzed to correlate the RANK and RANKL expression with DFS and OS. Therefore, expression was quantified using immunohistochemical staining of a tissue microarray. H-scores were determined with the cut-off value of 8.5 for RANK and 0 for RANKL expression, respectively.RANK and RANKL immunohistochemistry were assessed by H-score. Both biomarkers did not correlate (ρ = −0.04). According to molecular subtypes, triple-negative tumors and HER2-positive tumors showed a higher number of RANK-positive tumors (H-score ≥ 8.5), however, no subtype-specific expression of RANKL could be detected. Higher RANKL expression tended to correlate with a better prognosis. However, RANK and RANKL expression could not be identified as statistically significant prognostic factors within the study cohort.Tumor-specific RANK and RANKL expressions are not applicable as prognostic factors for DFS and OS, but might be associated with subtype-specific breast cancer progression.

Prognostic factors and survival of breast cancer in patients over 40 years of age

Aims: Breast cancer is the cancer with the highest incidence and mortality in women. There are differences in prognosis and survival between women over and under the age of 40. In this article, we aimed to examine breast cancer prognostic factors and survival results in people over the age of 40. Methods: 1187 patients aged 40 and over who underwent surgery at the Ondokuz Mayıs University Department of General Surgery between August 2005 and April 2019 and whose data were accessible were retrospectively examined. Data were obtained from the hospital automation system, the Ministry of Health’s online database, hospital archives, patients, and/or their relatives. They were classified separately in terms of type of surgery, axillary metastasis status (according to radiological status if axilla surgery is not performed), type of axilla surgery performed, pathological tumor size, number of pathological lymph nodes, pathological stage, lymphovascular and perineural invasion status, hormone receptor positivity, C-erb B2 and Ki-67 status, neoadjuvant treatment status, and molecular subgroup. Variables were analyzed individually for recurrence, mortality, and survival. Results found to be significant were subjected to multivariate analysis testing. Statistical significance was accepted as p&lt;0.05. Results: As a result of multivariate analysis performed by excluding data that disrupted homogeneous distribution, perineural invasion, lymphovascular invasion, grade, and progesterone receptor status were determined to be independent prognostic factors in terms of recurrence. Lymphovascular invasion and progesterone receptor status were found to be independent prognostic factors for mortality. Conclusion: A lot of studies have been conducted, and criteria have been determined for breast cancer prognosis and survival. In our results, lymphovascular invasion and progesterone receptor status were found to be independent prognostic markers for both recurrence and mortality. More reliable results can be obtained with prospective study analyses.

The Correlation between Morpho-Dynamic Contrast-Enhanced Mammography (CEM) Features and Prognostic Factors in Breast Cancer: A Single-Center Retrospective Analysis.

Breast cancer, a major contributor to female mortality globally, presents challenges in detection, prompting exploration beyond digital mammography. Contrast-Enhanced Mammography (CEM), integrating morphological and functional information, emerges as a promising alternative, offering advantages in cost-effectiveness and reduced anxiety compared to MRI. This study investigates CEM's correlation with breast cancer prognostic factors, encompassing histology, grade, and molecular markers. In a retrospective analysis involving 114 women, CEM revealed diverse lesion characteristics. Statistical analyses identified correlations between specific CEM features, such as spiculated margins and irregular shape, and prognostic factors like tumor grade and molecular markers. Notably, spiculated margins predicted lower grade and HER2 status, while irregular shape correlated with PgR and Ki-67 status. The study emphasizes CEM's potential in predicting breast cancer prognosis, shedding light on tumor behavior. Despite the limitations, including sample size and single-observer analysis, the findings advocate for CEM's role in stratifying breast cancers based on biological characteristics. CEM features, particularly spiculated margins, irregular shape, and enhancement dynamics, may serve as valuable indicators for personalized treatment decisions. Further research is crucial to validate these correlations and enhance CEM's clinical utility in breast cancer assessment.

Molecular subtype identification and prognosis stratification based on lysosome-related genes in breast cancer

BackgroundLysosomes are known to have a significant impact on the development and recurrence of breast cancer. However, the association between lysosome-related genes (LRGs) and breast cancer remains unclear. This study aims to explore the potential role of LRGs in predicting the prognosis and treatment response of breast cancer. MethodsBreast cancer gene expression profile data and clinical information were downloaded from TCGA and GEO databases, and prognosis-related LRGs were screened for consensus clustering analysis. Lasso Cox regression analysis was used to construct risk features derived from LRGs, and immune cell infiltration, immune therapy response, drug sensitivity, and clinical pathological feature differences were evaluated for different molecular subtypes and risk groups. A nomogram based on risk features derived from LRGs was constructed and evaluated. ResultsOur study identified 176 differentially expressed LRGs that are associated with breast cancer prognosis. Based on these genes, we divided breast cancer into two molecular subtypes with significant prognostic differences. We also found significant differences in immune cell infiltration between these subtypes. Furthermore, we constructed a prognostic risk model consisting of 7 LRGs, which effectively divides breast cancer patients into high-risk and low-risk groups. Patients in the low-risk group have better prognostic characteristics, respond better to immunotherapy, and have lower sensitivity to chemotherapy drugs, indicating that the low-risk group is more likely to benefit from immunotherapy and chemotherapy. Additionally, the risk score based on LRGs is significantly correlated with immune cell infiltration, including CD8 T cells and macrophages. This risk score model, along with age, chemotherapy, clinical stage, and N stage, is an independent prognostic factor for breast cancer. Finally, the nomogram composed of these factors has excellent performance in predicting overall survival of breast cancer. ConclusionsIn conclusion, this study has constructed a novel LRG-derived breast cancer risk feature, which performs well in prognostic prediction when combined with clinical pathological features.

KNSTRN Is a Prognostic Biomarker That Is Correlated with Immune Infiltration in Breast Cancer and Promotes Cell Cycle and Proliferation.

Kinetochore-localized astrin/SPAG5-binding protein (KNSTRN) promotes the progression of bladder cancer and lung adenocarcinoma. However, its expression and biological function in breast cancer remain largely unknown. Therefore, this study aimed to analyze KNSTRN expression, prognoses, correlation with immune infiltration, expression-associated genes, and regulated signaling pathways to characterize its role in regulating the cell cycle using both bioinformatics and in vitro functional experiments. Analyses of The Cancer Genome Atlas, Gene Expression Omnibus, TIMER, and The Human Protein Atlas databases revealed a significant upregulation of KNSTRN transcript and protein levels in breast cancer. Kaplan-Meier survival analyses demonstrated a significant association between high expression of KNSTRN and poor overall survival, relapse-free survival, post-progression survival, and distant metastases-free survival in patients with breast cancer. Furthermore, multivariate Cox regression analyses confirmed that KNSTRN is an independent prognostic factor for breast cancer. Immune infiltration analysis indicated a positive correlation between KNSTRN expression and T regulatory cell infiltration while showing a negative correlation with Tgd and natural killer cell infiltration. Gene set enrichment analysis along with single-cell transcriptome data analysis suggested that KNSTRN promoted cell cycle progression by regulating the expression of key cell cycle proteins. The overexpression and silencing of KNSTRN in vitro, respectively, promoted and inhibited the proliferation of breast cancer cells. The overexpression of KNSTRN enhanced the expression of key cell cycle regulators, including CDK4, CDK6, and cyclin D3, thereby accelerating the G1/S phase transition and leading to aberrant proliferation of breast cancer cells. In conclusion, our study demonstrates that KNSTRN functions as an oncogene in breast cancer by regulating immune response, promoting G1/S transition, and facilitating breast cancer cell proliferation. Moreover, KNSTRN has potential as a molecular biomarker for diagnostic and prognostic prediction in breast cancer.

Inflammatory indicators as a prognostic factor of clinical response in locally advanced breast cancer (LABC) patients receiving neoadjuvant chemotherapy (NAC)

ObjectivesBreast cancer is a prevalent and fatal cancer worldwide. Neoadjuvant chemotherapy is a treatment option used to reduce tumor size in patients with locally advanced breast cancer. The neutrophil–lymphocyte ratio (NLR), lymphocyte–monocyte ratio (LMR), and platelet–lymphocyte ratio (PLR) are inflammatory markers that have been studied as prognostic factors in breast cancer. This cross-sectional study aimed to investigate the role of NLR, LMR, and PLR in the clinical response to neoadjuvant chemotherapy in women with locally advanced breast cancer. Materials and methodsWe used a cross-sectional research design for this study with the aim of observing the relation between NLR, LMR, and PLR and the clinical response of neoadjuvant chemotherapy. The study was conducted in Cipto Mangunkusumo General Hospital. We analyzed the medical records of 84 patients treated with neoadjuvant chemotherapy between 2016 and 2021. ResultsOur study found that majority of the subjects receives CAF combination of NAC with inoperable breast cancer. Most of the subjects have luminal B type of breast cancer and no clinical response to chemotherapy regimen. Surgery has significant association with clinical response in patients receiving NAC (P = <.001). There are no significant correlation between NLR, LMR, and PLR with clinical response to neoadjuvant chemotherapy. However, we did observe a significant association between NLR and 1-year mortality rate. ConclusionIn conclusion, significant association between NLR and 1-year morality rate suggest that NLR may serve as a useful prognostic factor in breast cancer patients receiving neoadjuvant chemotherapy.

Prognostic impact of tumor-associated neutrophils in breast cancer.

Neutrophils are the most common type of leukocyte in mammals and play an essential role in the innate immune system and anti-cancer responses. However, recent studies identified the presence of tumor-associated neutrophils (TANs) as a poor prognostic factor. The present study investigated whether relationships exist between TANs and the clinicopathological factors and genetic status of breast cancer. A total of 196 breast cancer patients with sufficient biopsy, breast-conserving surgery, or mastectomy specimens between 2014 and 2021 in Hokuto Hospital were included. TANs were individually counted in the tumor stroma (TS) and tumor nest (TN). A higher density of TANs in both TS and TN correlated with tumor size (TS P = 0.010; TN P = 0.001), a high histological grade (TS P < 0.001; TN P < 0.001), the histological type (TS P = 0.009; TN P = 0.034), a high ratio of lymph node metastasis (TS P < 0.001; TN P < 0.001), an advanced stage of cancer (TS P < 0.001; TN P = 0.002), intrinsic subtypes (TS P < 0.001; TN P < 0.001), ERBB2 (TS P < 0.001; TN P < 0.001), MAP3K1 (TS P = 0.002; TN P = 0.023), and TP53 (TS P < 0.001; TN P < 0.001). A higher density of TANs in TS and TN also correlated with shorter disease-free survival and overall survival (P < 0.001). The present results suggest that a higher density of TANs correlates with unfavorable prognostic factors in breast cancer. Further research on clinicopathological and genetic factors associated with TANs in breast cancer is needed.