Prognostic Factor In Breast Cancer Research Articles

Abstract 4135712: Mortality and Cardiovascular Complications Associated with Weight Loss Drugs among Breast Cancer Females Under Cardiotoxic Therapies: A Real-World Populational Study in the United States

Background: Obesity is an adverse prognostic factor for breast cancer (BC). While liraglutide and semaglutide, derived from antidiabetic glucagon-like peptide-1 receptor agonists (GLP1RA), are established weight loss drugs known for their cardiovascular safety in the general obese population, their safety in BC patients undergoing cardiotoxic antineoplastic therapies remains less understood. Objective: To investigate the mortality and cardiovascular outcomes related to GLP1RA used for weight loss among the highly susceptible BC females. Methods: This retrospective cohort study was based on the TrinetX network, comprising real-time health records from over 60 US healthcare organizations. The study population included obese females (≥18 years old) who received at least three prescriptions of either exclusive GLP1RA (liraglutide or semaglutide) or non-GLP1RA weight loss drugs (phentermine, bupropion-naltrexone, orlistat) upon BC diagnosis between 01/01/2015 and 01/01/2022. The index date was the initiation of systemic anti-cancer treatment, including chemotherapy (anthracycline, taxane, or cyclophosphamide), and/or anti-HER2 agents (trastuzumab, pertuzumab, or lapatinib). We used 1:1 propensity score-matching (PSM) to balance demographics, BMI, comorbidities, concurrent medications for cardiovascular diseases and metabolic disorders, BC receptor status and prior treatment, and levels of serum cholesterol (LDL, HDL) and hemoglobin A1c. Cox regression models were applied to compute hazard ratios (HR) and 95% confidence intervals (CIs). Follow-up continued until 05/24/2024, or until adverse cardiovascular events or death occurred. Results: Among 380 PSM-balanced pairs, the GLP1RA group (mean age: 57.6±11) showed significantly lower risks of all-cause mortality (HR 0.593, 95% CI 0.457-0.77), acute heart failure (HR 0.496, 95% CI 0.286-0.859), angina pectoris (HR 0.566, 95% CI 0.343-0.936), and acute stroke (HR 0.661, 95% CI 0.46-0.951) than the non-GLP1RA group (mean age: 57.5±12). Otherwise, no significant difference was shown in acute myocardial infarction (HR 0.787, 95% CI 0.495-1.251), pulmonary hypertension (HR 0.777, 95% CI 0.55-1.099), or arrhythmias (HR 0.829, 95% CI 0.566-1.215). Conclusion: Compared to non-GLP1RA weight loss agents, GLP1RA offers better survival and cardiovascular protection for BC patients undergoing cardiotoxic therapies. Future studies are warranted to validate the safety of these weight loss drugs during the BC treatment continuum.

Identification of sentinel lymph node macrometastasis in breast cancer by deep learning based on clinicopathological characteristics

The axillary lymph node status remains an important prognostic factor in breast cancer, and nodal staging using sentinel lymph node biopsy (SLNB) is routine. Randomized clinical trials provide evidence supporting de-escalation of axillary surgery and omission of SLNB in patients at low risk. However, identifying sentinel lymph node macrometastases (macro-SLNMs) is crucial for planning treatment tailored to the individual patient. This study is the first to explore the capacity of deep learning (DL) models to identify macro-SLNMs based on preoperative clinicopathological characteristics. We trained and validated five multivariable models using a population-based cohort of 18,185 patients. DL models outperform logistic regression, with Transformer showing the strongest results, under the constraint that the sensitivity is no less than 90%, reflecting the sensitivity of SLNB. This highlights the feasibility of noninvasive macro-SLNM prediction using DL. Feature importance analysis revealed that patients with similar characteristics exhibited different nodal status predictions, indicating the need for additional predictors for further improvement.

Risk of incident cancer in patients with Inflammatory Bowel Disease with prior breast cancer: a multicenter cohort study

Background and AimsBreast cancer is the most common malignancy observed in patients with inflammatory bowel diseases (IBD). The aim of our study was to evaluate incident cancer rate (recurrence or new-onset cancer) in a cohort of IBD patients with a history of breast cancer according to the subsequent IBD treatment provided. MethodsA multicenter retrospective study included consecutive IBD patients with prior breast cancer. The inclusion date corresponded to the diagnosis of index malignancy. Follow-up lasted from cancer diagnosis until the occurrence of incident cancer. ResultsAmong 207 patients included (median disease duration: 13 years [IQR 6 - 21]), first line treatment (median interval of 28 months [IQR 7 - 64]) was a conventional immunosuppressant in 19.3 % of patients, anti-TNF in 19.8 %, vedolizumab in 7.2 % and ustekinumab in 1.9 %.After a median follow-up of 71 months [IQR, 34 - 148], 42 (20%) incident cancers were observed (34 breast cancer recurrences). Adjusted incidence rates per 1000 person-years were 10.2 (95%CI 6.0- 16.4) for the untreated arm and 28.9 (95%CI 11.6-59.6) for exposed patients (p= 0.0519). There was no significant difference between treated patients and controls regarding incident-cancer free survival rates (p=0.4796). In multivariable analysis, factors associated with incident cancer were stage T4d (p=0.036), triple negative tumor (p=0.016) and follow-up of less than 71 months (p=0.005). ConclusionWe did not find a statistically significant increase in incident breast cancer related to IBD treatment beyond the already known poor prognostic factors of breast cancer.

Radiomics for Predicting Prognostic Factors in Breast Cancer: Insights from Contrast-Enhanced Mammography (CEM).

Objectives: To evaluate the correlation between radiomic features extracted from contrast-enhanced mammography (CEM) tumor lesions and peritumoral background with prognostic factors in breast cancer (BC). Methods: In this retrospective, single-center study, 134 women with histologically confirmed breast cancer underwent CEM examination. Radiomic features were extracted from manually segmented lesions and lesion contours were automatically delineated using PyRadiomics. The extracted features were categorized into seven classes: First-order Features, Shape Features (2D), Gray Level Co-occurrence Matrix (GLCM), Gray Level Run Length Matrix (GLRLM), Gray Level Size Zone Matrix (GLSZM), and Neighboring Gray Tone Difference Matrix (NGTDM). Histological examination assessed tumor type, grade, receptor structure (ER, PgR, HER2), Ki67 index, and lymph node involvement. Pearson correlation and multivariate regression were applied to evaluate associations between radiomic features and prognostic factors. Results: Significant correlations were found between First-order Features and prognostic factors such as ER, PgR, and Ki67 (p < 0.05). GLCM-based texture features showed strong associations with Ki67 and HER2 (p < 0.01). Radiomic features from peritumoral regions, especially shape and GLSZM metrics, were significantly correlated with Ki67 and lymph node involvement. Conclusions: Radiomic analysis of both tumor and peritumoral regions offers significant insights into BC prognosis. These findings support the integration of radiomics into personalized diagnostic and therapeutic strategies, potentially improving clinical decision making in BC management.

Comprehensive single-cell and bulk transcriptomic analyses to develop an NK cell-derived gene signature for prognostic assessment and precision medicine in breast cancer.

Natural killer (NK) cells play crucial roles in mediating anti-cancer activity in breast cancer (BRCA). However, the potential of NK cell-related molecules in predicting BRCA outcomes and guiding personalized therapy remains largely unexplored. This study focused on developing a prognostic and therapeutic prediction model for BRCA by incorporating NK cell-related genes. The data analyzed primarily originated from the TCGA and GEO databases. The prognostic role of NK cells was evaluated, and marker genes of NK cells were identified via single-cell analysis. Module genes closely associated with immunotherapy resistance were identified by bulk transcriptome-based weighted correlation network analysis (WGCNA). Following taking intersection and LASSO regression, NK-related genes (NKRGs) relevant to BRCA prognosis were screened, and the NK-related prognostic signature was subsequently constructed. Analyses were further expanded to clinicopathological relevance, GSEA, tumor microenvironment (TME) analysis, immune function, immunotherapy responsiveness, and chemotherapeutics. Key NKRGs were screened by machine learning and validated by spatial transcriptomics (ST) and immunohistochemistry (IHC). Tumor-infiltrating NK cells are a favorable prognostic factor in BRCA. By combining scRNA-seq and bulk transcriptomic analyses, we identified 7 NK-related prognostic NKRGs (CCL5, EFHD2, KLRB1, C1S, SOCS3, IRF1, and CCND2) and developed an NK-related risk scoring (NKRS) system. The prognostic reliability of NKRS was verified through survival and clinical relevance analyses across multiple cohorts. NKRS also demonstrated robust predictive power in various aspects, including TME landscape, immune functions, immunotherapy responses, and chemotherapeutic sensitivity. Additionally, KLRB1 and CCND2 emerged as key prognostic NKRGs identified through machine learning and external validation, with their expression correlation with NK cells confirmed in BRCA specimens by ST and IHC. We developed a novel NK-related gene signature that has proven valuable for evaluating prognosis and treatment response in BRCA, expecting to advance precision medicine of BRCA.

Comparison of Sentinel Lymph Node Sampling with Positron Emission Tomography in the Evaluation of Axillary Lymph Node Involvement in Breast Cancer Patients

Objectives Axillary lymph node status is the most important prognostic factor in breast cancer patients.: This study was carried out to evaluate the diagnostic accuracy of FDG-PET/CT as a noninvasive technique and intraoperative frozen biopsy of sentinel lymphadenectomy (SLNB) in detecting axillary lymph node metastasis. Materials and Methods This study was carried out retrospectively on 44 patients diagnosed with breast cancer, who underwent preoperative FDGPET/ CT imaging and intraoperative SLNB, at the General Surgery Clinic of Istanbul Medeniyet University Göztepe Training and Research Hospital. The axilla was clinically negative in all patients. Preopative FDG-PET/CT imaging and intraoperative SLNB were performed. FDG-PET/CT results were compared with the histopathological results of SLNB and axillary lymph node dissection (ALND). Results According to the pathology results of axillary dissection, metastatic nodes were detected in 22 of 44 cases, and FDG-PET/ CT imaging gave false-negative results in 10. The number of false negative cases of SLNB was 3; Axillary involvement was detected as a result of pathology in one of them, while the others were evaluated as skip metastases. The sensitivity of SLNB and FDG-PET/CT imaging was measured as 86.3% and 54.5%. The specificity values were 95.4% and 100%. FDG-PET/CT imaging has low sensitivity; specificity and positive predictive value were at acceptable levels Conclusion: The sensitivity of FDG-PET/CT imaging is low in detecting axillary involvement, and SLNB is needed in those with negative axillary involvement in FDG-PET/ CT imaging. In our study, SLNB examination was superior to FDG-PET/CT imaging in detecting axillary nodal status. Bangladesh Journal of Medical Science Vol. 23 No. 04 October’24 Page : 1083-1094

Vitamin D receptor is associated with prognostic characteristics of breast cancer after neoadjuvant chemotherapy-an observational study.

Breast cancer (BC) is the most commonly diagnosed malignant tumor in women. The disease and its subsequent treatment pose a serious burden on the quality of life of patients. Neoadjuvant chemotherapy (NAC) has become one of the crucial strategies for the management of BC. Since the identification of the vitamin D receptor (VDR) in mammary tissues, extensive mechanistic research has been conducted on its function. The expression of VDR in BC cells and the tumor microenvironment could be a new prognostic factor for BC after NAC. This observational, single-center study compared data from clinical and histopathological records of 111 female subjects with the expression of VDR in different cellular and tissue components of breast specimens obtained from surgery after NAC. VDR expression was evaluated using an immunoreactive score assigned after immunohistochemistry. Intergroup comparisons and logistic regression were used to identify associations between VDR expression and clinicopathological features of BC. We found that the expression of VDR is associated with various clinical features (i.e., age, menopausal status, and NAC cycle number) and characteristics of prognostic significance, such as residual cancer burden class. Logistic regression analysis revealed that the expression of VDR in the nuclei and cytoplasm of surrounding normal mammary cells predicted vascular invasion and lymph node involvement. The expression of VDR in tumor cells and their microenvironment is related to the clinicopathological characteristics of BC after NAC.

ABO Blood Type and Pretreatment Systemic Inflammatory Response Index Associated with Lymph Node Metastasis in Patients with Breast Cancer.

Lymph node metastasis (LNM) is an important prognostic factor for breast cancer. Inflammatory stimulation can change tumor microenvironment and lead to LNM, but the relationship between LNM and peripheral immunoinflammatory indices has not been clarified in breast cancer. The clinical information of 1918 patients with breast cancer admitted to Meizhou People's Hospital from October 2017 to December 2023 were retrospectively analyzed. The relationship of clinicopathological features (age, body mass index (BMI), ABO blood types, family history of cancer, tumor site, disease stage, LNM, distant metastasis, and molecular subtypes) and peripheral immunoinflammatory indices (pan-immune inflammation value (PIV), systemic immune inflammation index (SII), and system inflammation response index (SIRI)) were analyzed. There were 935 (48.7%) patients had no LNM and 983 (51.3%) had LNM. There were statistically significant differences in the distributions of ABO blood groups (p=0.022) and molecular subtypes (p<0.001) between the two groups. PIV, SII, and SIRI levels in patients with LNM were significantly higher than those without LNM (all p<0.05). The proportions of LNM in patients with high PIV, SII, and SIRI levels were higher than those with low PIV, SII, and SIRI levels, respectively. Logistic regression analysis showed that non-O blood type (non-O blood type vs O blood type, odds ratio (OR): 1.327, 95% confidence interval (CI): 1.056-1.667, p=0.015), luminal B subtype (luminal B vs luminal A, OR: 2.939, 95% CI: 2.147-4.022, p<0.001), HER2+ subtype (HER2+ vs luminal A, OR: 2.044, 95% CI: 1.388-3.009, p<0.001), and high SIRI level (≥0.875 vs <0.875, OR: 1.572, 95% CI: 1.092-2.265, p=0.015) were independently associated with LNM. Non-O blood type, luminal B and HER2+ subtypes, and high SIRI level (≥0.875) have potential role in predicting the status of LNM in breast cancer patients.

Do elastography values correlate with molecular subtype of breast cancer or is morphology the key player?

Objectives We evaluated the association between shear wave elastography (SWE) parameters and the molecular subtypes and other prognostic factors of breast cancer. We also examined the influence of morphological characteristics and other prognostic factors of breast cancers on elastography values. Materials and Methods This is a retrospective observational study on 148 patients with biopsy-proven 152 breast cancers who underwent both B-mode ultrasonography and SWE. The analysis involved calculating the correlation between the five quantitative parameters on SWE (mean, minimum, maximum, standard deviation, and ratio) and the molecular subtyping and other prognostic factors of breast cancer. We analyzed the influence of morphology and other prognostic factors on SWE parameters. Results The mean, minimum, and maximum values in SWE were significantly lower (P&lt;0.05) in cases where the lesion displayed non-mass abnormality, circumscribed margins, posterior acoustic enhancement, and non-ductal histopathology. Hormone positive tumors frequently exhibited spiculated margins and higher (P &lt; 0.05) elastography values, although within this category, circumscribed masses demonstrated lower elastography values compared to the remaining cases. Triple negative breast cancers often displayed circumscribed margins and lower (P &lt; 0.05) elastography values; however, among this subgroup, masses with spiculated margins exhibited higher values compared to the rest. Conclusion Our findings indicate that elastography independently do not correlate with molecular subtypes in breast cancer. Morphological features and histopathological subtypes appear to have strong influence on elastography values.

Factors influencing pathological complete response and tumor regression in neoadjuvant radiotherapy and chemotherapy for high-risk breast cancer

BackgroundPathological complete response (pCR) is a well-established prognostic factor in breast cancer treated with neoadjuvant systemic therapy (naST). The determining factors of pCR are known to be intrinsic subtype, proliferation index, grading, clinical tumor and nodal stage as well as type of systemic therapy. The addition of neoadjuvant radiotherapy (naRT) to this paradigm might improve response, freedom from disease, toxicity and cosmetic outcome compared to adjuvant radiotherapy. The factors for pCR and primary tumor regression when neoadjuvant radiation therapy is added to chemotherapy have not been thoroughly described.MethodsWe performed a retrospective analysis of 341 patients (cT1-cT4/cN0-N+) treated with naRT and naST between 1990 and 2003. Patients underwent naRT to the breast and mostly to the supra-/infraclavicular lymph nodes combined with an electron or brachytherapy boost. NaST was given either sequentially or simultaneously to naRT using different regimens. We used the univariate and multivariate regression analysis to estimate the effect of different subgroups and treatment modalities on pCR (ypT0/Tis and ypN0) as well as complete primary tumor response (ypT0/Tis; bpCR) in our cohort. Receiver operating characteristic (ROC) analysis was performed to evaluate the interval between radiotherapy (RT) and resection (Rx) as well as radiotherapy dose.ResultsOut of 341 patients, pCR and pbCR were achieved in 31% and 39%, respectively. pCR rate was influenced by resection type, breast cancer subtype, primary tumor stage and interval from radiation to surgery in the multivariate analysis. Univariate analysis of bpCR showed age, resection type, breast cancer subtype, clinical tumor stage and grading as significant factors. Resection type, subtype and clinical tumor stage remained significant in multivariate analysis. Radiation dose to the tumor and interval from radiation to surgery were not significant factors for pCR. However, when treatment factors were added to the model, a longer interval from radiotherapy to resection was a significant predictor for pCR.ConclusionsThe factors associated with pCR following naST and naRT are similar to known factors after naST alone. Longer interval to surgery might to be associated with higher pCR rates. Dose escalation beyond 60 Gy did not result in higher response rates.

TP53 signature predicts pathological complete response after neoadjuvant chemotherapy for breast cancer: Observational and confirmational study using prospective study cohorts

The TP53 signature is considered a predictor of neoadjuvant chemotherapy (NAC) response and prognostic factor in breast cancer. The objective of this study was to confirm TP53 signature can predict pathological complete response (pCR) and prognosis in cohorts of breast cancer patients who received NAC in prospective studies.Development cohorts (retrospective [n = 37] and prospective [n = 216] cohorts) and validation cohorts (NAC administered prospective study cohorts [n = 407] and retrospective perioperative chemotherapy (PC)-naïve, hormone receptor (HrR)-positive cohort [PC-naïve_HrR+ cohort] [n = 322]) were used. TP53 signature diagnosis kit was developed using the development cohorts. TP53 signature predictability for pCR and the relationship between recurrence-free survival (RFS), overall survival (OS), and the TP53 signature were analyzed.The pCR rate of the mutant (mt) signature group was significantly higher than that of the wild-type (wt) signature group (odds ratio, 5.599; 95 % confidence interval = 1.876–16.705; P = 0.0008). The comparison of the RFS and OS between the HrR+ and HER2− subgroup of the NAC cohort and of the PC-naïve_HrR+ cohort indicated that the RFS and OS benefit of NAC was greater in the mt signature group than in the wt signature group. From post hoc analyses, the RFS and OS benefit from adding capecitabine to FEC+T as NAC might be observed only in the mt signature group.The TP53 signature can predict the pCR after NAC, and the RFS and OS benefit from NAC may be greater in the mt signature group than in the wt signature group.

Combination of IVIM with DCE-MRI for diagnostic and prognostic evaluation of breast cancer

PurposeTo identify the most effective combination of DCE-MRI (Ktrans,Kep) and IVIM (D,f) and analyze the correlations of these parameters with prognostic indicators (ER, PR, and HER2, Ki-67 index, axillary lymph node (ALN) and tumor size) to improve the diagnostic and prognostic efficiency in breast cancer. MethodsThis is a prospective study. We performed T1WI, T2WI, IVIM, DCE-MRI at 3 T MRI examinations on benign and malignant breast lesions that met the inclusion criteria. We also collected pathological results of corresponding lesions, including ER, PR, and HER2, Ki-67 index, axillary lymph node (ALN) and tumor size. The diagnostic efficacy of DCE-MRI, IVIM imaging, and their combination for benign and malignant breast lesions was assessed. Correlations between the DCE-MRI and IVIM parameters and prognostic indicators were assessed. ResultsOverall,59 female patients with 62 lesions (22 benign lesions and 40 malignant lesions) were included in this study. The malignant group showed significantly lower D values (p < 0.05) and significantly higher Ktrans, Kep, and f values (p < 0.05). The AUC values of DCE, IVIM, DCE + IVIM were 0.828, 0.882, 0.901. Ktrans, Kep, D and f values were correlated with the pathological grade (p < 0.05); Ktrans was negatively correlated with ER expression (r = −0.519, p < 0.05); Kep was correlated with PR expression and the Ki-67 index (r = −0.489, 0.330, p < 0.05); the DCE and IVIM parameters showed no significant correlations with the HER2 and ALN (p > 0.05). Tumor diameter was correlated with the Kep, D and f values (r = 0.246, −0.278, 0.293; p < 0.05). ConclusionIVIM and DCE-MRI allowed differential diagnosis of benign and malignant breast lesions, and their combination showed significantly better diagnostic efficiency. DCE- and IVIM-derived parameters showed correlations with some prognostic factors for breast cancer.

Time-varying effect in older patients with early-stage breast cancer: a model considering the competing risks based on a time scale.

Patients with early-stage breast cancer may have a higher risk of dying from other diseases, making a competing risks model more appropriate. Considering subdistribution hazard ratio, which is used often, limited to model assumptions and clinical interpretation, we aimed to quantify the effects of prognostic factors by an absolute indicator, the difference in restricted mean time lost (RMTL), which is more intuitive. Additionally, prognostic factors of breast cancer may have dynamic effects (time-varying effects) in long-term follow-up. However, existing competing risks regression models only provide a static view of covariate effects, leading to a distorted assessment of the prognostic factor. To address this issue, we proposed a dynamic effect RMTL regression that can explore the between-group cumulative difference in mean life lost over a period of time and obtain the real-time effect by the speed of accumulation, as well as personalized predictions on a time scale. A simulation validated the accuracy of the coefficient estimates in the proposed regression. Applying this model to an older early-stage breast cancer cohort, it was found that 1) the protective effects of positive estrogen receptor and chemotherapy decreased over time; 2) the protective effect of breast-conserving surgery increased over time; and 3) the deleterious effects of stage T2, stage N2, and histologic grade II cancer increased over time. Moreover, from the view of prediction, the mean C-index in external validation reached 0.78. Dynamic effect RMTL regression can analyze both dynamic cumulative effects and real-time effects of covariates, providing a more comprehensive prognosis and better prediction when competing risks exist.

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.

Effect of breast cancer prognostic factors on ovarian reserve and response in fertility preservation

Research questionDo breast cancer prognostic factors influence ovarian reserve and response to ovarian stimulation in the context of fertility preservation? DesignObservational, bicentric retrospective study of 352 women with breast cancer who underwent ovarian stimulation using a random start gonadotrophin releasing hormone antagonist protocol and vitrified oocytes between November 2015 and August 2022. Serum anti-Müllerian hormone (AMH) levels and antral follicle count (AFC) were measured. The number of oocytes recovered, maturation rate and follicular output rate (FORT) were analysed according to patients’ characteristics and breast cancer prognostic factors. ResultsMedian age was 34 years (31.1–37.1). Median AFC and serum AMH level were 17 (12–26) follicles and 2 (1.2–3.4) ng/ml, respectively. After ovarian stimulation, 10.5 (6.0–16.0) oocytes were recovered, with eight (4–13) being mature. Mean oocyte maturation rate was 79% (62–92). Antral follicle count (>12) significantly affected the risk of recovering fewer than eight mature oocytes (P < 0.0001, multivariate analysis). Follicular responsiveness to FSH, assessed by the follicular output rate (FORT index) and number of oocytes recovered, were 31% (21–50) and 10.5% (6.0–16.0), respectively. FORT index and ovarian stimulation outcomes were not influenced by breast cancer prognostic factors. ConclusionBreast cancer prognostic factors do not influence ovarian reserve markers or response to ovarian stimulation in fertility preservation. Therefore, tumour grade, triple-negative status, HER2 overexpression and high Ki67 should not alter the fertility-preservation strategy when considering ovarian stimulation for oocyte vitrification.