Breast Cancer Research Articles

Secondary Transcriptomic Analysis of Triple-Negative Breast Cancer Reveals Reliable Universal and Subtype-Specific Mechanistic Markers

Background/Objectives: Breast cancer is diagnosed in 2.3 million women each year and kills 685,000 (~30% of patients) worldwide. The prognosis for many breast cancer subtypes has improved due to treatments targeting the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). In contrast, patients with triple-negative breast cancer (TNBC) tumors, which lack all three commonly targeted membrane markers, more frequently relapse and have lower survival rates due to a lack of tumor-selective TNBC treatments. We aim to investigate TNBC mechanistic markers that could be targeted for treatment. Methods: We performed a secondary TNBC analysis of 196 samples across 10 publicly available bulk RNA-sequencing studies to better understand the molecular mechanism(s) of disease and predict robust mechanistic markers that could be used to improve the mechanistic understanding of and diagnostic capabilities for TNBC. Results: Our analysis identified ~12,500 significant differentially expressed genes (FDR-adjusted p-value < 0.05), including KIF14 and ELMOD3, and two significantly modulated pathways. Additionally, our novel findings include highly accurate mechanistic markers identified using machine learning methods, including CIDEC (97.1% accuracy alone), CD300LG, ASPM, and RGS1 (98.9% combined accuracy), as well as TNBC subtype-differentiating mechanistic markers, including the targets PDE3B, CFD, IFNG, and ADM, which have associated therapeutics that can potentially be repurposed to improve treatment options. We then experimentally and computationally validated a subset of these findings. Conclusions: The results of our analyses can be used to better understand the mechanism(s) of disease and contribute to the development of improved diagnostics and/or treatments for TNBC.

Tumor NOS2 and COX2 Spatial Juxtaposition with CD8+ T Cells Promote Metastatic and Cancer Stem Cell Niches that Lead to Poor Outcome in ER- Breast Cancer.

Estrogen receptor-negative breast cancer is an aggressive subtype with limited therapeutic options. Elevated nitric oxide synthase (NOS2) and cyclo-oxygenase (COX2) mediates immunosuppression and poor survival in these tumors. Therefore, the influence of tumor NOS2/COX2 on immune architecture was examined in 16 African American and 5 Caucasian ER- tumors. Elevated tumor NOS2/COX2 limited CD8+ T cell infiltration at 5-yr survival. Distinct CD8+/-NOS2+/-COX2+/- phenotypes defining metastatic and cancer stem cell niches, and immune desert regions were identified. These results were supported by an unbiased, unsupervised nonlinear dimensionality-reduction UMAP technique incorporating spatial relations between cells and validated in a separate gene expression cohort using NOS2/CD8 and COX2/CD8 ratios. Additionally, elongated tumor cells were specifically in CD8-NOS2+COX2+ regions, suggesting metastatic hot spots. This work demonstrates predictive power of spatial analyses of CD8/NOS2/COX2 architecture and supports the use of clinically available NOS2/COX2 inhibitors for improved survival in patients with these aggressive tumors.

The Cancer Patient Empowerment Program: A Comprehensive Approach to Reducing Psychological Distress in Cancer Survivors, with Insights from a Mixed-Model Analysis, Including Implications for Breast Cancer Patients

Background/Objectives: Psychological distress is a significant concern among cancer patients, negatively affecting their quality of life and adherence to treatment. The Cancer Patient Empowerment Program (CancerPEP) was developed as a comprehensive, home-based intervention aimed at reducing psychological distress by incorporating physical activity, dietary guidance, and social support. This study aimed to evaluate the feasibility, accrual and attrition rates, safety, and effectiveness of the CancerPEP intervention, with and without the biofeedback device, on psychological distress from baseline to 6 months, specifically focusing on the effects of group randomization and the difference between pre- and post-intervention results. Methods: This single-site, crossover randomized clinical trial included 104 cancer patients who were randomized to receive the CancerPEP intervention, with or without a Heart Rate Variability (HRV) biofeedback monitor. At 6 months, participants who did not receive the device were allowed to use one until the end of the year, while those who did receive the device were followed up to 12 months. Randomization was stratified by the presence or absence of clinically significant psychological distress and metastatic status. Psychological distress was assessed using the Kessler Psychological Distress Scale (K10) at baseline, 6 months, and 12 months. The primary endpoint was the presence of nonspecific psychological distress, as measured by the K10 scale at 6 months from the trial start, based on group randomization. A secondary exploratory analysis assessed psychological distress at baseline, 6 months, and 12 months for both groups, while controlling for group randomization and prognostic covariates. Prognostic covariates included age; comorbidities; time between diagnosis and randomization; treatment modality; relationship status; and use of prescribed medications for anxiety, depression, or both. An exploratory sub-analysis was conducted for the breast cancer subgroup, based on the sample size available after recruitment. The trial is registered at ClinicalTrials.gov (NCT05508412). Results: The provision of the HRV biofeedback monitor in conjunction with the CancerPEP intervention did not significantly affect the primary outcome in either the full sample or the breast cancer subgroup, indicating that the HRV biofeedback provision was not beneficial in this trial. No self-reported or otherwise discovered adverse events at the 6-month mark were observed. About 10% of participants were lost to follow-up in both the early and late HRV monitor provision groups. Participation in the CancerPEP program led to a significant reduction in psychological distress over time. The odds of psychological distress were significantly higher at the start of the trial than at the end of the intervention (aOR = 2.64, 95% CI: 1.53–4.56) or 6 months after the intervention (aOR = 2.94, 95% CI: 1.62–5.30). Similarly, in the breast cancer subgroup, distress was higher at the trial’s start than at 6 months, i.e., after the intervention (aOR = 2.25, 95% CI: 1.24–4.08), or at the end of the trial at 12 months (aOR = 2.73, 95% CI: 1.35–5.52). Conclusions: CancerPEP significantly reduces psychological distress in cancer patients, with consistent improvements noted across various cancer types and stages, including benefits specifically for breast cancer patients. These findings build upon the success of the Prostate Cancer Patient Empowerment Program (PC-PEP), indicating that a similar comprehensive intervention can be advantageous for all cancer patients and may be further tailored to address specific needs. With its holistic approach—encompassing physical, dietary, and psychosocial support—CancerPEP shows promise as a vital component of survivorship care. Ongoing 24-month evaluations will yield critical data on its long-term benefits. Additionally, a randomized trial with a control group (usual care without intervention) for breast cancer patients is currently under way and could potentially guide the integration of CancerPEP into standard oncology care to enhance patient outcomes and quality of life.

Exploring the Impact of Sarcopenia on Mortality in Breast Cancer Patients: A Comprehensive Systematic Review and Meta-Analysis

Background: This study assesses the frequency of sarcopenia in patients with breast cancer (BC) and its association with mortality rates. Methods: An all-encompassing search across (PubMed, Scopus, Web of Science, and CINAHL) was done, to identify studies, published until August 2023, that report data on sarcopenia and mortality in BC patients. A meta-analysis was then done using a random-effects model. Results: Out of 989 initially identified potential studies, 19 met inclusion criteria. Analysis of 15 studies showed a rate of sarcopenia of 38% (95% CI 29-48%), with moderate heterogeneity (I2 = 25.8%). Sarcopenia was linked to increased mortality risk in BC patients across 16 studies (HR: 1.77, CI: 1.35 – 2.32, p = <0.001) with both shorter and longer follow-up periods. Similarly, mortality risks were significantly higher in metastatic (HR: 1.52, CI: 1.14 – 2.03, p = 0.004) and non-metastatic (HR: 2.55, CI: 1.66 – 3.93, p < 0.001) BC patients with sarcopenia. Conclusion: Our analysis demonstrates a substantial prevalence of sarcopenia in BC patients. Importantly, sarcopenia was significantly linked to elevated risk of mortality in this population. Subgroup analyses, stratified by follow-up periods and disease stage, consistently reveal increased mortality risks associated with sarcopenia, underscoring its clinical relevance in both short- and long-term patient outcomes. Our findings further strengthen the need to recognize and address sarcopenia as a critical factor in BC management and prognosis.

Hormonal Contraception and Breast Cancer Risk for Carriers of Germline Mutations in BRCA1 and BRCA2.

It is uncertain whether, and to what extent, hormonal contraceptives increase breast cancer (BC) risk for germline BRCA1 or BRCA2 mutation carriers. Using pooled observational data from four prospective cohort studies, associations between hormonal contraceptive use and BC risk for unaffected female BRCA1 and BRCA2 mutation carriers were assessed using Cox regression. Of 3,882 BRCA1 and 1,509 BRCA2 mutation carriers, 53% and 71%, respectively, had ever used hormonal contraceptives for at least 1 year (median cumulative duration of use, 4.8 and 5.7 years, respectively). Overall, 488 BRCA1 and 191 BRCA2 mutation carriers developed BC during median follow-up of 5.9 and 5.6 years, respectively. Although for BRCA1 mutation carriers, neither current nor past use of hormonal contraceptives for at least 1 year was statistically significantly associated with BC risk (hazard ratio [HR], 1.40 [95% CI, 0.94 to 2.08], P = .10 for current use; 1.16 [0.80 to 1.69], P = .4, 1.40 [0.99 to 1.97], P = .05, and 1.27 [0.98 to 1.63], P = .07 for past use 1-5, 6-10, and >10 years before, respectively), ever use was associated with increased risk (HR, 1.29 [95% CI, 1.04 to 1.60], P = .02). Furthermore, BC risk increased with longer cumulative duration of use, with an estimated proportional increase in risk of 3% (1%-5%, P = .002) for each additional year of use. For BRCA2 mutation carriers, there was no evidence that current or ever use was associated with increased BC risk (HR, 0.70 [95% CI, 0.33 to 1.47], P = .3 and 1.07 [0.73 to 1.57], P = .7, respectively). Hormonal contraceptives were associated with increased BC risk for BRCA1 mutation carriers, especially if used for longer durations. Decisions about their use in women with BRCA1 mutations should carefully weigh the risks and benefits for each individual.

Physical activity, screening cancer, and savings rate as indicators of health responsibility

Introduction: The health of individuals can change gradually over time as a result of the choices they make. Aim: The study aimed to examine indicators such as physical activity levels, screening participation, and household savings in the context of their role as potential measures of individual health responsibility. The second aim was to identify cognitive barriers and motivations influencing physical activity, breast and cervical cancer screening participation, and money-saving habits. Material and methods: The analysis used available data on physical activity, the screening level (for breast and cervical cancer), and household savings rates. Then, the data for Poland were presented against the background of available averages for the European Union. The data came from Eurostat, Eurobarometer - the official survey instrument used by the European Parliament. Results: According to Eurobarometer data, 65% of respondents in Poland have never been physically active in 2022 (vs in the European Union 45%). In 2022, the percentage of women who were screened for cervical cancer in Poland was 34% of women. And the cervical cancer program (cytology) was used by 10.9% of people. In 2022, the household saving rate was 12.7 % in the EU, and in Poland -2.89%, where the lowest rate occurred in Greece and the highest in Germany (Eurostat data). Conclusion: The low level of physical activity and participation in screening tests in Poland, compared to EU countries, highlights the need to intensify public health promotion activities. Additionally, promoting saving as an important element of health responsibility can not only improve the financial well-being of citizens but also have a positive impact on their mental health.

Impact of Structural Racism and Social Determinants of Health on Disparities in Breast Cancer Mortality.

The striking ethnic and racial disparities in breast cancer mortality are not explained fully by pathological or clinical features. Structural racism contributes to adverse conditions that promote cancer inequities, but the pathways by which this occurs are not fully understood. Social determinants of health (SDOH), such as economic status and access to care, account for a portion of this variability, yet interventions designed to mitigate these barriers have not consistently led to improved outcomes. Based on the current evidence from multiple disciplines, we describe a conceptual model in which structural racism and racial discrimination contribute to increased mortality risk in diverse groups of patients by promoting adverse SDOH that elevate exposure to environmental hazards and stress; these exposures in turn contribute to epigenetic and immune dysregulation, thereby altering breast cancer outcomes. Based on this model, opportunities and challenges arise for interventions to reduce racial and ethnic disparities in breast cancer mortality.

Use of empegfilgrastim for primary prevention of febrile neutropenia in patients receiving myelosuppressive therapy. Experience of the Arkhangelsk Clinical Oncological Dispensary

Background. Granulocyte colony-stimulating factors (G-CSFs) are used in oncology practice for prevention of febrile neutropenia caused by cytotoxic chemotherapy. Despite the proven safety of G-CSFs use in randomized clinical trials and in real clinical practice, clinicians have questions about the tolerability of this group of drugs.Aim. To demonstrate the safety profile of a long-acting G-CSF produced in Russia which was used to prevent febrile neutropenia and maintain dose intensity of drug therapy in patients with various solid tumors undergoing chemotherapy at the Arkhangelsk Clinical Oncological Dispensary.Materials and methods. The retrospective analysis included patients with a confirmed diagnosis of malignant neoplasm who received various chemotherapy regimens that required the inclusion of G-CSF. For primary prevention of febrile neutropenia, patients were prescribed empegfilgrastim (Extimia®) at a dose of 7.5 mg subcutaneously once per course of chemotherapy.Results. Data of 151 patients were analyzed for the period from July 2021 to April 2023. The average age was 57 years (28–75). The group of elderly patients (over 65 years) consisted of 38 (25 %) patients. The majority of patients were diagnosed with breast cancer (56 (37 %) patients) and gastric cancer (37 (25 %) patients). The number of empegfilgrastim injections over the entire observation period was 773. Adverse reactions associated with the use of empegfilgrastim were registered in 13 (8.6 %) patients, the most common of which was grade 1–2 leukocytosis according to the CTCAE v.5 classification. One patient developed a serious adverse reaction: grade 4 neutropenia according to the CTCAE v.5 classification. A subgroup of patients with metastatic pancreatic cancer treated with FOLFIRINOX was analyzed separately to assess the relative dose intensity of the chemotherapy courses. Nine patients with metastatic pancreatic cancer received FOLFIRINOX therapy with a median of 8 (5–12) courses. A total of 69 chemotherapy cycles were administered to 9 patients with a median of 7.5 (2–13) cycles. The relative dose intensity of the chemotherapy courses was 83.71 ± 19.33.Conclusion. Empegfilgrastim has shown a favorable safety and tolerability profile in patients with various solid tumors in real-world clinical practice including the highly toxic FOLFIRINOX regimen.

Evaluation of Treatment and Recurrence-Free Survival in Patients with Early HER2-Positive Breast Cancer: Real-Life Data Comparing Public and Private Healthcare

Abstract Introduction The present study was designed to compare the treatment provided in private and public health care facilities for women positive for early breast cancer of the human epidermal growth factor receptor 2 (HER2) subtype, who received anti-HER2 therapy in neoadjuvant or adjuvant settings, with an evaluation of the recurrence-free survival (RFS) and pathological complete response (pCR) rates. Materials and Methods The current is a retrospective study carried out at the Instituto Brasileiro de Controle do Cancer (IBCC Oncologia), in the city of São Paulo, Brazil. We included patients treated between 2015 and 2020. Results The study included 472 medical records of early HER2-positive breast cancer patients treated in the public and private health care systems who received neoadjuvant or adjuvant treatments. The pathological complete response (pCR) was related to a lower recurrence rate and a longer recurrence-free survival (RFS). The results showed no statistically significant difference between the public and private health care systems in terms of RFS. Discussion Although the public health care patients were diagnosed with more advanced diseases than the private health care patients, both presented similar survival rates. In spite of the small number of patients evaluated, the dual HER2 blockade did not improve the clinical outcomes. These findings should be confirmed through studies with a larger number of patients and a longer follow-up period.

An Optimized Liquid Chromatography–Mass Spectrometry Method for Ganglioside Analysis in Cell Lines

Gangliosides are glycosphingolipids composed of a sialylated glycan head group and a ceramide backbone. These anionic lipids form lipid rafts and play crucial roles in regulating various proteins involved in signal transduction, adhesion, and cell–cell recognition. Neuroblastoma, a pediatric cancer of the sympathetic nervous system, is treated with intensive chemotherapy, radiation, and an antibody targeting the GD2 ganglioside. Gangliosides are critical in neuroblastoma development and serve as therapeutic targets, making it essential to establish a reliable, rapid, and cost-effective method for profiling gangliosides, particularly one capable of isomeric separation of intact species. In this study, liquid chromatography–mass spectrometry (LC-MS) was optimized using standard gangliosides, followed by the optimization of sphingolipid extraction methods from cell lines by comparing Folch and absolute methanol extraction techniques. Percent recovery and the number of identified sphingolipids were used to evaluate the analytical merits of these methods. A standard gangliosides calibration curve demonstrated excellent linearity (R2 = 0.9961–0.9975). The ZIC-HILIC column provided the best separation of ganglioside GD1 isomers with a 25 min runtime. GD1a elutes before GD1b on the ZIC-HILIC column. Absolute methanol yielded better percent recovery (96 ± 7) and identified 121 different sphingolipids, the highest number between the two extraction methods. The optimized method was applied to profile gangliosides in neuroblastoma (COG-N-683), pancreatic cancer (PSN1), breast cancer (MDA-MB-231BR), and brain tumor (CRL-1620) cell lines. The ganglioside profile of the neuroblastoma cell line COG-N-683 showed an inverse relationship between GD1 and GD2. Ceramide, Hex1Cer, GM1, and GM3 were highly abundant in CRL-1620, PSN1, and MDA-MB-231BR, respectively. These results suggest that our method provides a sensitive, reliable, and high-throughput workflow for ganglioside profiling across different cell types.

B-352 Effects of COVID-19 on Breast Cancer Positivity: A Retrospective and Predictive Study

Abstract Background The COVID-19 pandemic has had a significant impact on the healthcare system, resulting in overall reduction in access to healthcare services, including the suspension of screening programs and postponement of surgeries and medical treatments. The aim of this study was to evaluate the effects of the pandemic on breast cancer positivity from cases received at a laboratory in São Paulo, Brazil. Methods A retrospective analysis of a database from a pathology laboratory in São Paulo, Brazil, was performed during the 2017-2023 period and classified as following: pre-pandemic (January 2017-February 2020), pandemic (March 2020 - April-2022), and post-pandemic (May 2022-December 2023). Cases were classified as negative or positive for malignancies. Positive anatomopathological examinations (breast biopsies and surgical specimens) considered primary, metastatic mesenchymal or endothelial malignancies. The Mann-Kendall test was used to evaluate the trend, and the PACF (Partial Autocorrelation Function) correlogram was used to analyze historical memory for definition of the autoregressive model. The augmented Dickey-Fuller hypothesis test was applied to analyze whether the series is stationary or not, and the first differences test was applied. The ARIMA model was used for the estimates (1,1,1). Statistics were performed using the gretl software and pymannkendall library in the Python language. Results A total of 74,973 samples were evaluated during the 2017-2023 period. In the three-year pre-pandemic period, 32,644 tests were recorded, with an average of 29.34% positive cases. From the analysis of the pre-pandemic time series, there was a positive trend towards an increase in cases (p < 0.0001, z=6.1360, Tau=0.6955). In a non-pandemic scenario, from March 2020 to February 2021, the number of new tests expected would be 11,535; however, in the pandemic period, only 8,904 were observed, a 22.81% reduction on expected cases. According to the historical average positivity rate in the pre-pandemic period, the expected and observed total were, respectively, 3,384 and 2,566 positive cases for malignancy. Conclusions This study reveals a significant decrease of approximately 22.81% in new breast anatomopathological diagnoses during the COVID-19 pandemic in a laboratory in São Paulo, Brazil. For comparison purposes, we identified a 24.17% of missed opportunities on diagnoses of new malignancy-positive cases, compared to the pre-pandemic period. These findings highlight the need for strategies to mitigate the negative effects of the pandemic on the early detection and treatment of breast cancer.

A phenocopy signature of TP53 loss predicts response to chemotherapy

In preclinical studies, p53 loss of function impacts chemotherapy response, but this has not been consistently validated clinically. We trained a TP53-loss phenocopy gene expression signature from pan-cancer clinical samples in the TCGA. In vitro, the TP53-loss phenocopy signature predicted chemotherapy response across cancer types. In a clinical dataset of 3003 breast cancer samples treated with neoadjuvant chemotherapy, the TP53-loss phenocopy samples were 56% more likely to have a pathologic complete response (pCR), with a significant association between TP53-loss phenocopy and pCR in both ER positive and ER negative tumors. In an independent clinical validation in the I-SPY2 trial (N = 987), we confirmed the association with neoadjuvant chemotherapy pCR and found higher rates of chemoimmunotherapy response in TP53-loss phenocopy tumors compared to non-TP53-loss phenocopy tumors (64% vs. 28%). The TP53-loss phenocopy signature predicts chemotherapy response across cancer types in vitro, and in a proof-of-concept clinical validation is associated with neoadjuvant chemotherapy response across multiple clinical breast cancer cohorts.

MTAS-02 PREDICTORS OF BRAIN METASTASIS IN CANCER PATIENTS IN CAMEROON

Abstract BACKGROUND Cancer still remains one of the leading causes of death globally, with higher burden faced by low- and middle-income countries. A third of all brain tumors are attributed to metastatic disease. However, in Cameroon, there is scarcity of data assessing predicting factors associated with brain metastasis patients. METHODS We conducted a review of patient records from the 1/1/2020 to 31/12/2023 at the oncology center in Douala, Cameroon. Multivariate logistic regression was used to assess for potential predictors associated with brain metastasis. RESULTS Overall, 1500 patient charts were reviewed. A total of 229 charts (15.3%) were complete. Majority of patients were female 159(69.4%), and the mean age was 52.2 (SD=15.7). The proportion of cancer patients with brain metastasis was 15.7%(n=36), with breast cancer accounting most for metastasis 17(47.2%). Age and primary tumor size were the factors significantly (p =0.033 and p= 0.037 respectively) associated with brain metastasis. CONCLUSION Brain metastasis was common in patients with breast cancer. Age and primary tumor size play a key role in predicting development of brain metastasis in this study group. LIMITATIONS 1. Majority of reviewed charts had incomplete information. 2. Retrospective nature of the study. 3. Single center study.

B-122 Improving the Diagnostic Utility of Multiplexed Assays in Laboratory Medicine with Machine Learning

Abstract Background The application of machine learning (ML) and artificial intelligence (AI) in precision medicine is of great interest and continues to grow. ML approaches offer a flexible and data-centric methodology for modeling diagnostic and prognostic trends, capable of identifying complex non-linear patterns and relationships between predictor variables and outcomes within large data sets. Although ML holds great promise, there are several common pitfalls that must be avoided for ML models to provide clinical utility. In the current study, we provide a rigorous and systematic evaluation of the utility of ML algorithms to predict disease in several representative data sets generated via multiplexed biomarker assays. We compare five major classes of ML algorithms compared to more traditional combinatorial analysis (logistic regression) to offer perspective against the current gold standard. Methods We obtained five data sets from published literature that include measurements of multiplexed biomarkers in patients with obstructive sleep apnea, sepsis, and breast and colon cancers in comparison to healthy controls. These datasets were generated by bead-based and planar multiplexed immunoassays. We chose representative ML algorithms from the classes of support vector machines (SVM), random forests (RF), neural networks (NNet), and extreme gradient boosting (xgBoost) in comparison to logistic regression (LR). Datasets were randomly split into internal validation and external validation sets via 10 iterations of permutation analysis. We tuned and validated the models using 5-fold cross validation, then tested those on external subsets. We report the average of several model classification metrics and associated variances across all resampled data sets. Results For the classification of sepsis using inflammatory cytokines measured on the Luminex bead-based immunoassay, RF outperformed LR in external validation sets by a 9.8% increase in AUROC. For classification of breast cancer patients, xgBoost and RF performed best with 20.0% and 16.9% increases in AUROC, respectively, whereas for classification of colon cancer patients, NNet outperformed LR by 11.5%. Across all datasets, on average, all ML algorithms outperformed LR in the internal validation sets by a 7.9% (6.3% - 9.9%) increase in AUROC. However, in external validation sets, only xgBoost and SVM outperformed LR, where RF and NNet showed signs of overfitting. Conclusions Overall, certain ML algorithms show improvement over LR for diagnostic applications using multiplexed assays, by up to 20% increase in AUROC. Interpretation of ML results must be performed rigorously to prevent overly optimistic and unrealistic conclusions. In the context of laboratory medicine, our results showcase the utility of ML in clinical applications, while highlighting potential disadvantages of ML. This analysis underscores the need for establishing rigorous guidelines to support data analytics during the development of novel multiplexed assays, which is needed to advance precision medicine.

Predictors of mastectomy in breast cancer patients with complete remission of primary tumor after neoadjuvant therapy: A retrospective study

IntroductionNeoadjuvant therapy (NAT) should increase the rate of breast-conserving surgery (BCS) in non-metastatic breast cancer (BC) patients, especially in those achieving tumor shrinkage. Still, the conversion from a pre-planned mastectomy to BCS in patients responding to NAT is not a widespread standard. We aimed to identify factors influencing surgical choices in this setting. Materials and methodsWe retrospectively collected data of BC patients with complete remission of primitive tumor (ypT0) after NAT, treated with BCS or mastectomy in two Italian breast units. Predictors of mastectomy were explored using logistic regression. Distant recurrence and event-free survival were assessed in the BCS and mastectomy cohort. Results243 patients were included, 147 (60.5 %) treated with BCS and 96 (39.5 %) treated with mastectomy. In the mastectomy group, there were more centrally-located, multiple and larger tumors. At univariate regression analysis, central location, baseline tumor extension on ultrasound (US) and magnetic resonance imaging (MRI), multiple foci and clinical stage were significantly associated with the chance of receiving mastectomy. At multivariate analysis, only baseline focality on US and extension on MRI retained significance as predictors of mastectomy. Distant recurrence and event-free survival were significantly longer in patients undergoing BCS. ConclusionBaseline tumor extension and focality were the main predictors of mastectomy in patients with ypT0 after NAT. However, BCS did not negatively affect survival outcomes in our cohort. An effort should be made to avoid potentially unnecessary mastectomy in this population, aiming at minimizing surgery-associated toxicities and improving patients’ quality of life.

Gender-specific risks for incident cancer in patients with different heart failure phenotypes.

There is conflicting evidence regarding whether heart failure (HF) increases the risk of developing cancer. This study aimed to assess the association between HF and incident cancer, considering gender differences and HF phenotypes. This retrospective study was conducted on data of adult individuals, free of cancer at baseline, from the First Affiliated Hospital of Wenzhou Medical University between January 2009 and February 2023. The patients with HF were categorized as HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). The primary outcome was incident cancer, including obesity-related, tobacco-related, lung, colorectal and breast cancers. Of 33033 individuals enrolled, 16722 were diagnosed with HF, including 10086 (60.3%) with HFpEF and 6636 (39.7%) with HFrEF. During a median follow-up period of 4.6years (inter-quartile range: 2.6-7.3), incident cancer was diagnosed in 10.5% (1707 patients) of the non-HF group and 15.1% (2533 individuals) of the HF group. After adjusting for potential confounding factors, patients with HF had a 58% increased risk of cancer than those without HF [adjusted hazard ratio (HR) 1.58, 95% confidence interval (CI) 1.48-1.69, P<0.001]. This risk was consistent across genders (female: adjusted HR 1.95, 95% CI 1.74-2.18, P<0.001; male: adjusted HR 1.41, 95% CI 1.30-1.54, P<0.001) and HF phenotypes (HFpEF: adjusted HR 1.69, 95% CI 1.57-1.81, P<0.001; HFrEF: adjusted HR 1.32, 95% CI 1.20-1.46, P<0.001). Both HFpEF and HFrEF are associated with an increased risk of incident cancer. This correlation maintains its validity across genders.

Adiposity throughout Adulthood and Risk of Young Onset Breast Cancer Tumor Subtypes in the Young Women's Health History Study.

The role of adult adiposity in young-onset breast cancer (YOBC) subtype risk is not well understood. In this population-based case(n=1812)-control(n=1381) study of invasive YOBC (aged <50 years), cases were identified from the Los Angeles County and Metropolitan Detroit SEER registries, 2010-2015. Area-based, frequency-matched controls were sampled from the 2010 Census. General adiposity (body mass index (BMI)) and central adiposity (waist circumference (WC), waist-to-height ratio (WHtR)) across adulthood and covariates were collected from in-person interviews and measurements. Odds ratios (ORs) and 95% confidence intervals (CIs) for adiposity and YOBC tumor subtypes (i.e., luminal A, luminal B, HER2+, triple negative (TN)) were calculated, overall and by parity, using multivariable weighted logistic regression. Obese young adult BMI was inversely associated with luminal A YOBC (OR=0.35, 95% CI 0.16-0.79); other subtype associations were non-significant. Similarly, adult overweight and obese BMIs were inversely associated with luminal A (respectively OR=0.66, 95% CI 0.48-0.91 and OR=0.59, 95% CI 0.46-0.87), but not other subtypes. Conversely, larger WC was associated with higher odds of luminal B and TN YOBC (respectively OR=1.48, 95% CI 1.01-2.15 and OR=2.48, 95% CI 1.52-3.88), but not other subtypes (with similar results for WHtR); highest odds were among parous women. Findings show greater general adult adiposity is associated with reduced odds of luminal A YOBC, while greater central adiposity is associated with increased odds of luminal B and TN YOBC, particularly among parous women. Additional studies of central adiposity and YOBC subtype risk, especially incorporating pregnancy history, are warranted.

Development of a polygenic score predicting drug resistance and patient outcome in breast cancer

Gene expression profiles of hundreds of cancer cell-lines and the cell-lines’ response to drug treatment were analyzed to identify genes whose expression correlated with drug resistance. In the GDSC dataset of 809 cancer cell lines, expression of 36 genes were associated with drug resistance (increased IC50) to many anti-cancer drugs. This was validated in the CTRP dataset of 860 cell lines. A polygenic score derived from the correlation coefficients of the 36 genes in cancer cell lines, UAB36, predicted resistance of cell lines to Tamoxifen. Although the 36 genes were selected from cell line behaviors, UAB36 successfully predicted survival of breast cancer patients in three different cohorts of patients treated with Tamoxifen. UAB36 outperforms two existing predictive gene signatures and is a predictor of outcome of breast cancer patients independent of the known clinical co-variates that affect outcome. This approach should provide promising polygenic biomarkers for resistance in many cancer types against specific drugs.

Predicting p53-dependent cell transitions from thermodynamic models.

A cell's fate involves transitions among its various states, each defined by a distinct gene expression profile governed by the topology of gene regulatory networks, which are affected by 3D genome organization. Here, we develop thermodynamic models to determine the fate of a malignant cell as governed by the tumor suppressor p53 signaling network, taking into account long-range chromatin interactions in the mean-field approximation. The tumor suppressor p53 responds to stress by selectively triggering one of the potential transcription programs that influence many layers of cell signaling. These range from p53 phosphorylation to modulation of its DNA binding affinity, phase separation phenomena, and internal connectivity among cell fate genes. We use the minimum free energy of the system as a fundamental property of biological networks that influences the connection between the gene network topology and the state of the cell. We constructed models based on network topology and equilibrium thermodynamics. Our modeling shows that the binding of phosphorylated p53 to promoters of target genes can have properties of a first order phase transition. We apply our model to cancer cell lines ranging from breast cancer (MCF-7), colon cancer (HCT116), and leukemia (K562), with each one characterized by a specific network topology that determines the cell fate. Our results clarify the biological relevance of these mechanisms and suggest that they represent flexible network designs for switching between developmental decisions.

B-309 Evaluation of the Analytical Performance of Breast and Ovarian Cancer Antigen Assays on the Atellica CI Analyzer

Abstract Background The Atellica® CI Analyzer is an automated, high-throughput integrated chemistry and immunoassay analyzer utilizing both Atellica® CH and Atellica® IM Assays. This study evaluated the analytical performance of the Atellica IM breast cancer antigen CA 15-3™ (CA 15-3) and the ovarian cancer antigen CA 125II™ (CA 125II) Assays on the Atellica CI Analyzer. Methods Precision studies were performed according to CLSI EP05-A3 using native and contrived human serum samples as well as contrived horse serum samples for CA 15-3. One aliquot of each sample pool was tested in duplicate in two runs per day ≥2 hours apart on each analyzer for ≥20 days. Precision studies were evaluated with one reagent lot on two systems. Method comparison studies were performed using three reagent lots according to CLSI EP09c. Individual native and contrived human serum samples were analyzed using the Atellica IM CA 15-3 and CA 125II Assays on the Atellica IM Analyzer and the Atellica CI Analyzer. LoB, LoD, and LoQ were determined as described in CLSI EP17-A2. Results Representative precision and method comparison results for each assay are listed in the table. For the two assays tested, repeatability and within-lab %CVs were &amp;lt;2.4% and &amp;lt;6.9%, respectively. Slopes determined by the weighted Deming linear regression model were approximately 1. Detection capability for the Atellica IM CA 15-3 Assay on the Atellica CI Analyzer was estimated to be 1.0 U/mL, 2.0 U/mL and 3.0 U/mL for LoB, LoD, and LoQ, respectively. When using the Atellica IM CA 125II Assay, detection capability was estimated to be 2.0 U/mL, 3.0 U/mL and 3.0 U/mL for LoB, LoD, and LoQ, respectively. Conclusions Evaluation of the Atellica IM CA 15-3 and CA 125II Assays using the Atellica CI Analyzer demonstrated good precision and equivalent performance compared to the same assays on the Atellica IM Analyzer.