Advanced Stage Breast Cancer Patients Research Articles

Analysis of Presentation Delay in Patients with Advanced Breast Cancer Visiting Dharmais National Cancer Hospital

Background: Breast cancer is still one of the significant causes of the increasing mortality rate due to cancer. Treatment of breast cancer patients was delayed by 66.34%. The majority of patients arrive at stages IIIB and IV and are therefore treated at an advanced stage. This study aimed to analyze the factors causing the arrival delay of breast cancer patients to Dharmais Cancer Hospital with advanced stages. Methods: A descriptive study with a qualitative approach was used as the research design. Indepth interviews and document reviews were used to collect data. In-depth interviews were conducted with 12 advanced-stage breast cancer patients. Thematic data analysis was performed by tracing and identifying the main topics of the entire interview process. The triangulation method was used to validate the data by conducting interviews with 4 patient families and 2 oncology surgeons, as well as document review. Results: The presentation delay of advanced breast cancer patients was analyzed based on the interpretation and recognition of symptoms. There was an attitude of ignoring when there were symptoms and not seeking treatment. On psychological factors, there was a feeling of fear after being diagnosed and a sense of worry in the treatment process. On socioeconomic factors, there was no early detection, lack of information on early detection, waiting time constraints, and the selection of alternative treatments. Conclusions: Late-stage breast cancer patients were drawn to Dharmais Cancer Hospital due to issues with the interpretation and experience of symptoms, psychological issues patients reported, and socioeconomic difficulties during treatment. As a result, patients must be given additional care to deal with late arrivals, especially in cases of advanced breast cancer.

Abstract 6772: A 3D model of breast cancer-bone metastasis to mimic dysregulation of bone remodeling and drug response

Abstract Introduction: Bone metastases are common among advanced stage breast cancer patients and induce dysregulation of bone remodeling. Crosstalk between cancer cells and the bone niche drives the vicious cycle of bone loss and breast cancer growth. To accelerate discovery of targeted therapies, there is a critical need for experimental models that can mimic breast cancer-induced dysregulation of bone remodeling in patients. Mouse models are the current gold standard, but are low throughput, costly, and cannot fully recapitulate human-human cell interactions. To address these limitations, our goal is to engineer a fully human 3D in vitro model of breast cancer-bone metastasis that can mimic dysregulation of bone remodeling and drug responses in patients, and enable screening of potential new drug candidates. Methods: Two human breast cancer cell lines (MDA-MB-231, MCF-7) were chosen given their well characterized clinical features and tendency to invade bone. Our 3D model comprises an outer ring of tissue engineered (TE) bone and a center of breast cancer cells to mimic invasion through the bone marrow/long bone interface. Human mesenchymal stem cells were encapsulated in 3D gelatin microribbon scaffolds and cultured in osteogenic media for 28 days to form TE bone. Human monocyte-derived osteoclasts were seeded onto the bone, and the center was replaced with GFP-labeled breast cancer cells. Denosumab and zoledronic acid were selected as they are standard treatments for reducing bone loss in patients, and were used to treat the model at 30 µg/mL and 2 µg/mL, respectively. Intermittent parathyroid hormone (iPTH) treatment was selected as it showed efficacy in animal models, and was used to treat the model at 10 µg/mL for 6 hours daily. All groups were treated with drugs for 14 days. Bone volume was assessed using microCT. Cancer cell proliferation and invasion into bone was monitored with fluorescence confocal microscopy. Results: MicroCT imaging showed both breast cancer cell lines induced bone loss in the triculture model, compared to the control with no breast cancer cells in the center. Consistent with known clinical features, the more aggressive cell line (MDA-MB-231) induced a greater amount of bone loss than the less aggressive breast cancer cell line (MCF-7). Consistent with clinical findings, both denosumab and zoledronic acid reduced bone loss in our 3D model, and zoledronic acid further reduced breast cancer cell invasion and proliferation. Finally, the 3D model recapitulated the in vivo drug response of iPTH treatment, reducing bone resorption and breast cancer invasion. Conclusions: Here we report a fully human triculture model of breast cancer-bone metastasis that can mimic key clinical features of breast cancer-induced bone resorption and drug response in patients. Such a 3D model could enable screening of drug candidates with reduced time and cost and enable identification of novel druggable targets. Citation Format: Michelle Tai, Eva C. González Díaz, Callan E. Monette, Joy Wu, Fan Yang. A 3D model of breast cancer-bone metastasis to mimic dysregulation of bone remodeling and drug response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6772.

Breast cancer patient experiences in the Botswana health system: Is it time for patient navigators?

BackgroundNew models of care are required to support women with breast cancer due to rising incidence and mortality in sub-Saharan Africa (SSA). This study gives voice to the experiences of advanced-stage breast cancer patients in the Botswana healthcare system, to guide improved service provision and the potential utility of patient navigator (PN) programs. Methodsfocus group discussions (FGD) were conducted with advanced-stage breast cancer patients recruited from the oncology ward of the public Princess Marina Hospital located in Gaborone, Botswana. ResultsFGDs included 7 female breast cancer patients and their 7 caregivers (2 male and 5 females). Findings fell into the following themes: experiences with cancer diagnosis, experiences with treatment, roles of caregivers, information needs, views on cancer resources, and attitudes towards cancer research. The study identified several barriers across the cascade of care for breast cancer patients in the Botswana health system. These correspond to challenges with timely diagnosis and comprehensive management and highlight community level barriers to achieving the targets of the WHO Global Breast Cancer initiative (GBCI). ConclusionThe study findings suggest PN programs have the potential to bridge barriers identified in the Botswana healthcare system by improving communication, meeting information needs, providing emotional or practical support, and by addressing logistical barriers to cancer diagnosis and treatment in Botswana.

Correlation between Level of Depression and Degree of Pain on Quality of Life in Advanced Stage Breast Cancer Patients (III and IV) at H. Adam Malik General Hospital Medan

Correlation between Level of Depression and Degree of Pain on Quality of Life in Advanced Stage Breast Cancer Patients (III and IV) at H. Adam Malik General Hospital Medan

Patient-Derived Breast Cancer Bone Metastasis In Vitro Model Using Bone-Mimetic Nanoclay Scaffolds

The unavailability of reliable models for studying breast cancer bone metastasis is the major challenge associated with poor prognosis in advanced-stage breast cancer patients. Breast cancer cells tend to preferentially disseminate to bone and colonize within the remodeling bone to cause bone metastasis. To improve the outcome of patients with breast cancer bone metastasis, we have previously developed a 3D in vitro breast cancer bone metastasis model using human mesenchymal stem cells (hMSCs) and primary breast cancer cell lines (MCF-7 and MDAMB231), recapitulating late-stage of breast cancer metastasis to bone. In the present study, we have tested our model using hMSCs and patient-derived breast cancer cell lines (NT013 and NT023) exhibiting different characteristics. We investigated the effect of breast cancer metastasis on bone growth using this 3D in vitro model and compared our results with previous studies. The results showed that NT013 and NT023 cells exhibiting hormone-positive and triple-negative characteristics underwent mesenchymal to epithelial transition (MET) and formed tumors in the presence of bone microenvironment, in line with our previous results with MCF-7 and MDAMB231 cell lines. In addition, the results showed upregulation of Wnt-related genes in hMSCs, cultured in the presence of excessive ET-1 cytokine released by NT013 cells, while downregulation of Wnt-related genes in the presence of excessive DKK-1, released by NT023 cells, leading to stimulation and abrogation of the osteogenic pathway, respectively, ultimately mimicking different types of bone lesions in breast cancer patients.

Association of altered metabolic profiles and long non-coding RNAs expression with disease severity in breast cancer patients: analysis by 1H NMR spectroscopy and RT-q-PCR.

Globally, one of the major causes of cancer related deaths in women is breast cancer. Although metabolic pattern is altered in cancer patients, robust metabolic biomarkers with a potential to improve the screening and disease monitoring are lacking. A complete metabolome profiling of breast cancer patients may lead to the identification of diagnostic/prognostic markers and potential targets. The aim of this study was to analyze the metabolic profile in the serum from 43 breast cancer patients and 13 healthy individuals. We used 1H NMR spectroscopy for the identification and quantification of metabolites. q-RT-PCR was used to examine the relative expression of lncRNAs. Metabolites such as amino acids, lipids, membrane metabolites, lipoproteins, and energy metabolites were observed in the serum from both patients and healthy individuals. Using unsupervised PCA, supervised PLS-DA, supervised OPLS-DA, and random forest classification, we observed that more than 25 metabolites were altered in the breast cancer patients. Metabolites with AUC value > 0.9 were selected for further analysis that revealed significant elevation of lactate, LPR and glycerol, while the level of glucose, succinate, and isobutyrate was reduced in breast cancer patients in comparison to healthy control. The level of these metabolites (except LPR) was altered in advanced-stage breast cancer patients in comparison to early-stage breast cancer patients. The altered metabolites were also associated with over 25 signaling pathways related to metabolism. Further, lncRNAs such as H19, MEG3 and GAS5 were dysregulated in the breast tumor tissue in comparison to normal adjacent tissue. The study provides insights into metabolic alteration in breast cancer patients. It also provides an avenue to examine the association of lncRNAs with metabolic patterns in patients.

Quality of life assessment in breast cancer patients during palliative treatment in Indonesia

Abstract Background This study aimed to prospectively assess quality of life (QOL), QOL domains, and pain severity in advanced stage breast cancer patients during palliative oncology treatment in Indonesia. Methods Advanced stage breast cancer patients > 18 years (n = 160) who began palliative oncology treatment were enrolled in the study using convenience sampling. They completed the EORTC QLQ-C15-PAL questionnaire and pain severity (Visual Analogue Scale, VAS) score at three-time points (baseline (T0), three-(T1) and six-months (T2) follow-up). The repeated measures analysis of variance (ANOVA) model was used to assess the QOL, QOL domains, and pain severity changes over time adjusted for age, place of residence, marital status, and Karnofsky Performance Status score at baseline. We classified the change over time in three qualitative groups (deterioration, improvement, or trivial/no difference). We considered it clinically relevant if patients had a 10-point difference. Results The mean age of included patients (n = 159) was 50 years. Most lived in an urban area (72.3%), had low education (71.7%), and were married (81.8%). The repeated measures ANOVA showed that the QOL score, emotional functioning, fatigue, dyspnea, appetite loss, constipation, and VAS pain score remained stable over the 6-months period. In contrast: physical functioning declined (medium to large deterioration (-19.8 (95% CI -27.2 to -12.5)) between T0 to T2), however there was an improvement in the insomnia domain (medium improvement (-13.4 (95% CI -19.9 to -6.9)) between T0 to T2). Conclusions Our findings indicated that advanced stage breast cancer patients adapted well to palliative oncology treatment over six months of observation. There was deterioration in physical functioning, but improvement in insomnia. However, more attention is needed from clinicians to achieve improvement in the overall QOL score and specific QOL domains. Key messages • Focusing on improvement overall QOL score and specific QOL domains will lead to better advanced stage breast cancer patients’ satisfaction and care. • Information is limited on palliative treatment satisfaction in low and lower middle-income countries, therefore this study has important impact on further policy considerations in Indonesia.

Effects of Neo-Adjuvant Chemotherapy on CD8 + Serum Levels in Local Advanced Stage Breast Cancer Patients

Introduction.CD8 + CTLs are important components of tumor specific cellular adaptive immunity in breast cancer. Chemotherapy can increase the response of cytotoxic lymphocytes and provide anti-tumor immunity. Therefore, chemotherapy can cause cell death and trigger tumor antigens that are processed by APC and activate CD8 + cells to destroy tumor cells. Evaluation of the immune system before treatment can predict chemotherapy response. The purpose of this study was to assess the effect of neo-adjuvant chemotherapy on serum CD8 + levels in patients with locally advanced breast cancer.Methods.Non-comparative clinical trials were conducted at Dr. Mohammad Hoesin Hospital Palembang from October 2017 to June 2018.The sample of this study was 30 breast cancer patients who met the inclusion criteria. All samples underwent FAC neo-adjuvant chemotherapy and data were analyzed with SPSS version 21. Results.The mean age of advanced breast cancer patients was 45.97 ± 10,526 years with an age range of 30-66 years. Serum CD8 + levels after chemotherapy decreased significantly compared to before chemotherapy (p = 0.000). The value of serum CD8 + before chemotherapy has a sensitivity of 42.86% and specificity of 43.48% with a cut of point of 660.7 cells / mm3.Conclusion.Neo-adjuvant chemotherapy significantly decreases serum CD8 + levels in local advanced breast cancer patients.Keyword: CD8 +, locally advanced breast cancer, immune system, neo-adjuvant chemotherapy

Prognostic value of HER2 status on circulating tumor cells in advanced-stage breast cancer patients with HER2-negative tumors.

Discordance between HER2 expression in tumor tissue (tHER2) and HER2 status on circulating tumor cells (cHER2) has been reported. It remains largely underexplored whether patients with tHER2-/cHER2+ can benefit from anti-HER2 targeted therapies. cHER2 status was determined in 105 advanced-stage patients with tHER2- breast tumors. Association between cHER2 status and progression-free survival (PFS) was analyzed by univariate and multivariate Cox models and survival differences were compared by Kaplan-Meier method. Compared to the patients with low-risk cHER2 (cHER2+ < 2), those with high-risk cHER2 (cHER2+ ≥ 2) had shorter survival time and an increased risk for disease progression (hazard ratio [HR] 2.16, 95% confidence interval [CI] 1.20-3.88, P = 0.010). Among the patients with high-risk cHER2, those who received anti-HER2 targeted therapies had improved PFS compared with those who did not (HR 0.30, 95% CI 0.10-0.92, P = 0.035). In comparison, anti-HER2 targeted therapy did not affect PFS among those with low-risk cHER2 (HR 0.70, 95% CI 0.36-1.38, P = 0.306). Similar results were obtained after adjusting covariates. A longitudinal analysis of 67 patients with cHER2 detected during follow-ups found that those whose cHER2 status changed from high-risk at baseline to low-risk at first follow-up exhibited a significantly improved survival compared to those whose cHER2 remained high-risk (median PFS: 11.7weeks vs. 2.0weeks, log-rank P = 0.001). In advanced-stage breast cancer patients with tHER2- tumors, cHER2 status has the potential to guide the use of anti-HER2 targeted therapy in patients with high-risk cHER2.

Abstract P6-10-23: Presence of circulating tumor cell clusters and elevated platelet counts interactively predict disease progression in advanced-stage breast cancer patients

Abstract Background: Circulating tumor cells (CTCs) and their clusters (CTC-clusters) are promising prognostic markers in breast cancer. Recently studies showed that platelets interact with tumor cells in the circulation and promote metastasis. However, no study has been reported to explore the effects of interactions between CTCs/CTC-clusters and platelets on the prognosis of breast cancer at the population level. Methods: A total of 146 female advanced-stage breast cancer patients were included in this study. CTCs and CTC-clusters were enumerated using the CellSearch system. Platelet count was obtained from laboratory tests. The individual and joint effects of CTCs/CTC-clusters and platelets on progression free survival (PFS) were evaluated using the Cox proportional hazards model. Results: Elevated CTCs (≥ 5 CTCs/7.5 mL), presence of CTC-clusters, or high platelet counts (≥ 400 × 109/L) were individually associated with PFS (hazard ratio [HR] 2.69, 2.71, and 1.79, respectively). We further stratified patients into three risk groups according to the status of CTCs/CTC-clusters in combination with the level of platelet counts, including: 1) low-risk group: for CTC-related analyses, low CTCs (&amp;lt; 5 CTCs/7.5 mL) and platelet counts (&amp;lt; 400 × 109/L); for CTC-cluster-related analyses, absence of CTC-cluster and low platelet counts; 2) medium-risk group: for CTC-related analyses, either elevated CTCs (≥ 5 CTCs/7.5 mL) or high platelet counts (≥ 400 × 109/L), but not both; for CTC-cluster-related analyses, either presence of CTC-clusters or high platelet counts, but not both; 3) high-risk group: for CTC-related analyses, both elevated CTCs and high platelet counts; for CTC-cluster-related analyses, presence of CTC-clusters and high platelet counts. A significantly increased risk for disease progression was observed in high-risk patients, especially in patients with both CTC-clusters and high platelet counts (adjusted HR 16.06, P = 0.0003, log-rank P&amp;lt; 0.0001). Furthermore, we identified a multiplicative interaction between CTC-clusters and platelets on PFS (P for interaction = 0.0483), and the patients with both CTC-clusters and high platelet counts had the shortest time of development of new metastatic sites. Conclusions: Our results indicated the effects of interactions between the presence of CTC-clusters and high platelet counts on tumor progression and dissemination in breast cancer. Future studies are warranted to validate our findings and explore their biological mechanisms and clinical relevance. Citation Format: Chun Wang, Zhong Ye, Zhenchao Zhang, Maysa Abu-Khalaf, Daniel Silver, AnaMaria Lopez, Frederick Fellin, Saveri Bhattacharya, Rebecca Jaslow, Kaelan Yao, Darayus Toorkey, Neha Pancholy, Ronald Myers, Hushan Yang. Presence of circulating tumor cell clusters and elevated platelet counts interactively predict disease progression in advanced-stage breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-23.

The Effect of P-Glycoprotein (P-gp), Nuclear Factor-Kappa B (Nf-κb), and Aldehyde Dehydrogenase-1 (ALDH-1) Expression on Metastases, Recurrence and Survival in Advanced Breast Cancer Patients

Objective::To investigate the level of three drug resistance proteins; P-glycoprotein 1 (P-gp), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and aldehyde dehydrogenase isoform 1 (ALDH1) expression and their relationship to metastasis, recurrence and survival in advanced breast cancer patients that received neoadjuvant chemotherapy.Methods:This study is a combination of prospective and retrospective cohort study involving one hundred and thirty one cases of advanced stage invasive breast cancer that have received neoadjuvant chemotherapy. Initial biopsy specimens (incisional biopsy or core biopsy) were taken from paraffin blocks. Immunohistochemistry (IHC) was used to detect P-gp, NF-κB, and ALDH1 expression. Prospectively analysed patients were followed for five years and evaluated for recurrence and death.Results:The expression of P-gp has no significant statistical correlation to metastases (p = 0.659), recurrence (p = 0.862) and survival (p = 0.835) in advanced stage breast cancer patients who received neoadjuvant chemotherapy. Similarly, ALDH1 was not correlated to metastases (p=0.120), recurrence (p = 0.186) and survival (p = 0.254) statistically. We found that NF-κB expression showed a significant correlation to metastases (p=0.004), recurrence (p = 0.016) and overall survival (p = 0.041) in advanced stage breast cancer patients after neoadjuvant chemotherapy.Conclusion:NF-κB expression is a potential marker that can be used to assess or to predict increasing risk of metastases, recurrence and survival in advanced stage breast cancer patients who receive neoadjuvant chemotherapy.

Abstract P3-12-20: The use of new delineation tool “MIRADA”, step-by-step development and first results of its use in early and locally advanced breast cancer patients

Abstract Objectives: To describe the practical procedure of implementation and optimization of delineation using “Mirada” software, as well as evaluation of the automatic segmentation for the daily practice of lymph nodes (LN) and OARs (organs at risk) in early as well as locally advanced stage breast cancer patients. Methods: Forty patients' CT scans in treatment position were selected and re-contoured according to the ESTRO guidelines. The atlas of dataset was then created for automatic delineation. Thirty patients with breast/chest wall and lymph nodes regions irradiated were recruited for evaluation. With the same treatment position, the CT scan images were acquired and then contoured by the MIRADA system automatically as well as by the radiation oncologist manually (as the reference). The Conformity Index (CI) was used to evaluate the concordance between both of them. Results: The mean time for manual contour was 24.1±5.1 mins and 26.4±2.8 mins for the LN and the OARs resp. All the volumes of interest were contoured using the software (including corrections) in 30 minutes, which reduced the time of delineation of target volumes and OAR by about 40%. Of the 30 cases evaluated, the mean CI of 5 principal OARs showed ≥ 0.8. While the automatic contour of LN was less satisfactory with mean CI of 0.43±0.1 (0.23-0.52). Conclusions: For the breast cancer patients, the studied software permitted to save time for delineation with acceptable OAR contours. The improvement of LN regions contour is needed. More cases and further evaluation are needed for the system to realize its routine use. Citation Format: Xu H, Arsene Henry A, Robillard M, Amessis M, Kirova YM. The use of new delineation tool “MIRADA”, step-by-step development and first results of its use in early and locally advanced breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-12-20.

Abstract 3726: Design of personalised polymer based combination therapeutics for advanced stage breast cancer patients

Abstract Our objective is to engineer tumour-targeted polymer-based combination therapies specifically designed to treat metastatic breast cancer (BC) in a personalised manner. Our strategy is to develop novel multicomponent polymer conjugates and assess structure activity relationships in clinically relevant models to understand mechanisms of action. Furthermore, we are searching for novel drug combinations, including tumour-derived exosome release pathway inhibitors due to their association with metastasis and tumour drug resistance mechanisms. NCA polymerization techniques have allowed us to precisely control the synthesis of well-defined star-based (STP) and linear (LTP) polypeptidic architectures. After fluorescence labelling, we studied our systems in vitro demonstrating a much more rapid uptake for STP through clathrin-coated mediated endocytosis. pK and biodistribution in healthy mice revealed renal excretion profiles and greater terminal and accumulation half-lives for STP architectures when compared to the LTP. Remarkably, we also observed clear accumulation in immune system-related organs including the spleen and lymph nodes (LN) (up to 40% ID/g tissue accumulation in the LN after i.v. administration). This is possibly due to their inherent structural and morphological features, such as their size (≈100nm), highly negative z-potential values, and/or hydrophilic surfaces. These data highlight the great potential of our stabilized self-assemblies as carriers to target LN metastasis, cancer immunotherapy, or immune system-related approaches, such as vaccination. In parallel, we have performed a High Throughput Screening to select synergistic drug combinations to be used in polymer-based combination approaches through rationally designed linkers that confer adequate drug release kinetics. To perform this approach we selected four metastatic human BC cell lines representing clinical BC subtypes. All cell models have been fully characterized regarding their Cathepsin B activity, intracellular pH, as well as oestrogen, progesterone, Her2 receptors, GSH and exosomes levels; all representing patient-specific biomarkers. Cell viability and exosomes release modulation have been studied following treatments and several drug combinations have been selected for each specific BC subtype. With selected drug combinations different linking chemistry has been designed. We have studied a combination conjugate with the chemotherapeutic agent conjugated to PGA through two different length pH-labile hydrazone linkers. This provided different therapeutic outputs in cells and in a metastatic immunocompetent orthotopic breast cancer model, not only for the primary tumor but also for metastasis progression. The results obtained so far open up a wide range of opportunities for the currently unsuccessful clinical approaches to target LN metastasis and cancer immunotherapy. Citation Format: Ana Armiñán, Zoraida Andreu, Juan J Arroyo-Crespo, David Charbonnier, Esther Masiá, Fernanda Rodriguez-Otomin, Aroa Duro-Castano, Vicent J Nebot, Maria J Vicent. Design of personalised polymer based combination therapeutics for advanced stage breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3726.

Cardiac autonomic modulation impairments in advanced breast cancer patients.

To compare cardiac autonomic modulation in early- versus advanced-stage breast cancer patients before any type of cancer treatment and investigate associated factors. This cross-sectional study included women (30-69years old) with primary diagnosis of breast cancer and women with benign breast tumors. We evaluated cardiac modulation by heart rate variability and assessed factors of anxiety, depression, physical activity, and other relevant medical variables. Patients were divided into three groups based on TNM staging of cancer severity: early-stage cancer (n = 42), advanced-stage cancer (n = 37), or benign breast tumors to serve as a control (n = 37). We analyzed heart rate variability in time and frequency domains. The advanced-stage cancer group had lower vagal modulation than early-stage and benign groups; also, the advance-stage group had lower overall heart rate variability when compared to benign conditions. Heart rate variability was influenced by age, menopausal status, and BMI. Heart rate variability seems to be a promising, non-invasive tool for early diagnosis of autonomic dysfunction in breast cancer and detection of cardiovascular impairments at cancer diagnosis. Cardiac autonomic modulation is inversely associated with breast cancer staging.

Decreased expression of microRNA-26b in locally advanced and inflammatory breast cancer

Advanced-stage breast cancer patients comprise a smaller proportion of breast cancer patients than do early stage patients and are more likely to experience a poor outcome. Understanding the underlying molecular mechanisms and identifying new biomarkers for treatment in this subgroup of patients is paramount. With the aim of identifying microRNAs that are regulated in advanced-stage breast cancer, we found lower expression of miR-26b, a member of the miR-26 family, in inflammatory breast cancer and noninflammatory locally advanced breast cancer tissue than in normal breast tissue, by quantitative real-time polymerase chain reaction and in situ hybridization. Quantitative real-time polymerase chain reaction (but not in situ hybridization) also revealed lower miR-26b expression in inflammatory breast cancer than in noninflammatory locally advanced breast cancer. Furthermore, lower expression of miR-26b was correlated with shorter distant metastasis-free survival and overall survival in univariate analysis, and with shorter overall survival in multivariate analysis. The expression of miRNA-26b was inversely associated with EZH2 protein expression in several breast cancer cell lines, and overexpression and knockdown of miR-26b caused corresponding changes in EZH2 expression. Our study shows that miR-26b may regulate EZH2 expression in breast cancer and may be useful as a therapeutic target for inflammatory breast cancer and noninflammatory locally advanced breast cancer.

Anti-angiogenic Therapy-Mediated Endothelial Damage: A Driver of Breast Cancer Recurrence?

Anti-angiogenic therapy was conceived originally as a silver bullet able to maintain tumor dormancy indefinitely. By targeting new blood vessel formation, anti-angiogenic agents were expected to suppress the growth of any type of primary or metastatic tumor, independent of their subtype or genetic landscape. However, more that 20years after the first anti-angiogenic preclinical trial, the astonishing inhibition of metastatic outgrowth originally observed in mouse models never translated into clinics. Indeed, whereas anti-angiogenic agents (sometimes) prolong progression-free survival, they fail to impact overall survival, particularly in breast cancer. This observation revealed to be true in early- and advanced-stage breast cancer patients treated either in adjuvant or neo-adjuvant settings, suggesting that the effect of anti-angiogenic therapy on repressing growth of overt metastases- and also on preventing outgrowth of disseminated tumor cells and micrometastases- is limited. What are the reasons underlying this failure? And, more importantly, is there still room for improvement?

CD 105 As Prognostic Factors in Advanced Stage Breast Cancer Patients

CD 105 As Prognostic Factors in Advanced Stage Breast Cancer Patients

Pretreatment Insulin Levels as a Prognostic Factor for Breast Cancer Progression.

Based on the hypothesis that impaired glucose metabolism might be associated with survival outcomes independently of overt diabetes, we sought to investigate the prognostic value of routinely used glycemic parameters in a prospective study of breast cancer (BC) patients. Fasting blood glucose, insulin and HbA1c levels, and insulin resistance (assessed by the Homeostasis Model Assessment [HOMA] index) at diagnosis were evaluated in 286 nondiabetic BC patients (249 with primary cancer, 37 with metastatic) with respect to those parameters' possible associations with clinicopathological features and survival outcomes. As a control group, 143 healthy women matched in a 2:1 ratio for age, blood lipid levels, and body mass index were also investigated. Fasting blood glucose level (mean ± SD: 99 ± 26 vs. 85 ± 15 mg/dL), insulin level (median: 10.0 vs. 6.8 μIU/mL), and HOMA index (median: 2.2 vs. 1.4), but not HbA1c level, were significantly elevated in BC patients compared with control subjects. Receiver operating characteristics analysis showed comparable areas for blood glucose and insulin levels, and HOMA index (ranging from 0.668 to 0.671). Using a cutoff level of 13 μIU/mL, insulin had the best specificity (92%) and sensitivity (41%), was significantly associated with disease stage, and acted as a negative prognostic marker of progression-free survival (hazard ratio: 2.17; 95% confidence interval: 1.13-4.20) independently of menopausal status, disease stage, hormone receptor status, and human epidermal growth factor receptor 2 and Ki67 expression. These results suggest that insulin determination might provide prognostic information in BC and support the hypothesis that lifestyle and/or pharmacological interventions targeting glucose metabolism could be considered to improve survival outcome of selected BC patients. Pretreatment insulin levels may represent a biomarker of adverse prognosis in nondiabetic women with breast cancer, independently of other well-established prognostic factors (i.e., stage, hormone receptors, HER2/neu, and Ki67). This finding has important implications, because it provides the rationale for lifestyle or insulin-targeting pharmacologic interventions as a means of improving breast cancer outcomes not only in early stages, but also in advanced-stage breast cancer patients with aggressive tumor phenotypes (HER2-negative hormone-resistant, or triple-negative breast cancer), in which treatments are still challenging. The possibility of using insulin as a biomarker to guide insulin-targeted interventions also should be taken into account.

CXCL8, IL-1β and sCD200 are pro-inflammatory cytokines and their levels increase in the circulation of breast carcinoma patients.

The influence of biomarkers on carcinogenesis has been investigated extensively. Whether they promote carcinogenesis or work against cancer development remains to be elucidated. To the best of our knowledge, the novel molecule cluster of differentiation 200 (CD200) has not been studied on human breast cancer subjects. The present study aimed to evaluate interleukin-1β (IL-1β), C-X-C motif chemokine ligand 8 (CXCL8), cancer antigen 15.3 (CA 15.3) and the soluble CD200 (sCD200) levels in the serum samples of breast carcinoma patients in order to predict their role in breast carcinoma. The subjects included individuals with early and advanced stage breast cancers, as well as healthy controls. Commercially available ELISA kits were used to measure the serum concentrations of sCD200, IL-1β, CXCL8, CA 15.3, C-reactive protein (CRP) and leukocyte count. A total of 130 subjects were recruited; 50 early stage cancer, 50 advanced stage and 30 control subjects. Serum sCD200, CXCL8, IL-1β and CRP levels were significantly higher in the early as well as the advanced stage breast cancer patients compared to the control group. The level of CA 15.3 was statistically different between early and advanced stage. There were significant positive correlations between IL-1β and CXCL8, and IL-1β and serum sCD200 levels in the control group. These correlations did not persist in the early or the advanced stage cancer groups except CRP and CA 15.3, but new correlations appeared between serum sCD200 level and leukocyte count for advanced stage breast cancer group. Multivariate regression correlation analysis revealed positive correlation between IL-1β and sCD200; and IL-1β and CXCL8. In conclusion, sCD200, CXCL8, CA 15.3 and IL-1β are proinflammatory molecules and their levels are influenced in breast cancer patients.

Abstract OT1-01-01: A phase I trial of the safety and immunogenicity of a multiple antigen vaccine (STEMVAC) in HER2 negative advanced stage breast cancer patients

Abstract Background: Biologically relevant epithelial to mesenchymal transformation (EMT) associated proteins, a subpopulation of tumor cells with stem like properties, have been identified and are responsible for tumor initiation, metastasis formation and resistance to cancer therapies involved in breast cancer (BC) initiation. It is hypothesized that the acquisition of stem cell properties is driven by EMT induction and that BC stem cells express EMT-associated proteins. A vaccine which would educate the immune system to recognize and eliminate cells that have up-regulated proteins associated with BC stem cells/EMT could eradicate BC at the time of initiation or relapse. We have identified 5 stem cell/EMT proteins that are immunogenic in BC patients and created a vaccine, STEMVAC, composed of extended Th1 epitopes derived from these proteins. STEMVAC is safe and inhibits tumor growth in preclinical murine studies. Trial design: Phase I dose escalation study evaluating 3 doses of STEMVAC admixed with 100 mcg of GMCSF. Patients enrolled sequentially into 1 of 3 dose arms (10 patients/arm): Arm 1=150 mcg, Arm 2=300 mcg, and Arm 3=600 mcg. 3 patients must complete 3 monthly vaccines and month 4 evaluation with no dose limiting toxicity before further accrual to that arm. Patients may receive 2 boosters, 3 and 9 months after their 3rd vaccine. Toxicity is assessed at baseline through end of study. Serial blood draws for immunologic monitoring is done. Eligibility criteria: Stage III-IV HER2 negative BC patients treated with standard therapy who: (1) are without evidence of disease or have stable bone-only disease, (2) are 28 days from last chemotherapy, radiotherapy, systemic steroids, (3) have adequate blood counts, (4) have no active autoimmune disease. Endocrine therapy and bisphosphonates are allowed. Specific aims: (1) Determine the safety of 3 escalating doses of STEMVAC, (2) Determine the most immunogenic dose, (3) Determine whether a STEMVAC Th1 polyepitope plasmid based vaccine elicits persistent T cell memory, and (4) Evaluate if STEMVAC modulates T regulatory and myeloid derived suppressor cells. Statistical methods: Safety will be determined by laboratory and clinical parameters. Descriptive statistics will be used to summarize changes from baseline. Safety benchmarks to move to the next arm will be grade 3 toxicity rate of ≤ 15% and grade 4 toxicity rate of ≤ 5% in the first 3 vaccinations. Immunogenicity evaluated by generation of antigen specific Th1 immunity via ELISPOT. Immunologic efficacy is defined as achievement of significant increase in Th1 immunity for ≥50% of the immunizing antigens compared to baseline; and a greater proportion of patients developing T-cell immunity to a greater number of the antigens included in the vaccine. Exploratory analysis will be used to assess memory Th1 dominant immune response to all 5 antigens. Treg and MDSC will be defined as present or absent, and the probability of each will be estimated as a simple proportion. Target accrual: 30 patients-no patients accrued to date. Citation Format: Higgins DM, Childs JS, Salazar LG, Disis ML. A phase I trial of the safety and immunogenicity of a multiple antigen vaccine (STEMVAC) in HER2 negative advanced stage breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-01-01.