Cohort Of Breast Cancer Patients Research Articles

Annotation-free deep learning algorithm trained on hematoxylin & eosin images predicts epithelial-to-mesenchymal transition phenotype and endocrine response in estrogen receptor-positive breast cancer

Recent evidence indicates that endocrine resistance in estrogen receptor-positive (ER+) breast cancer is closely correlated with phenotypic characteristics of epithelial-to-mesenchymal transition (EMT). Nonetheless, identifying tumor tissues with a mesenchymal phenotype remains challenging in clinical practice. In this study, we validated the correlation between EMT status and resistance to endocrine therapy in ER+ breast cancer from a transcriptomic perspective. To confirm the presence of morphological discrepancies in tumor tissues of ER+ breast cancer classified as epithelial- and mesenchymal-phenotypes according to EMT-related transcriptional features, we trained deep learning algorithms based on EfficientNetV2 architecture to assign the phenotypic status for each patient utilizing hematoxylin & eosin (H&E)-stained slides from The Cancer Genome Atlas database. Our classifier model accurately identified the precise phenotypic status, achieving an area under the curve (AUC) of 0.886 at the tile-level and an AUC of 0.910 at the slide-level. Furthermore, we evaluated the efficacy of the classifier in predicting endocrine response using data from an independent ER+ breast cancer patient cohort. Our classifier achieved a predicting accuracy of 81.25%, and 88.7% slides labeled as endocrine resistant were predicted as the mesenchymal-phenotype, while 75.6% slides labeled as sensitive were predicted as the epithelial-phenotype. Our work introduces an H&E-based framework capable of accurately predicting EMT phenotype and endocrine response for ER+ breast cancer, demonstrating its potential for clinical application and benefit.

Optimized Synthetic Correlated Diffusion Imaging for Improving Breast Cancer Tumor Delineation.

Breast cancer is a significant cause of death from cancer in women globally, highlighting the need for improved diagnostic imaging to enhance patient outcomes. Accurate tumor identification is essential for diagnosis, treatment, and monitoring, emphasizing the importance of advanced imaging technologies that provide detailed views of tumor characteristics and disease. Recently, a new imaging modality named synthetic correlated diffusion imaging (CDIs) has been showing promise for enhanced prostate cancer delineation when compared to existing MRI imaging modalities. In this study, we explore the efficacy of optimizing the correlated diffusion imaging (CDI) protocol to tailor it for breast cancer tumor delineation. More specifically, we optimize the coefficients of the calibrated signal mixing function in the CDIs protocol that controls the contribution of different gradient pulse strengths and timings by maximizing the area under the receiver operating characteristic curve (AUC) across a breast cancer patient cohort. Experiments showed that the optimized CDIs can noticeably increase the delineation of breast cancer tumors by over 0.03 compared to the unoptimized form, as well as providing the highest AUC when compared with gold-standard modalities. These experimental results demonstrate the importance of optimizing the CDIs imaging protocol for specific cancer applications to yield the best diagnostic imaging performance.

TP53 missense allele predisposing to high risk of breast cancer but not pediatric cancers.

Pathogenic TP53 germline variants cause young-onset breast cancer and other cancers of the Li-Fraumeni syndrome (LFS) spectrum, but the clinical consequences of partial-loss-of function TP53 variants are incompletely understood. In the consecutive cohort of Palestinian breast cancer patients of the Middle East Breast Cancer Study (MEBCS), breast cancer risk among TP53 p. R181C heterozygotes was 50% by age 50 y and 81% by age 80 y. In contrast, prevalence of pediatric cancers in the MEBCS was similar among first degree relatives of TP53 p. R181C carriers (3/519 = 0.0058) and first degree relatives of MEBCS patients with no pathogenic germline variant in any known breast cancer gene (7/1082 = 0.0065; OR = 0.90, 95%CI [0.23,3.49], Fisher P = .90 (2-tailed)). This result suggests that in families harboring this TP53 allele, genetic testing in children is unwarranted, and screening children for LFS tumors is unnecessary. More generally, some TP53 missense alleles can predispose to very high risk of breast cancer without pleiotropic effects.

Recurrence patterns-analysis from a South Indian breast cancer patient cohort.

The current study analyzes the pattern of recurrence/relapse in breast cancer patients belonging to different receptor subtypes to help enhance therapeutic and surveillance methods. This is an observational prospective study of a cohort of 543 patients from South India. Associations between various factors and their significance in relapse were assessed by odds ratio (OR), Chi-square test, and two-sided P value. Relapse of cancer in all receptor subtypes was significantly associated with stage III (P = 0.0029). Of the 48 patients who had a relapse of cancer, 42% had relapsed at a distance recurrence (DR), 23% (P = 0.02) had loco/locoregional recurrence (LLR) and the rest had relapsed at distant and loco/locoregional sites. HER2+ (human epidermal growth factor receptor) (83%) and hormone receptor (HR+/HER2-) (77%) patients had higher DR rates with an OR of 2 (95% Confidence Interval, 0.6-6) and 0.47 (95% CI, 0.1-2.1), respectively compared to TNBC (triple-negative breast cancer) patients. TNBCs (80%) had higher LLR rates over HER2+ (50%) and HR+/HER2- (44%) with an OR of 2 (95% CI, 0.6-6) and 2.1 (95% CI, 0.47-9.3), respectively. Bones and lungs in HR+/HER2- patients, liver and lungs for HER2 + patients, and bones in TNBC patients were the preferred sites for metastasis. The number of metastatic sites followed the order, TNBCs > HER2+>HR+/HER2-. HR+/HER2- and HER+ patients were more associated with DRs and TNBC patients were associated with LLR. TNBC patients recurred at multiple sites compared to the other two subtypes. Overall, there seems to be a trend in the recurrence across receptor subtypes. Understanding this recurrence pattern will help in enhancing therapeutic and surveillance methods.

Blood-based tumor mutational burden impacts clinical outcomes of immune checkpoint inhibitor treated breast and prostate cancers

BackgroundBreast and prostate tumors are known to be less responsive to immune checkpoint inhibitors (ICIs). Tissue-based tumor mutation burden (tTMB) has emerged as a predictive biomarker of response to ICIs, including in these “cold tumors”. In clinical practice, when tTMB is not available, blood-based TMB score (bTMB) can be used to consider treatment with ICIs.MethodsThis retrospective, real-world study included a final cohort of metastatic breast and prostate cancer patients treated with an ICI following a liquid biopsy test. Multiple bTMB-High cut-offs were assessed. Clinical, genomic, and outcomes data were collected. We hypothesized that a cut-off of bTMB ≥10 mut/Mb is not a strong predictor of response to ICIs in this setting. The Guardant Health genomic database (GHGD) was then queried (N = 13,992) for associations of bTMB with genomic alterations.ResultsIn the clinical cohort (N = 48), ICI treatment is offered after a median of 3 (1–9) lines of treatment. The median bTMB is 16.4 (10–186) mut/Mb. The median time on ICI and PFS is 2.1 (0–1.7) and 3.1 months (95%CI, 1.6–4.6) respectively; no difference by MSI/MMR status (p = 0.152). Response rate among eligible patients (n = 36) is 16.7%; only N = 1/6 in bTMB <16 mut/Mb. High bMSI is associated with higher bTMB (correlation test, r = 0.66, p = 0.000). In the GHGD, patients with bTMB high have significantly more alterations than bTMB low and TP53, PIK3CA, ATM, ESR1, NF1, BRCA2, ARID1A, and APC were the most frequently altered genes.ConclusionsIn this study, the practice of offering an ICIs based on bTMB was uncommon and did not independently predict ICI benefits in patients with refractory, advanced breast and prostate cancers.

A commonly inherited human PCSK9 germline variant drives breast cancer metastasis via LRP1 receptor.

Identifying patients at risk for metastatic relapse is a critical medical need. We identified a common missense germline variant in proprotein convertase subtilisin/kexin type 9 (PCSK9) (rs562556, V474I) that is associated with reduced survival in multiple breast cancer patient cohorts. Genetic modeling of this gain-of-function single-nucleotide variant in mice revealed that it causally promotes breast cancer metastasis. Conversely, host PCSK9 deletion reduced metastatic colonization in multiple breast cancer models. Host PCSK9 promoted metastatic initiation events in lung and enhanced metastatic proliferative competence by targeting tumoral low-density lipoprotein receptor related protein 1 (LRP1) receptors, which repressed metastasis-promoting genes XAF1 and USP18. Antibody-mediated therapeutic inhibition of PCSK9 suppressed breast cancer metastasis in multiple models. In a large Swedish early-stage breast cancer cohort, rs562556 homozygotes had a 22% risk of distant metastatic relapse at 15 years, whereas non-homozygotes had a 2% risk. Our findings reveal that a commonly inherited genetic alteration governs breast cancer metastasis and predicts survival-uncovering a hereditary basis underlying breast cancer metastasis.

The effect of cancer and cancer treatment on attention control: evidence from anti-saccade performance.

Cancer and cancer treatment have been associated with cognitive changes in survivorship, with forgetfulness and distractibility reported years post-treatment. Deficits in attention control may explain these difficulties. We assessed breast cancer survivors using a primary measure of attention control, the saccade/antisaccade task, to assess the effects of diagnosis and treatment. Saccade performance was studied in a cohort of breast cancer patients at two time points, (1) after surgery before adjuvant treatment and (2) approximately 2years after enrollment, and compared to non-cancer controls. Saccade performance was assessed in a prosaccade task as well as in visually guided and unguided antisaccade tasks. We assessed the frequency of directional errors and saccadic reaction time. Survivors were more likely than controls to make directional errors in an unguided antisaccade task, with older survivors exhibiting the most significant difficulties following adjuvant treatment. Survivor and control performance were much more similar in a visually guided antisaccade task. These results indicate a main effect of cancer diagnosis on attention control, with greater deficits following treatment and in older survivors. Deficits in attention control may lead to greater difficulties in the initial learning of information, explaining reports of forgetfulness in survivors. These findings underscore the enduring impact of cancer and its treatment on attention control, particularly highlighting that older breast cancer survivors may experience more pronounced difficulties with inhibitory control in daily life. Antisaccade performance may provide a useful metric for quantifying this impact.

Worse Clinical and Survival Outcomes in Breast Cancer Patients Living in Puerto Rico Compared to Hispanics, Non-Hispanic Blacks, and Non-Hispanic Whites from Florida.

Herein, we report the characterization of four cohorts of breast cancer patients including (1) non-Hispanic Whites in Florida, (2) non-Hispanic Blacks in Florida, (3) Hispanics in Florida, and (4) Hispanics in Puerto Rico. Data from female breast cancer patients were collected from cancer registry (n = 9361) and self-reported patient questionnaires (n = 4324). Several statistical tests were applied to identify significant group differences. Breast cancer patients from Puerto Rico were least frequently employed and had the lowest rates of college education among the groups. They also reported more live births and less breastfeeding. Both Hispanic groups reported a higher fraction experiencing menstruation at age 11 or younger (Floridian Hispanics [38%] and Puerto Ricans [36%]) compared to non-Hispanic Whites (20%) and non-Hispanic Blacks (22%). Non-Hispanic Black and Puerto Rican women were significantly older at breast cancer diagnosis than their non-Hispanic White and Floridian Hispanic counterparts. The Puerto Rican and non-Hispanic Black groups more frequently had pathology stage T2 or higher primary breast tumors at diagnosis (non-Hispanic Whites [29%], non-Hispanic Blacks [39%], Floridian Hispanics [33%], Puerto Ricans [46%]). The Puerto Rican (73%, 95% CI [66, 82]) and non-Hispanic Black (79%, 95% CI [75, 84]) groups demonstrate reduced 5-year survival compared to non-Hispanic Whites (89%, 95% CI [86, 92]) and Floridian Hispanics (89%, 95% CI [86, 90]). These findings demonstrate that Puerto Rican breast cancer patients suffer significant breast cancer health disparities relative to non-Hispanic Whites and Hispanics from Florida similar to the disparities observed for non-Hispanic Blacks. Future work must seek to better understand and address these disparities.

Breast tumor microbiome regulates anti-tumor immunity and T cell-associated metabolites.

Breast cancer, the most common cancer type among women, was recently found to contain a specific tumor microbiome, but its impact on host biology remains unclear. CD8+ tumor-infiltrating lymphocytes (TILs) are pivotal effectors of anti-tumor immunity that influence cancer prognosis and response to therapy. This study aims to elucidate interactions between CD8+ TILs and the breast tumor microbiome and metabolites, as well as how the breast tumor microbiome may affect the tumor metabolome. We investigated the interplay among CD8+ TILs, the tumor microbiome, and the metabolome in a cohort of 46 breast cancer patients with mixed subtypes (Cohort A). We characterized the tumor metabolome by mass spectrometry and CD8+ TILs by immunohistochemistry. Microbiome composition and T cell gene transcript levels were obtained from data from our previous study, which utilized 16S rRNA gene sequencing and a targeted mRNA expression panel. To examine interactions between intratumoral Staphylococcus and specific breast cancer subtypes, we analyzed RNA sequencing data from an independent cohort of 370 breast cancer patients (Cohort B). We explored the functions of the tumor microbiome using mouse models of triple-negative breast cancer (TNBC). In tumors from Cohort A, the relative abundance of Staphylococcus positively correlated with the expression of T cell activation genes. The abundances of multiple metabolites exhibited significant correlations with CD8+ TILs, of which NADH, γ-glutamyltryptophan, and γ-glutamylglutamate displayed differential abundance in Staphylococcus-positive versus Staphylococcus-negative breast tumors. In a larger breast cancer cohort (Cohort B), we observed positive correlations between tumoral Staphylococcus and CD8+ TIL activity exclusively in TNBC. Preclinical experiments demonstrated that intratumoral administration of S. aureus, the predominant species of Staphylococcus in human breast tumors, resulted in a depletion of total NAD metabolites, and reduced the growth of TNBC tumors by activating CD8+ TILs. We identified specific metabolites and microbial taxa associated with CD8+ TILs, delineated interactions between the breast tumor microbiome and metabolome, and demonstrated that intratumoral Staphylococcus influences anti-tumor immunity and TIL-associated metabolites. These findings highlight the role of low-biomass microbes in tumor tissues and provide potential biomarkers and therapeutic agents for breast cancer immunotherapy that merit further investigation.

Validation of the HFA-ICOS risk assessment tool with real-world data from a prospective cohort of breast cancer patients in treatment with anthracyclines and trastuzumab

Abstract Background The increasing prevalence of cancer therapy-related cardiovascular toxicity (CTRCD) poses a significant challenge to patient management, necessitating accurate risk assessments. Previous methodologies have struggled with precise risk stratification, partly due to varying definitions of CTRCD and the specificity of cancer treatments. Purpose This study aimed to evaluate the assessment tool proposed by the Heart Failure Association and the International Cardio-Oncology Society (HFA-ICOS) in predicting the risk of CTRCD in patients undergoing anthracycline and trastuzumab treatment for breast cancer at a national reference center. Methods A prospective cohort study was conducted, encompassing 172 patients treated from January 2022 to July 2023. Patients were assessed at baseline, three months, and six months post-treatment initiation, with exclusion criteria including baseline left ventricular ejection fraction (LVEF) &amp;lt;50%, history of heart failure, and stage IV breast cancer. The study utilized the HFA-ICOS tool for risk stratification and CTRCD was defined with the current criteria of the European Society of Cardiology guideline. Descriptive statistics were calculated, and incidence rates and Cox proportional-hazards models were developed according to the risk category. Results In our study, 138 (80.2%) patients were classified as low risk, 23 (13.4%) as moderate risk and 11 (6.4%) as high risk. We identified 81 (47.1%) patients that developed CTRCD in follow-up. Descriptive characteristics can be found in Table 1. The global incidence rate for CTRCD in our cohort was of 2.4 new cases per 1000 person-days, however no differences in incidence rates were found when stratifying by risk category (Figure 1A). Moreover, patients with moderate to high risk according to the HFA-ICOS tool did not show a significantly increased hazard ratio for cardiotoxicity (HR 0.41, 95%CI 0.15-1.12, p=0.082 and HR 1.39, 95%CI 0.50-3.86, p=0.5, respectively) as shown in Figure 1B. Conclusion While the HFA-ICOS tool provides a structured framework for assessing cardiotoxicity risk, its predictive value in this cohort was limited. The findings underscore the complexity of cancer therapy-related cardiotoxicity and the need for enhanced, individualized risk assessment tools. Future research should focus on refining risk prediction models, incorporating broader clinical and genetic factors to improve patient outcomes in cardio-oncology.Table 1.Clinical CharacteristicsFigure 1.Incidence rates and Cox models

Echocardiographic variables may improve baseline risk prediction of cancer therapy related cardiac dysfunction

Abstract Background Baseline prediction of cancer therapy related cardiac dysfunction (CTRCD) in clinical practice is difficult, despite many known cancer and cardiovascular risk factors. Risk scores exist, including the HFA-ICOS score which is recommended by the 2022 European Society of Cardiology (ESC) Cardio-Oncology guidelines. Validation of such risk scores is required though, and identification of alternative risk factors that may improve risk prediction is needed. Purpose To assess the accuracy of the HFA-ICOS score for predicting CTRCD, and identify new risk factors with a focus on baseline echocardiography. Methods Echocardiograms and medical records were assessed for a cohort of breast cancer patients receiving trastuzumab or an anthracycline, who underwent serial echocardiographic monitoring. CTRCD was defined according to the 2022 ESC Cardio-Oncology guidelines. Baseline risk factors and echocardiography were compared between CTRCD and non-CTRCD groups, and the accuracy of the HFA-ICOS score in predicting CTRCD assessed. Results Data from 258 patients were analysed with CTRCD occurring in 23 (9%). 135 were low risk, 85 moderate-risk, 31 high-risk and 8 very high-risk according to the HFA-ICOS score with a trend of increasing rates of CTRCD with each risk category: 5%, 12%, 10%, 25%, respectively. The sensitivity and specificity of a combined moderate/high/very high-risk group was 70% and 54% (AUC 0.618, 95% CI 0.5-0.73). Only three individual baseline variables were associated with CTRCD in this cohort; ejection fraction 50-54%, (18% vs 2%, p=0.0027), borderline/abnormal average global longitudinal strain &amp;lt;-18, (43% vs 19%, p=0.04) and combination anthracycline plus trastuzumab, (45% vs 22%, p=0.0392). Left atrial volume index &amp;gt;34mL/m² was also higher in the CTRCD group (38% vs 23%) although not statistically significant. A simplified risk score using only these variables yielded a sensitivity and specificity of 74% and 53%, respectively (AUC 0.633, 95% CI 0.52-0.75). Conclusion Baseline prediction of CTRCD remains difficult in clinical practice. Although HFA-ICOS risk categories correlate with CTRCD diagnosis, the overall sensitivity is only moderate. Echocardiographic variables may further enhance risk prediction to enable development of targeted monitoring strategies.HFA-ICOS risk score categoriesROC curves

Assessing the long-term prognostic ability of the 70 gene expression signature MammaPrint in an Italian single-center prospective cohort study of early-stage intermediate-risk breast cancer patients

PurposeThe aim of this study was to assess the prognostic performance of the 70-gene signature, MammaPrint, in an Italian single-center prospective cohort of early-stage intermediate-risk breast cancer (BC) patients. MethodsA total of 195 eligible early BC cases were tested for genomic risk between 2006 and 2013. In this retrospective analysis, the association of genomic risk with distant metastasis-free survival (DMFS) and overall survival (OS) were assessed using Cox regression models, adjusting for clinical and pathological tumor characteristics. ResultsMammaPrint identified 118 (60.5 %) patients with genomically Low Risk tumors and 77 (39.5 %) patients with genomically High Risk tumors. Age, menopausal status, tumor size, receptor status, and nodal status were comparable between MammaPrint Risk categories. The median follow-up was 8.4 years for DMFS and 9.3 years for OS; 8-year follow-up was reported for both endpoints. The 8-year DMFS was 90.4 % (95 % CI 84.9–95.9) in patients with MammaPrint Low Risk tumors compared to 60.8 % (95 % CI 49.8–71.8) for patients with High Risk tumors. Patients with MammaPrint Low Risk tumors exhibited significantly superior 8-year OS (97.3 %; 95 % CI 94.4–100) compared with MammaPrint High Risk tumors (89.5 %; 95 % CI 82.6–96.4; p = 0.028). Multivariate analyses identified MammaPrint as significantly associated with 8-year DMFS and MammaPrint together with Progesterone Receptor positivity with 8-year OS. ConclusionThe prognostic performance of MammaPrint was demonstrated in early-stage clinically intermediate to high-risk BC patients. Moreover, patients with MammaPrint Low Risk tumors had good outcome regardless of treatment regimen, thus supporting personalized treatment choices.

Higher risk of recurrence in early-stage breast cancer patients with increased levels of ribosomal protein S6

PI3K/AKT/mTOR pathway is implicated in breast cancer progression and recurrence. The identification of PIK3CA and AKT1 mutations and loss of PTEN serve as selection criterion for targeted therapies involving selective inhibitors. However, they do not consistently align with pathway activation, and high-cost determinations limit their routine application. PI3K-downstream epigenetic regulatory mechanisms broaden the alterations that amplify pathway activity and, consequently, sensitivity to selective inhibitors. In this retrospective observational study, conducted within a cohort of early-stage breast cancer patients, we determined phosphorylated ribosomal protein S6 (pS6) at Ser240/244 by immunohistochemistry as an indicator of PI3K pathway activation. Log-Rank test and Cox proportional hazards regression were used to analyze the clinical relevance of pS6, alone and together with clinicopathological variables, regarding recurrence-free survival. ROC curves and the area under the curves were used to evaluate the calibration and discrimination properties of uni- and multivariate models. Our results show that a high percentage of pS6 positive tumor cells was associated with an unfavorable prognosis in a cohort of 129 hormone receptor positive/HER2 negative breast cancer patients (Hazard Ratio = 5.92; Log-Rank p = 9.5e-08; median follow-up = 53 months). When assessed in combination with lymph node status, the predictive capacity was higher compared to both univariate models individually. In conclusion, pS6 could represent a novel independent marker for predicting recurrence risk in luminal breast cancer.

Bi-level Graph Learning Unveils Prognosis-Relevant Tumor Microenvironment Patterns in Breast Multiplexed Digital Pathology.

The tumor microenvironment is widely recognized for its central role in driving cancer progression and influencing prognostic outcomes. There have been increasing efforts dedicated to characterizing this complex and heterogeneous environment, including developing potential prognostic tools by leveraging modern deep learning methods. However, the identification of generalizable data-driven biomarkers has been limited, in part due to the inability to interpret the complex, black-box predictions made by these models. In this study, we introduce a data-driven yet interpretable approach for identifying patterns of cell organizations in the tumor microenvironment that are associated with patient prognoses. Our methodology relies on the construction of a bi-level graph model: (i) a cellular graph, which models the intricate tumor microenvironment, and (ii) a population graph that captures inter-patient similarities, given their respective cellular graphs, by means of a soft Weisfeiler-Lehman subtree kernel. This systematic integration of information across different scales enables us to identify patient subgroups exhibiting unique prognoses while unveiling tumor microenvironment patterns that characterize them. We demonstrate our approach in a cohort of breast cancer patients and show that the identified tumor microenvironment patterns result in a risk stratification system that provides new complementary information with respect to standard stratification systems. Our results, which are validated in two independent cohorts, allow for new insights into the prognostic implications of the breast tumor microenvironment. This methodology could be applied to other cancer types more generally, providing insights into the cellular patterns of organization associated with different outcomes.

Likelihood adaptively incorporated external aggregate information with uncertainty for survival data.

Population-based cancer registry databases are critical resources to bridge the information gap that results from a lack of sufficient statistical power from primary cohort data with small to moderate sample size. Although comprehensive data associated with tumor biomarkers often remain either unavailable or inconsistently measured in these registry databases, aggregate survival information sourced from these repositories has been well documented and publicly accessible. An appealing option is to integrate the aggregate survival information from the registry data with the primary cohort to enhance the evaluation of treatment impacts or prediction of survival outcomes across distinct tumor subtypes. Nevertheless, for rare types of cancer, even the sample sizes of cancer registries remain modest. The variability linked to the aggregated statistics could be non-negligible compared with the sample variation of the primary cohort. In response, we propose an externally informed likelihood approach, which facilitates the linkage between the primary cohort and external aggregate data, with consideration of the variation from aggregate information. We establish the asymptotic properties of the estimators and evaluate the finite sample performance via simulation studies. Through the application of our proposed method, we integrate data from the cohort of inflammatory breast cancer (IBC) patients at the University of Texas MD Anderson Cancer Center with aggregate survival data from the National Cancer Data Base, enabling us to appraise the effect of tri-modality treatment on survival across various tumor subtypes of IBC.

Single Versus Separate Incisions in Oncoplastic Breast Surgery Techniques

Abstract Background Patient concerns with aesthetics have prompted the improvement of oncoplastic surgical approaches. It has been shown that the aesthetic success in breast malignancy surgical treatment leads enhanced sexual and social recovery. In this study a prospective comparison between cohorts of early-stage breast cancer patients treated with oncoplastic breast surgery. The first cohort will be treated with the single incision approach and the second cohort will be treated by the conventional breast conservative technique, which will be performed with double incision (one for the tumour resection and the other for the axillary dissection). Objective to compare between single incision &amp; separate incisions in approach to axillary lymph nodes in oncoplastic breast surgery. Patients and Methods This is a prospective cohort comparative study between single incision &amp; separate incisions in approach to axillary lymph nodes in oncoplastic breast surgery. This study will be conducted at breast surgery unit at Ain Shams University Hospitals and Maddi Military Complex starting from June 2022 to June 2023. Approval of the Ethical Committee and written informed consent from all participants will be obtained. Results There was significant no statistical difference in both group as regards the operative timing, seroma and the hospital stay but there is a statistical difference regarding hematoma between the two groups. In our study, 86.7% of the patients attained good to excellent cosmetic outcomes (70% as excellent and 26.7% as good) regarding single incision and 79.7% of the patients attained good to excellent cosmetic outcomes (65% as excellent and 26.7% as good) regarding separate incision. High cosmetic outcome was obtained as the patients were satisfied with presence and shape of their breasts relatively. Conclusion The choice of the oncoplastic technique is mainly based upon the location of the tumor, size of the breast and distance of the tumor from the nipple areola complex. So all cases should be adequately reviewed in order to tailor the decisions for every single case. There is statistically difference between Single incision in breast cancer lesion and separate incision as regards hematoma and the cosmetic outcome.

Immunohistochemical Evaluation of Cathepsin B, L, and S Expression in Breast Cancer Patients

PurposeCysteine cathepsins are proteases that play a role in normal cellular physiology and neoplastic transformation. Elevated expression and enzymatic activity of cathepsins in breast cancer (BCa) indicates their potential as a target for tumor imaging. In particular cathepsin B (CTSB), L (CTSL), and S (CTSS) are used as targets for near-infrared (NIR) fluorescence imaging (FI), a technique that allows real-time intraoperative tumor visualization and resection margin assessment. Therefore, this immunohistochemical study explores CTSB, CTSL, and CTSS expression levels in a large breast cancer patient cohort, to investigate in which BCa patients the use of cathepsin-targeted NIR FI may have added value.ProceduresProtein expression was analyzed in tumor tissue microarrays (TMA) of BCa patients using immunohistochemistry and quantified as a total immunostaining score (TIS), ranging from 0–12. In total, the tissues of 557 BCa patients were included in the TMA.ResultsCTSB, CTSL, and CTSS were successfully scored in respectively 340, 373 and 252 tumors. All tumors showed CTSB, CTSL, and/or CTSS expression to some extent (TIS > 0). CTSB, CTSL, and CTSS expression was scored as high (TIS > 6) in respectively 28%, 80%, and 18% of tumors. In 89% of the tumors scored for all three cathepsins, the expression level of one or more of these proteases was scored as high (TIS > 6). Tumors showed significantly higher cathepsin expression levels with advancing Bloom-Richardson grade (p < 0.05). Cathepsin expression was highest in estrogen receptor (ER)-negative, human epidermal growth factor receptor 2(HER2)-positive and triple-negative (TN) tumors. There was no significant difference in cathepsin expression between tumors that were treated with neoadjuvant systemic therapy and tumors that were not.ConclusionsThe expression of at least one of the cysteine cathepsins B, L and S in all breast tumor tissues tested suggests that cathepsin-activatable imaging agents with broad reactivity for these three proteases will likely be effective in the vast majority of breast cancer patients, regardless of molecular subtype and treatment status. Patients with high grade ER-negative, HER2-positive, or TN tumors might show higher imaging signals.

Blood Pressure and Cardiovascular Risk in Women With Breast Cancer: The Pathways Heart Study

BackgroundHypertension is an important contributor to cardiovascular disease (CVD) in breast cancer (BC) survivors; however, research on blood pressure (BP) and CVD outcomes in BC survivors is limited. ObjectivesThe purpose of this study was to better characterize the association between BP and CVD in a large, longitudinal cohort of BC patients. MethodsWomen with invasive BC diagnosed from 2005 to 2013 at Kaiser Permanente Northern California were matched 1:5 to women without BC. Patient data were obtained from electronic health records. Multivariable Cox regression and penalized spline models were used to explore the linear and nonlinear relationship of systolic blood pressure (SBP) and diastolic blood pressure (DBP) on CVD outcomes. ResultsBC cases (n = 12,713) and controls (n = 55,886) had median follow-up of 9.6 years (IQR: 5.0-11.9 years). Women with BC had a mean age of 60.6 years; 64.8% were non-Hispanic White. For ischemic heart disease (IHD), every 10 mmHg increase in SBP and DBP was associated with 1.23 (95% CI: 1.14-1.33) and 1.10 (95% CI: 0.98-1.24) risk, respectively, in women with BC. For stroke, every 10 mmHg increase in SBP and DBP was associated with a 1.45 (95% CI: 1.34-1.58) and 1.91 (95% CI: 1.68-2.18) risk, respectively. A U-shaped relationship was observed between heart failure/cardiomyopathy and BP. The associations between BP and risk of IHD, stroke, and any primary CVD were not statistically different comparing women with BC to controls, but risks varied by BC status for heart failure/cardiomyopathy (P for interaction = 0.01). ConclusionsWomen with and without BC showed similar risks for IHD, stroke, and any primary CVD suggesting similar BP targets should be pursued regardless of BC survivorship status.

The mevalonate pathway contributes to breast primary tumorigenesis and lung metastasis.

The mevalonate pathway plays an important role in breast cancer and other tumor types. However, many issues remain obscure as yet regarding its mechanism of regulation and action. In the present study, we report that the expression of mevalonate pathway enzymes is mediated by theRHO guanosine nucleotide exchange factors VAV2 and VAV3 in a RAC1- and sterol regulatory element-binding factor (SREBF)-dependent manner in breast cancer cells. Furthermore, in vivo tumorigenesis experiments indicated that the two most upstream steps of this metabolic pathway [3-hydroxy-3-methylglutaryl-coenzyme A synthase 1 (HMGCS1) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)] are important for primary tumorigenesis, angiogenesis, and cell survival in breast cancer cells. HMGCR, but not HMGCS1, is also important for the extravasation and subsequent fitness of breast cancer cells in the lung parenchyma. Genome-wide expression analyses revealed that HMGCR influences the expression of gene signatures linked to proliferation, metabolism, and immune responses. The HMGCR-regulated gene signature predicts long-term tumor recurrence but not metastasis in cohorts of nonsegregated and chemotherapy-resistant breast cancer patients. These results reveal a hitherto unknown, VAV-catalysis-dependent mechanism involved in the regulation of the mevalonate pathway in breast cancer cells. They also identify specific mevalonate-pathway-dependent processes that contribute to the malignant features of breast cancer cells.

Preoperative inter-arm differences and normative-based thresholds for lymphedema in Chinese breast cancer patients: Insights from a large cohort study

ObjectiveEarly detection and diagnosis of lymphedema are crucial for effective treatment and prevention of its progression. Normative-based diagnostic thresholds can enhance diagnostic accuracy in the absence of preoperative measurements. This study aimed to investigate preoperative inter-arm differences and the associated factors, as well as to determine normative-based thresholds for lymphedema in Chinese breast cancer patients. MethodsThis study utilized baseline data from a large cohort of Chinese breast cancer patients. Bilateral arm circumferences were measured at the wrist and at 10 cm intervals proximally up to 40 cm. Arm volumes were calculated using the truncated cone formula. Paired t test, repeated measures analysis of variance, and regression analysis were performed. ResultsA total of 1707 breast cancer patients were included. Paired t tests showed that the dominant arm circumferences and volumes were significantly larger than those of the nondominant arm (P < 0.001). Regression analysis and repeated measures analysis of variance revealed that hand dominance was the influencing factor of inter-arm differences (P < 0.05). Normative-based thresholds determined by two standard deviations above the mean inter-arm volume ratio were 1.057 for the dominant arm and 1.079 for the nondominant arm. ConclusionsThe absolute and relative normative-based thresholds for Chinese breast cancer patients differed slightly from the commonly used diagnostic criteria and those reported in Western populations and among Chinese healthy women. The normal variability and asymmetry associated with arm dominance underscore the importance of preoperative baseline assessments. Implementing normative-based diagnostic thresholds can facilitate more accurate lymphedema diagnosis when preoperative measurements are unavailable. Trial registrationRegistration No. ChiCTR2200057083.