Early-stage Breast Cancer Research Articles

Image-Guided Breast Conserving Surgery

Background: Breast-conserving surgery (BCS) has gained wide acceptance as the treatment of choice for early-stage breast cancer. One of the primary goals of BCS is to obtain tumor-free resection margins. In practice, the excision of a palpable breast carcinoma is guided by preoperative diagnostic images and the intraoperative tactile skills of the surgeon. The somewhat ‘blind’ approach of using palpation-guided surgery is known to be highly inaccurate, with studies worldwide reporting positive resection margins in up to 41% of patients. In recent years, ultrasonography has emerged as an effective guidance tool during surgery and ultrasound-guided surgery has been introduced into breast cancer surgery as a method of excising nonpalpable breast cancer. Objective: The aim of this study is comparing ultrasound-guided vs palpation-guided conservative breast surgery in obtaining tumor-free resection margins. Methods: This study was a prospective randomized controlled clinical trial where patients with early breast cancer (T1-T2) and eligible for breast conserving surgery are randomly assigned (1:1) into two arms. Arm A: included the patients who will undergo ultrasound-guided breast conserving surgery. Arm B: included the patients who will undergo the conventional palpation-guided breast conserving surgery. Results: Overall, 142 patients undergoing breast conserving surgery were enrolled: 71 were allocated to the Ultrasound-guided (US) group (Arm A) and 71 to the Palpation-guided (PG) group (Arm B). Patient and tumor characteristics were comparable between the two groups. Age, Body mass index, tumor laterality, tumor location and tumor stage were comparable in both groups and statistically insignificant. Despite that the final tumor size was comparable between both groups, IOUS significantly reduced the main specimen volume and the least negative margin width (p<0.001). The median operative time was significantly longer in the US group bey around 27 min than in the PG group and this was statistically significant in favor of the PG surgery (p<0.001). The involved resection margin rate was significantly higher in the PG group and thus the need for reoperation (p<0.001). Conclusion: IOUS is the only method allowing a true real-time visualization and continuous control of resection margins during all phases of BCS. In our single-institution study, IOUS demonstrated clear superiority over palpation-guided surgery in both oncological and surgical outcomes except for the operative time (smaller excision volume yet, with optimum resection margins). IOUs provides much better tumor localization in small breasts with dense fibroadenosis. Since all the other available localization techniques (including palpation) limit the surgeon’s visual guidance during BCS, IOUS could be regarded as one of the most significant modern technological innovations in the field of breast cancer surgery, restoring sight to the breast surgeon. Our findings strongly suggests that the integration of IOUS in breast conserving surgery could be regarded as a highly beneficial surgical approach.

Role function in postmenopausal women during aromatase inhibitor therapy for breast cancer.

Few studies have examined aromatase inhibitor therapy relating to role function in breast cancer survivors of working age. Our study sought to identify how pre-therapy sociodemographic and health/treatment-related characteristics, as well as patient-reported symptoms measured every six-months, influence role function during 18months of AI therapy for early-stage breast cancer. We performed a secondary analysis of longitudinal study data using linear mixed-effects modeling to examine role physical (RP) and role emotional (RE) functioning measured with the Medical Outcome Study Short Form 36 v2. The sample of postmenopausal women (N = 351) consisted of three cohorts: chemotherapy followed by anastrozole (CFAI), anastrozole only (AI only), and non-cancer controls. Our choice of variables and interpretation of findings was theoretically based on the Cancer Survivorship and Work Model. Stepwise backward deletion determined which predictors to include in the final model, accounting for treatment group. Both treatment groups were associated with greater limitations in RP functioning than controls. CFAI had twice the impact on RP compared to AI only. While the RP model displayed significant predictors across sociodemographic, health/treatment, and symptom characteristics, only symptoms were associated with greater limitations in RE functioning. Findings were significant at p < .05. Transitioning from acute to extended survivorship is a critical juncture in which multiple factors place breast cancer survivors at risk of diminished role function. Early interventions to address role function limitations during systemic treatment may lead to better work outcomes and improve the quality of long-term survivorship.

Serum metabolite and metal ions profiles for breast cancer screening

Enhancing early-stage breast cancer detection requires integrating additional screening methods with current diagnostic imaging. Omics screening, using easily collectible serum samples, could serve as an initial step. Alongside biomarker identification capabilities, omics analysis allows for a comprehensive analysis of prevalent histological types—DCIS and IDC. Employing metabolomics, metallomics, and machine learning, could yield accurate screening models with valuable insights into organism responses. Serum samples of confirmed breast cancer patients were utilized to analyze metabolite and metal ion profiles, using two distinct analysis methods, proton NMR for metabolomics and ICP-OES for metallomics. The resulting responses were then subjected to discriminant analysis, progression biomarker exploration, examination of correlations between patients’ metabolites and metal ions, and the impact of age and menopause status. Measured NMR spectra and metabolite relative integrals were used to achieve statistically significant discrimination through MVA between breast cancer and control groups. The analysis identified 24 metabolites and 4 metal ions crucial for discrimination. Furthermore, four metabolites were associated with disease progression. Additionally, there were important correlations and relationships between metabolite relative integrals, metal ion concentrations, and age/menopausal status subgroups. Quantified relative integrals allowed for discrimination between studied subgroups, validated with a holdout set. Feature importance and statistical analysis for metabolomics and metallomics extracted a set of common entities which in combination provides valuable insights into ongoing molecular disturbances and disease progression.

Local recurrence and residual tumor rates following cryoablation for small early-stage breast cancers: systemic review and meta-analysis.

Cryoablation is currently being investigated as a minimally invasive alternative to breast-conserving surgery. This meta-analysis investigates the local recurrence and residual tumor rates after cryoablation for small early-stage breast cancers. A systematic search was conducted on Embase, PubMed, Google Scholar, and the International Clinical Trials Registry Platform from inception to 16 June 2024. Studies of patients with breast cancers ≤ 20mm treated with cryoablation only or cryoablation followed by surgery were included. Pooled local recurrence rates (cryoablation only) and pooled residual tumors rates (cryoablation followed by surgery) were estimated with mixed-effects models. Between-study heterogeneity was assessed using I2 statistics. Where I2 exceeded 50%, outlier and influence analysis, followed by sensitivity analysis excluding outliers, were conducted. Twelve studies met inclusion criteria, of which 7 studies (530 female patients, 531 breast tumors) reported on patients treated with cryoablation only and 5 studies (220 female patients, 222 breast tumors) reported on patients treated with cryoablation followed by surgery. For studies on cryoablation only, pooled local recurrence rate was 1.1% (95% CI 0.42-3.03%) with low between-study heterogeneity (I2 value = 0%; 95% CI 0.0-70.8%; p = 0.95). For studies on cryoablation followed by surgery, pooled residual tumor rate was 12.0% (95% CI 3.85-31.64%); however, substantial between-study heterogeneity (I2 value = 76.1%; 95% CI 41.7-90.2%; p < 0.01) was present. Influence analysis revealed 1 outlier study. When this study was excluded, pooled residual tumor rate was 8.2% (95% CI 3.84-16.68%) with improvement in heterogeneity (I2 value = 0%; 95% CI 0.0-84.7%; p = 0.64). Pooled local recurrence and residual tumor rates after cryoablation are comparable to local recurrence rates after breast-conserving therapy and re-excision rates following breast-conserving surgery, respectively. These results are encouraging but should be interpreted with caution due to lack of comparative studies.

AI Survival Prediction Modeling: The Importance of Considering Treatments and Changes in Health Status over Time

Background and objectives: Deep learning (DL)-based models for predicting the survival of patients with local stages of breast cancer only use time-fixed covariates, i.e., patient and cancer data at the time of diagnosis. These predictions are inherently error-prone because they do not consider time-varying events that occur after initial diagnosis. Our objective is to improve the predictive modeling of survival of patients with localized breast cancer to consider both time-fixed and time-varying events; thus, we take into account the progression of a patient’s health status over time. Methods: We extended four DL-based predictive survival models (DeepSurv, DeepHit, Nnet-survival, and Cox-Time) that deal with right-censored time-to-event data to consider not only a patient’s time-fixed covariates (patient and cancer data at diagnosis) but also a patient’s time-varying covariates (e.g., treatments, comorbidities, progressive age, frailty index, adverse events from treatment). We utilized, as our study data, the SEER-Medicare linked dataset from 1991 to 2016 to study a population of women diagnosed with stage I–III breast cancer (BC) enrolled in Medicare at 65 years or older as qualified by age. We delineated time-fixed variables recorded at the time of diagnosis, including age, race, marital status, breast cancer stage, tumor grade, laterality, estrogen receptor (ER), progesterone receptor (PR), and human epidermal receptor 2 (HER2) status, and comorbidity index. We analyzed six distinct prognostic categories, cancer stages I–III BC, and each stage’s ER/PR+ or ER/PR− status. At each visit, we delineated the time-varying covariates of administered treatments, induced adverse events, comorbidity index, and age. We predicted the survival of three hypothetical patients to demonstrate the model’s utility. Main Outcomes and Measures: The primary outcomes of the modeling were the measures of the model’s prediction error, as measured by the concordance index, the most commonly applied evaluation metric in survival analysis, and the integrated Brier score, a metric of the model’s discrimination and calibration. Results: The proposed extended patients’ covariates that include both time-fixed and time-varying covariates significantly improved the deep learning models’ prediction error and the discrimination and calibration of a model’s estimates. The prediction of the four DL models using time-fixed covariates in six different prognostic categories all resulted in approximately a 30% error in all six categories. When applying the proposed extension to include time-varying covariates, the accuracy of all four predictive models improved significantly, with the error decreasing to approximately 10%. The models’ predictive accuracy was independent of the differing published survival predictions from time-fixed covariates in the six prognostic categories. We demonstrate the utility of the model in three hypothetical patients with unique patient, cancer, and treatment variables. The model predicted survival based on the patient’s individual time-fixed and time-varying features, which varied considerably from Social Security age-based, and stage and race-based breast cancer survival predictions. Conclusions: The predictive modeling of the survival of patients with early-stage breast cancer using DL models has a prediction error of around 30% when considering only time-fixed covariates at the time of diagnosis and decreases to values under 10% when time-varying covariates are added as input to the models, regardless of the prognostic category of the patient groups. These models can be used to predict individual patients’ survival probabilities based on their unique repertoire of time-fixed and time-varying features. They will provide guidance for patients and their caregivers to assist in decision making.

Autophagy is required for mammary tumor recurrence by promoting dormant tumor cell survival following therapy

BackgroundMortality from breast cancer is principally due to tumor recurrence. Recurrent breast cancers arise from the pool of residual tumor cells, termed minimal residual disease, that survive treatment and may exist in a dormant state for 20 years or more following treatment of the primary tumor. As recurrent breast cancer is typically incurable, understanding the mechanisms underlying dormant tumor cell survival is a critical priority in breast cancer research. The importance of this goal is further underscored by emerging evidence suggesting that targeting dormant residual tumor cells in early-stage breast cancer patients may be a means to prevent tumor recurrence and its associated mortality. In this regard, the role of autophagy in dormant tumor cell survival and recurrence remains unresolved, with conflicting reports of both pro-survival/recurrence-promoting and pro-death/recurrence-suppressing effects of autophagy inhibition in dormant tumor cells. Resolving this question has important clinical implications.MethodsWe used genetically engineered mouse models that faithfully recapitulate key features of human breast cancer progression, including minimal residual disease, tumor dormancy, and recurrence. We used genetic and pharmacological approaches to inhibit autophagy, including treatment with chloroquine, genetic knockdown of ATG5 or ATG7, or deletion of BECN and determined their effects on dormant tumor cell survival and recurrence.ResultsWe demonstrate that the survival and recurrence of dormant mammary tumor cells following therapy is dependent upon autophagy. We find that autophagy is induced in vivo following HER2 downregulation and remains activated in dormant residual tumor cells. Using genetic and pharmacological approaches we show that inhibiting autophagy by chloroquine administration, ATG5 or ATG7 knockdown, or deletion of a single allele of the tumor suppressor Beclin 1 is sufficient to inhibit mammary tumor recurrence, and that autophagy inhibition results in the death of dormant mammary tumor cells in vivo.ConclusionsOur findings demonstrate a pro-tumorigenic role for autophagy in tumor dormancy and recurrence following therapy, reveal that dormant tumor cells are uniquely reliant upon autophagy for their survival, and indicate that targeting dormant residual tumor cells by inhibiting autophagy impairs tumor recurrence. These studies identify a pharmacological target for a cellular state that is resistant to commonly used anti-neoplastic agents and suggest autophagy inhibition as an approach to reduce dormant minimal residual disease in order to prevent lethal tumor recurrence.

Retraction Note: Tumor microenvironment and immune system preservation in early-stage breast cancer: routes for early recurrence after mastectomy and treatment for lobular and ductal forms of disease

Retraction Note: Tumor microenvironment and immune system preservation in early-stage breast cancer: routes for early recurrence after mastectomy and treatment for lobular and ductal forms of disease

Characterization of EpCAM-Positive and EpCAM-Negative Tumor Cells in Early-Stage Breast Cancer.

Most studies on CTCs have focused on isolating cells that express EpCAM. In this study, we emphasize the presence of EpCAM-negative and EpCAMlow CTCs, in addition to EpCAMhigh CTCs, in early BC. We evaluated stem cell markers (CD44/CD24 and CD133) and EMT markers (N-cadherin) in each subpopulation. Our findings indicate that all stemness variants were present in both EpCAMhigh and EpCAM-negative CTCs, whereas only one variant of stemness (nonCD44+CD24-/CD133+) was observed among EpCAMlow CTCs. Nearly all EpCAMhigh CTCs were represented by CD133+ stem cells. Notably, the hybrid EMT phenotype was more prevalent among EpCAM-negative CTCs. scRNA-seq of isolated CTCs and primary tumor partially confirmed this pattern. Therefore, further investigation is imperative to elucidate the prognostic significance of EpCAM-negative and EpCAMlow CTCs.

The efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy versus endocrine therapy alone in the adjuvant treatment of patients with high-risk invasive HR+/HER2-early breast cancer: A comprehensive updated meta-analysis of randomized clinical trials

BackgroundThis paper aimed to evaluate the effectiveness of incorporating CDK 4/6 inhibitors (CDK4/6i) into ET for the adjuvant treatment of HR + HER2-resected early-stage breast cancer (ESBC) patients, employing meta-analysis. MethodsIn this paper, we compiled randomized clinical trials focusing on CDK4/6i used in the adjuvant treatment of high-risk invasive HR-positive and HER2-ESBC patients. A meta-analysis was performed in line with the PRISMA guidelines. ResultsWe identified four clinical trials that met our inclusion criteria and were published between 2020 and 2024. These trials involved a combined sample size of 17,749 patients diagnosed with breast cancer. The data obtained from the pooled analysis revealed a remarkable beneficial trend in terms of invasive disease-free survival (iDFS) for the use of ET in combination with CDK4/6i compared to the group receiving ET alone (HR = 0.81, 95 % CI: 0.67–0.98, p = 0.03). Of note, CDK4/6 inhibitors demonstrated a notably beneficial effect in both grade 2 (HR = 0.69, 95 % CI: 0.59–0.81, p < 0.001) and grade 3 (HR = 0.76, 95 % CI: 0.65–0.89, p < 0.001). Significant improvements were noted in terms of distant relapse-free survival (dRFS) in the groups treated with abemaciclib and ribociclib (HR = 0.65, 95 % CI: 0.56–0.76, p < 0.001; HR = 0.72, 95 % CI: 0.58–0.89, p = 0.003, respectively). CDK4/6i didn't yield a statistically significant difference in overall survival (OS) (HR = 0.96, 95 % CI: 0.77–1.19, p = 0.69). The use of CDK4/6i with ET was associated with an increased risk of adverse events, particularly anemia and neutropenia, compared with ET alone (OR = 9.12, 95 % CI = 5.04–16.48, p < 0.001). ConclusionThe findings of this paper demonstrate a significant improvement in iDFS when ET is combined with CDK4/6i, compared to ET alone. Specifically, treatments with abemaciclib and ribociclib showed notable enhancements in dRFS.

Real-World Implications of the SOUND Trial.

The SOUND trial demonstrated that omission of sentinel lymph node biopsy (SLNB) is noninferior to axillary staging in patients with early-stage breast cancer (BC) and negative axillary ultrasound (AxUS). We examined the generalizability of these findings in patients with hormone receptor (HR)+HER2- disease. Patients with cT1N0M0, HR+HER2- BC and negative AxUS undergoing breast conservation with SLNB from 2016 to 2023 were identified from a prospectively maintained database. Clinicopathologic characteristics, disease burden, adjuvant treatment, and oncologic outcomes were examined and compared with the SLNB arm of the SOUND trial. In postmenopausal patients, the impact of nodal status and 21-gene recurrence score on chemotherapy recommendations were also examined. Of 3972 patients with cT1N0M0 HR+HER2- breast cancer, 544 underwent AxUS; 312 met SOUND eligibility criteria. Median age was 57 (interquartile range [IQR] 48-64) years, and 199 (63.8%) were postmenopausal. Median (IQR) tumor size was 1.3 (0.9-1.7) cm, and 260 (83.3%) tumors were grade 1 or 2. Sentinel lymph node biopsy was positive in 38 (12.2%) patients. Only three (0.4%) had ≥ 4 positive lymph nodes. At a median follow-up of 26.2 (IQR 10.8-38.2) months, there were no axillary recurrences and one (0.3%) distant recurrence. Among postmenopausal women with recurrence score ≤ 25, chemotherapy recommendations were not associated with nodal status. Examination of our real-world HR+ HER2- "SOUND-eligible" population suggests that nodal disease burden and oncologic outcomes are similar to the SOUND trial population, supporting careful implementation of trial results into multidisciplinary practice. In postmenopausal patients, omission of SLNB does not appear to impact adjuvant chemotherapy recommendations.

Reductions in recurrence in women with early breast cancer entering clinical trials between 1990 and 2009: a pooled analysis of 155 746 women in 151 trials

Distant recurrence in women with oestrogen receptor-positive early breast cancer persists at a constant rate for more than 20 years after diagnosis, with little equivalent data for oestrogen receptor-negative breast cancer. Using the database of the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) we investigated rates of distant breast-cancer recurrence in oestrogen receptor-positive and oestrogen receptor-negative tumours and trends in outcomes over time. In this pooled analysis of randomised controlled trial data, patients in the EBCTCG database of more than 650 000 women in trials of treatment for early-stage breast cancer were screened for eligibility. Women were eligible if they were enrolled between 1990 and 2009 and newly diagnosed with oestrogen receptor-positive breast cancer and scheduled for at least 5 years of endocrine therapy, or oestrogen receptor-negative disease, and if they were younger than 75 years at diagnosis, had a tumour diameter of 50 mm or less, and fewer than ten positive axillary lymph nodes, and no evidence of distant metastases at entry. Trial of neoadjuvant therapy, or those in which adjuvant therapy was unclear, and women with oestrogen receptor-negative, progesterone receptor-positive disease, or those for whom outcome or baseline data were missing were excluded. The primary outcome was time to first distant recurrence as defined by each trial, ignoring any locoregional recurrence or contralateral breast cancer. 10-year risks of distant recurrence by period of diagnosis were compared using Cox regression adjusted for patient and tumour characteristics, trial, and assigned treatment. Of the 652 258 women with early breast cancer in the EBCTCG database on Jan 17, 2023, patient-level data were available from 151 randomised trials that included 155 746 women. Rates of distant tumour recurrence improved similarly in women with oestrogen receptor-positive and oestrogen receptor-negative tumours. 80·5% of the improvement for oestrogen receptor-positive disease and 89·8% of the improvement for eostrogen receptor-negative disease was explained by changes in patient and tumour characteristics and improved treatments, but remained significant (p<0·0001). More recently diagnosed patients were more likely to have node-negative disease. 10-year distant recurrence risks during 1990-99 versus 2000-09 were as follows: for node-negative disease, 10·1% versus 7·3% for oestrogen receptor-positive disease and 18·3% versus 11·9% for oestrogen receptor-negative disease; for disease with one to three positive nodes, 19·9% versus 14·7% for oestrogen receptor-positive disease and 31·9% versus 22·1% for oestrogen receptor-negative disease; and for disease with four to nine positive nodes, 39·6% versus 28·5% for oestrogen receptor-positive disease and 47·8% versus 36·5% for oestrogen receptor-negative disease. After adjustment for therapy, rates were reduced by 25% (oestrogen receptor-positive disease) and 19% (oestrogen receptor-negative disease) after 2000 versus the 1990s, with similar improvements observed in oestrogen receptor-positive disease beyond 5 years. Most of the improvement in trial outcomes is explained by a greater proportion of women with lower-risk disease entering trials and improved adjuvant treatment. After adjustment, women diagnosed since 2000 have about a fifth lower rate of distant recurrence than the 1990s. Long-term risks of distant recurrence for oestrogen receptor-positive disease remain, but are about a tenth lower now than in our previous report. Cancer Research UK, UK Medical Research Council.

Discerning the impact of ctDNA detection on patient decision-making in early-stage breast cancer

The impact of knowledge of circulating tumor DNA (ctDNA) status on patient decisions in high-risk triple-negative breast cancer (TNBC) weighing benefit and toxicity is unknown. Here, 286 women with a history of non-metastatic breast cancer who had received chemotherapy completed a survey mimicking scenarios of residual TNBC after chemotherapy and unknown, negative, or positive ctDNA status to determine the shift in the decision to receive adjuvant therapy. Participants were then presented scenarios mimicking possible post-neoadjuvant therapies and rated acceptability. A general linear model with repeated measures determined contributions of risk reduction and toxicity. When the hypothetical risk of recurrence mimicked ctDNA negativity, significantly less participants were accepting of adjuvant capecitabine versus no therapy. When presented with ctDNA positivity and increased recurrence risk, the degree of benefit impacted acceptability more than the toxicity profile. As genomic technology advances and ctDNA assays become commercially available, it is imperative to understand the impact on patient decision-making.

Comparative long-term oncological outcomes of intraoperative radiotherapy vs. whole-breast irradiation in early breast cancer: a single institute study.

Intraoperative radiation therapy (IORT) and whole breast irradiation (WBI) are both effective adjuvant radiotherapy methods for ductal carcinoma in situ (DCIS) or early-stage breast cancer (BC) patients undergoing breast-conserving surgery (BCS). We aim to evaluate the long-term oncological efficacy and refine patient selection criteria based on our findings. Female patients who underwent either IORT or WBI from January 2016 to December 2019, with a minimum follow-up of 12 months were collected. IORT was administered as a single fraction of 20 Gray (Gy) to the lumpectomy cavity using the Axxent electronic brachytherapy system, while WBI consisted of a standard fractionation of 50 Gy in 25 fractions, along with a reduced boost of 10 Gy. The clinicopathologic characteristics and oncological outcomes were retrospectively analyzed. A total of 247 patients were enrolled, comprising 164 with BC and 83 with DCIS. Among them, 112 underwent IORT, and 135 received WBI after BCS. The median age was 62.2 years, with median tumor sizes of 1.5cm for BC and 1.2cm for DCIS. At a median follow-up of 64.6 months, IORT demonstrated 11 locoregional recurrences (LRR), 1 metastasis, and 1 death, compared to 4 LRR, 5 metastases, and 2 deaths in the WBI group. WBI yielded significantly higher locoregional control (97.0% vs. 90.2%, p = 0.033), although metastasis-free (96.3% vs. 99.1%, p = 0.166) and overall survival rates (98.4% vs. 99%, p = 0.688) did not differ. The LRR rate was significantly higher in the IORT group among the DCIS or BC patients (p = 0.043). The hazard ratio for locoregional recurrence significantly increased in estrogen-receptor-negative (ER-) patients in both univariate analysis (HR = 4.98, 95% CI = 1.76-14.09, p = 0.002) and multivariate analysis (HR = 40.88, 95% CI = 1.29-1297.84, p = 0.035). Additionally, IORT was associated with increased LRR in the multivariate analysis (HR = 4.71, 95% CI = 1.16-19.06, p = 0.030). At a long-term follow-up, the LRR rate was higher in the BCS followed by IORT, without significant differences in metastasis-free or overall survival rates. Our data confirmed the importance of exclusion ER- patients for IORT.

Tumour cell-released autophagosomes promote lung metastasis by upregulating PD-L1 expression in pulmonary vascular endothelial cells in breast cancer.

Establishing an immunosuppressive premetastatic niche (PMN) in distant organs is crucial for breast cancer metastasis. Vascular endothelial cells (VECs) act as barriers to transendothelial cell migration. However, the immune functions of PMNs remain unclear. Tumour cell-released autophagosomes (TRAPs) are critical modulators of antitumour immune responses. Herein, we investigated the mechanism through which TRAPs modulate the immune function of pulmonary VECs in lung PMN in breast cancer. Immortalised mouse pulmonary microvascular endothelial cells were incubated with TRAPs in vitro. RNA sequencing, flow cytometry, and western blotting were employed to assess immunosuppressive function and mechanism. In vivo, TRAP-trained and autophagy-deficient tumour mice were used to detect immunosuppression, and high-mobility group box 1 (HMGB1)-deficient TRAP-trained and TLR4 knockout mice were utilised to investigate the underlying mechanisms of pulmonary VECs. Additionally, the efficacy of anti-programmed cell death ligand-1 (PD-L1) immunotherapy was evaluated in early tumour-bearing mice. HMGB1 on TRAPs surfaces stimulated VECs to upregulate PD-L1 via a TLR4-MyD88-p38/STAT3 signalling cascade that depended on the cytoskeletal movement of VECs. Importantly, PD-L1 on TRAP-induced VECs can inhibit T cell function, promote lung PMN immunosuppression, and result in more pronounced lung metastasis. Treatment with anti-PD-L1 reduces lung metastasis in early stage tumour-bearing mice. These findings revealed a novel role and mechanism of TRAP-induced immunosuppression of pulmonary VECs in lung PMN. TRAPs and their surface HMGB1 are important therapeutic targets for reversing immunosuppression, providing a new theoretical basis for the treatment of early stage breast cancer using an anti-PD-L1 antibody.

ASO Visual Abstract: Cryoablation without Excision for Early Stage Breast Cancer; ICE3 Trial 5-Year Follow-Up on Ipsilateral Breast Tumor Recurrence.

ASO Visual Abstract: Cryoablation without Excision for Early Stage Breast Cancer; ICE3 Trial 5-Year Follow-Up on Ipsilateral Breast Tumor Recurrence.

6550 National Statin Prescription Trends in Patients With Breast Cancer and Diabetes for Primary Cardiovascular Disease Prevention

Abstract Disclosure: A.B. Yang: None. G. Mhango: None. C. Kong: None. J.J. Lin: None. J.P. Wisnivesky: Consulting Fee; Self; Sanofi, Banook, PPD. Grant Recipient; Self; Sanofi, Regeneron Pharmaceuticals, Axella, Arnold Consultants. A. Leiter: None. Background: Cardiovascular disease (CVD) is the leading cause of death in older early-stage breast cancer (BC) survivors. Due to cardiotoxic BC treatments such as chemotherapy and radiation, patients with BC and diabetes (DM) are at increased risk of CVD. In patients with BC and DM, statins decrease CVD mortality. Since 2013, many clinical guidelines broadened statin indications for primary CVD prevention in patients with DM, making &amp;gt;85% of patients eligible. Little is known about statin prescription (Rx) patterns in older BC survivors with DM, a group at high risk of CVD. Hypothesis: We hypothesized that statin Rxs increased over time, but were less likely in BC survivors with more advanced locoregional BC and lower comorbidity burden. Methods: A population-based, retrospective cohort study was conducted using Surveillance, Epidemiology and End Results (SEER) cancer registry data linked to Medicare claims. We identified women with preexisting DM who were diagnosed with stage 0-III primary BC between 2008-17. We excluded patients with prior CVD who died &amp;lt;1 year after BC diagnosis. Statin Rx (atorvastatin, pravastatin, rosuvastatin, simvastatin, fluvastatin, lovastatin) was defined as ≥1 statin pharmacy claim &amp;lt;1 year after BC diagnosis. Comorbidity burden was assessed with a modified Charlson Comorbidity Index (CCI). We compared patient demographic and clinical characteristics by statin Rx status using the chi-square test. Using a multivariate logistic regression adjusting for age, race, CCI, BC stage, and diagnosis year, independent predictors of statin Rx were identified. Results: Of 8,423 BC patients with pre-existing DM, 5,698 (68%) had a statin Rx. Statin Rx increased over time (BC diagnosis year 2008-10: 66%, 2011-13: 66%, 2014-15: 69%, 2016-17: 70%; p=0.01) and differed by age (66-69: 66%, 70-74: 70%, 75-79: 69%, ≥80: 65%; p&amp;lt;0.01) and race (White: 68%, Black: 62%, Latinx: 66%, Other: 72%; p&amp;lt;0.01). Statin Rx did not differ by comorbidity burden (CCI 0: 68%, 1-2: 67%, ≥3: 67%; p=0.87) and declined with higher BC stage (0: 73%, I: 70%, II: 65%, III: 63%; p&amp;lt;0.01). In adjusted analyses, more recent BC diagnosis (2016-17 vs. 2008-10: odds ratio [OR]: 1.19, 95% confidence interval [CI]: 1.04-1.38), age group (70-74 vs. 66-69: OR: 1.24, 95% CI: 1.09-1.41), race (Black vs. White: OR 0.77, 95% CI: 0.66-0.89) and higher BC stages (II vs. 0: OR: 0.76, 95% CI: 0.58-1.00; III vs. 0: OR: 0.72, 95% CI: 0.54-0.97) remained predictors of statin Rx. Conclusions: In a nationally representative cohort analysis of older early-stage BC patients, statin Rx increased between 2008-17 and varied by age, race, and BC stage. Elucidating gaps in statin Rx can potentially improve guideline-concordant Rx in a group at high risk for CVD and reduce disparities. Presentation: 6/2/2024

6931 Weight Trends and Predictors of Weight Gain in Breast Cancer Survivors

Abstract Disclosure: M.D. Hurtado: None. E. Tama: None. D. Hodge: None. A. Weston: None. S. Fahad: None. K. Ruddy: None. J. Olson: None. F. Coach: None. R. Carter: None. S. D'Andre: None. A. Acosta: Consulting Fee; Self; Amgen Inc. Grant Recipient; Self; Vivus USA, Novo Nordisk. C. Shufelt: None. Background: Breast cancer (BC) is the most common cancer in women. Weight gain after treatment for early-stage BC is associated with a higher risk of recurrence. Excess adiposity is also a major risk factor for cardiovascular disease, the leading cause of non-BC related death in BC survivors. This study aimed to describe weight trends in a large cohort of BC survivors and to identify predictors of weight gain after BC diagnosis. Methods: This was a retrospective study of BC survivors from the prospectively consented Mayo Clinic Breast Cancer Registry, which has enrolled &amp;gt;10,000 patients seen at least once at Mayo Clinic Rochester for a BC diagnosed within the prior year. We extracted data on weights at baseline, and years 1, 4, and 6 after BC diagnosis to generate longitudinal weight trajectory curves on the change from baseline. Weights were either reported by patients in the registry questionnaires or extracted from the electronic health records. We identified BC survivors with weight gain &amp;gt;10% from baseline weight at years 1, 4, and 6. We then conducted univariable logistic regression analyses to identify predictors of &amp;gt;10% weight gain. Variables considered included: demographics, anthropometrics, BC clinical and pathologic characteristics, BRCA 1 and 2 genetic mutation status, and treatment (surgery, neoadjuvant or adjuvant chemotherapy, and/or radiotherapy). Results: We included 4744 BC survivors, mostly white (95%) and non-Hispanic (91%), with a mean age and weight at BC diagnosis of 58 ± 13 years and 76 ± 18 kg. Most patients had clinical stage I (43%) and ER+ and PR+ BC (83% and 76%, respectively). Most patients underwent breast preserving surgery (62%), half received radiation (54%), one third (36%) received systemic chemotherapy, and two thirds (61%) received endocrine therapy. At one year after BC diagnosis the average weight change was negligible compared to baseline (mean difference -0.2 ± 8 kg), but there were small but significant average increases by years 4 and 6 (0.5 ± 9 kg, p=0.002; and 0.8 ± 10 kg, p&amp;lt;0.001; respectively). At years 1, 4, and 6, the percentage of BC survivors gaining &amp;gt;10% of their baseline weight was 10%, 15%, and 18%, respectively. Baseline characteristics associated with &amp;gt;10% weight gain at 6 years included lower baseline weight (p&amp;lt;0.001), younger age at BC diagnosis (p&amp;lt;0.001), more advanced clinical and pathologic BC stage (p=0.008), ER+ and PR+ tumor biology (p=0.02 for both), BRCA2 mutation (p&amp;lt;0.001), mastectomy (compared to breast preserving surgeries, p=0.008), the use of systemic chemotherapy treatment (p&amp;lt;0.001), and the use of endocrine therapy (p=0.03). Conclusion: While most BC survivors do not experience weight gain after survivorship, 1 out 5 may experience excessive weight gain of more than 10%. Baseline anthropometric and BC-related variables are associated with excessive weight gain and could be used as predictors of weight gain in this population. Presentation: 6/3/2024

Single-cell transcriptome analysis reveals immune microenvironment changes and insights into the transition from DCIS to IDC with associated prognostic genes

BackgroundDuctal carcinoma in situ (DCIS) of the breast is an early stage of breast cancer, and preventing its progression to invasive ductal carcinoma (IDC) is crucial for the early detection and treatment of breast cancer. Although single-cell transcriptome analysis technology has been widely used in breast cancer research, the biological mechanisms underlying the transition from DCIS to IDC remain poorly understood.ResultsWe identified eight cell types through cell annotation, finding significant differences in T cell proportions between DCIS and IDC. Using this as a basis, we performed pseudotime analysis on T cell subpopulations, revealing that differentially expressed genes primarily regulate immune cell migration and modulation. By intersecting WGCNA results of T cells highly correlated with the subtypes and the differentially expressed genes, we identified six key genes: FGFBP2, GNLY, KLRD1, TYROBP, PRF1, and NKG7. Excluding PRF1, the other five genes were significantly associated with overall survival in breast cancer, highlighting their potential as prognostic biomarkers.ConclusionsWe identified immune cells that may play a role in the progression from DCIS to IDC and uncovered five key genes that can serve as prognostic markers for breast cancer. These findings provide insights into the mechanisms underlying the transition from DCIS to IDC, offering valuable perspectives for future research. Additionally, our results contribute to a better understanding of the biological processes involved in breast cancer progression.

Real world clinical outcomes from targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy for breast cancer: data from a large cohort at a national cancer institute.

Randomised evidence supports the use of partial breast irradiation (PBI) with targeted intraoperative radiotherapy (TARGIT-IORT) for early stage breast cancer, but prospective data from real-world adoption of this technique is also important. The aim of this study was to determine if the outcome reported in TARGIT-A trial could be replicated in large cohort of early stage breast cancer treated with TARGIT-IORT. This prospective observational study analysed all patients treated with TARGIT-IORT between 2004 and 2021 in a single national cancer institute. TARGIT-IORT during lumpectomy was performed according to the risk-adapted TARGIT-A protocol using the Intrabeam® device. We analysed the completeness of follow up, 5-year in-breast-tumour-recurrence (IBTR), long term local recurrence free survival, distant disease-free survival, overall survival and breast-cancer-related survival, using the Kaplan-Meier method. A covariate analysis was performed to investigate risk factors for IBTR. We also analysed high grade toxicity events. The study included 814 patients and the a median follow up was 72 months. The majority of patients (60.3%) received TARGIT-IORT as PBI modality ("exclusive IORT" group); 39.7% received additional EBRT. There was no significant difference between the 5 years IBTR for the whole study population and the "exclusive IORT" cohort (1.6% (95%CI=1.1-2.1%) and 2.5% (95%CI=1.7%-3.3%) respectively). 5 years overall survival and tumour related survival were >95%. In 21% of patients with recurrence, breast was preserved. Radiotherapy toxicity (CTCAE Grade>2) was very rare (0.9%). This large single institute study found that breast cancer control and survival outcomes with TARGIT-IORT were consistent with TARGIT-A trial results. This "real world" experience confirmed that the randomised evidence showing the value of TARGIT-IORT as partial breast irradiation modality that can be replicated in routine clinical practice.

Neoadjuvant Pembrolizumab Plus Chemotherapy in Early-Stage Triple-Negative Breast Cancer: A Nationwide Retrospective Turkish Oncology Group Study

Background/Objectives: Following the results of the phase 3 KEYNOTE-522 trial, the U.S. Food and Drug Administration approved pembrolizumab, a humanized IgG4 kappa monoclonal antibody, in combination with neoadjuvant chemotherapy as a new standard of care for high-risk early-stage triple-negative breast cancer (TNBC). This retrospective, multicenter study in Türkiye assessed the real-world efficacy and safety of neoadjuvant pembrolizumab combined with chemotherapy in early-stage TNBC. Methods: The study included 108 patients treated between 2021 and 2023 across 14 oncology centers. Three distinct neoadjuvant regimens incorporating pembrolizumab were administered at the discretion of the treating physicians. The primary outcomes were the pathological complete response (pCR) rate after neoadjuvant therapy and the 2-year event-free survival (EFS) and overall survival (OS) rates. Results: The observed pCR rate was 63.9%, closely mirroring the 64.8% reported in the KEYNOTE-522 trial. At the two-year mark, the EFS rate was 87.2% and the OS rate was 92.3%. Multivariable analysis identified pCR as the sole independent predictor of both EFS and OS. The safety profile was consistent with previous clinical trial data, with most adverse events being of grade 1–2 in severity. Conclusions: These findings provide valuable real-world confirmation of the efficacy and safety of neoadjuvant pembrolizumab–chemotherapy in early-stage TNBC, complementing evidence from randomized trials.