Variations in the Gut Microbiota in Breast Cancer Occurrence and Bone Metastasis

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Breast cancer is the most common cancer in women and the second most common cancer overall. Although advancements in the early diagnosis and therapy of breast cancer have occurred in recent years, the prognosis of breast cancer bone metastasis remains poor and this type of cancer is rarely cured. The gut microbiota is indispensable for internal homeostasis and regulates various biological processes. Understanding the gut microbiota profiles in normal controls (NCs), breast cancer patients with no metastasis (BNs), and breast cancer patients with bone metastasis (BMs) may shed light on the development of diagnostic and therapeutic targets for breast cancer and bone metastasis. We comprehensively analyzed the gut microbiota from NCs, BNs, and BMs and found that the community diversity decreased in the order of NCs, BNs, and BMs. Streptococcus, Campylobacter and Moraxellaceae showed higher abundances in BNs and BMs than in NCs. The lack of Megamonas and Akkermansia in the BM compared with those in the NC and BN groups was considered related to bone metastasis. Additionally, based on the distinct gut microbiota profiles, we predicted that lipid transportation and metabolism, as well as folate biosynthesis, participate in breast cancer occurrence and that steroid hormone biosynthesis influences bone metastasis. Our study demonstrated that variations in gut microbiota are associated with breast cancer occurrence and bone metastasis, providing attractive targets to develop therapeutic and diagnostic methods.

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  • Research Article
  • Cite Count Icon 1
  • 10.1158/1538-7445.sabcs19-p2-19-02
Abstract P2-19-02: Circulating osteocalcin-positive cells as a novel diagnostic biomarker for bone metastasis in breast cancer patients
  • Feb 14, 2020
  • Cancer Research
  • Sun Wook W Cho + 4 more

Purpose: Diagnosis of bone metastasis (BM) in breast cancer relies on structural changes of bone. We investigated whether circulating osteocalcin-positivecells (cOC) could detect the incipient and/or progressive BM earlier than image-based diagnostics. Experimental design: Metastatic breast cancer patients with or without bone metastasis (designated BM+ or BM-) were enrolled and cOC were quantified at baseline by flow cytometry. The progression of BM was evaluated after 18 months. Murine BM models were established by intra-tibial or -cardiac injection of MDA-MB-231 or 4T1 breast cancer cells. Results: In the baseline analysis, cOC was significantly higher in BM+ than BM- group. In the 18-month follow-up study of BM+ patients (n=63), baseline cOC was significantly associated with BM disease progression. Among BM- patients (n=33), three patients developed new bone metastasis within 18 months and were found to have had higher cOC at baseline. The patients with higher cOC showed shortened BM progression-free survival, compared with those with lower cOC (cutoff=0.045%; P<.001; HR 4.79; 95% CI 2.17-10.56). In murine intra-tibial injection models, cOC significantly increased at an early time-point, even when micro-metastases were evident only by histologic examination but undetectable by bioluminescence imaging. Additionally, in an intra-cardiac injection model, the mice with higher cOC developed BM at an earlier time point, compared with the mice with lower cOC. Conclusions: cOC is increased in the early phase of breast cancer BM and predict the disease progression. cOC can be a novel biomarker for early diagnosis and progression of BM. Citation Format: Sun Wook W Cho, Kyung-Hun Lee, Tae-Yong Kim, Serk In Park, Seock-Ah Im. Circulating osteocalcin-positive cells as a novel diagnostic biomarker for bone metastasis in 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 P2-19-02.

  • Research Article
  • 10.1200/jco.2025.43.16_suppl.e13109
Time-dependent prediction model using modified DeepSurv algorithm for dynamic risk assessment of post-operative bone metastases in breast cancer.
  • Jun 1, 2025
  • Journal of Clinical Oncology
  • Fei Ma + 10 more

e13109 Background: Breast cancer (BC) is the most common cancer in women, with bones being the primary site of metastases (~70%). Bone metastases often lead to skeletal-related events (SREs), adversely impacting patients' quality of life and survival. For post-operative BC, timely risk identification, screening, and intervention for bone metastases will reduce SREs and improve survival. However, formulating personized real-time screening recommendations poses a significant challenge. Our study aimed to develop a model to dynamically predict the risk of bone metastases in post-operative BC with the goal of providing an individual screening strategy. Methods: We retrospectively analyzed BC patients aged 20 to 70 years who were firstly diagnosed between 2010 and 2023 and received surgery from 9 medical centers in China (NCT06544668). Muti-center real-world data were collected and divided into 3 groups: Group A (recurrence with bone metastases), Group B (recurrence without bone metastases), and Group C (no recurrence). Univariable, multivariable and correlation analyses were used to identify risk factors related to bone metastases. Then Cox regression, machine learning (Random Forest, Support Vector Machine), and deep learning (DeepSurv) models and the modified version incorporating longitudinal disease trajectories data were constructed respectively. Tenfold cross-validation was used for hyperparameter tuning. A hold-out test was used to evaluate the performance of the models with concordance index (c-index) as an evaluation metric. Results: A total of 3,970 BC patients were enrolled (Group A, 2,078 [52.3%]; Group B, 817 [20.6%]; Group C, 1,075 [27.1%]). The median time of first recurrence from surgery was 44.1 months. In Group A, the median level of ALP gradually increased within the year prior to bone metastases, whereas no increase was observed in the other 2 groups. Univariate analysis showed that bone metastases were significantly associated with post-surgery baseline characteristics (tumor stage, node stage, pathological grade, nerve invasion, neoadjuvant therapy, and Ki-67) and dynamitic characteristics (ALP level and lung metastases). Among the base prediction models, the DeepSurv model demonstrated the most favorable performance for distinguishing the risk of bone metastases in the hold-out test dataset with c-index of 0.67, and 3, 5 years AUC of 0.66 and 0.69. After incorporating longitudinal data, the c-index of the modified DeepSurv model in test dataset was increased to 0.80, and the AUC values at 3, 5 years to 0.81 and 0.79. Conclusions: This study identified new dynamic risk factors for bone metastases in post-operative BC. By incorporating disease trajectory data, the modified DeepSurv model could dynamically predict bone metastases to enable personalized screening. Validation using external test databases is currently underway.

  • Research Article
  • Cite Count Icon 23
  • 10.1007/s12291-013-0399-8
Detection of Bone Metastases in Breast Cancer (BC) Patients by Serum Tartrate-Resistant Acid Phosphatase 5b (TRACP 5b), a Bone Resorption Marker and Serum Alkaline Phosphatase (ALP), a Bone Formation Marker, in Lieu of Whole Body Skeletal Scintigraphy with Technetium99m MDP.
  • Nov 20, 2013
  • Indian Journal of Clinical Biochemistry
  • B K D Sarvari + 3 more

Bone metastases are a serious problem in patients with advanced cancer disease and their presence usually signifies serious morbidity prior to the patient's death. In breast cancer patients the incidence of bone metastasis is observed to be very high at 70%, as seen during post-mortem examination. Bone metastasis is difficult to diagnose, treat or follow clinically without radiological tools. This study was designed to evaluate the utility of a novel bone resorption marker-serum tartrate-resistant acid phosphatase 5b (TRACP5b) and the bone formation marker such as serum total alkaline phosphatase (ALP), in comparison with whole body skeletal scintigraphy with Technetium99m MDP for the diagnosis of bone metastases (BM) in breast cancer (BC) patients. This study is intended to help the clinician to diagnose bone metastasis without resorting to radiological tools, as they are not cost effective and carry the risk of radiation. Four groups of samples were analysed. 1st group consists 52 normal female (cancer free women), 2nd group consists 38 BC patients without bone metastasis, 3rd group consists 27 breast cancer patients with limited bone metastasis (3 or less than 3 skeletal lesions) and 4th group consists 35 breast cancer patients with extensive bone metastasis (4 or more than 4 skeletal lesions), conformed by whole body skeletal scintigraphy with Technetium99m MDP. One way ANOVA was used to compare serum TRACP5b and serum ALP among these groups. Both serum TRACP5b and serum ALP are not markedly elevated in limited bone metastasis but are strongly elevated in extensive bone metastasis (p<0.0001). As seen in this study the biochemical bone resorption marker, serum TRACP5b, abnormally increased in extensive bone metastasis of breast cancer patients and can be used as a specific marker for bone metastasis in lieu of radiological tools.

  • Research Article
  • Cite Count Icon 111
  • 10.1186/1471-2407-9-102
Up-regulation of bone marrow stromal protein 2 (BST2) in breast cancer with bone metastasis
  • Apr 1, 2009
  • BMC Cancer
  • Dongqing Cai + 6 more

BackgroundBone metastases are frequent complications of breast cancer. Recent literature implicates multiple chemokines in the formation of bone metastases in breast cancer. However, the molecular mechanism of metastatic bone disease in breast cancer remains unknown. We have recently made the novel observation of the BST2 protein expression in human breast cancer cell lines. The purpose of our present study is to investigate the expression and the role of BST2 in bone metastatic breast cancer.MethodscDNA microarray analysis was used to compare the BST2 gene expression between a metastatic to bone human breast cancer cell line (MDA-231BO) and a primary human breast cancer cell line (MDA-231). The BST2 expression in one bone metastatic breast cancer and seven non-bone metastatic breast cancer cell lines were also determined using real-time RT-PCR and Western blot assays. We then employed tissue array to further study the BST2 expression in human breast cancer using array slides containing 20 independent breast cancer tumors that formed metastatic bone lesions, 30 non-metastasis-forming breast cancer tumors, and 8 normal breast tissues. In order to test the feasibility of utilizing BST2 as a serum marker for the presence of bone metastasis in breast cancer, we had measured the BST2 expression levels in human serums by using ELISA on 43 breast cancer patients with bone metastasis, 43 breast cancer patients without bone metastasis, and 14 normal healthy controls. The relationship between cell migration and proliferation and BST2 expression was also studied in a human breast recombinant model system using migration and FACS analysis.ResultsThe microarray demonstrated over expression of the BST2 gene in the bone metastatic breast cancer cell line (MDA-231BO) compared to the primary human breast cancer cell line (MDA-231). The expression of the BST2 gene was significantly increased in the bone metastatic breast cancer cell lines and tumor tissues compared to non-bone metastatic breast cancer cell lines and tumor tissues by real time RT-PCR, Western blot and TMA. Furthermore, serum levels of BST2 measured by ELISA were also significantly higher among patients with breast cancer metastatic to bone compared to breast cancer patients without metastatic to bone (P < .0001). Most importantly, the breast cancer cell line that transfected with BST2 demonstrated increased BST2 expressions, which was associated with increased cancer cell migration and cell proliferation.ConclusionThese results provide novel data indicating the BST2 protein expression is associated with the formation of bone metastases in human breast cancer. We believe that BST2 may be a potential biomarker in breast cancer with bone metastasis.

  • Research Article
  • Cite Count Icon 38
  • 10.1111/1462-2920.15517
Combined hormonal contraceptives are associated with minor changes in composition and diversity in gut microbiota of healthy women
  • May 6, 2021
  • Environmental Microbiology
  • Jovana Mihajlovic + 11 more

Recent human and animal studies have found associations between gut microbiota composition and serum levels of sex hormones, indicating that they could be an important factor in shaping the microbiota. However, little is known about the effect of regular hormonal fluctuations over the menstrual cycle or CHC-related changes of hormone levels on gut microbiota structure, diversity and dynamics. The aim of this study was to investigate the effect of CHCs on human gut microbiota composition. The effect of CHC pill intake on gut microbiota composition was studied in a group of 7 healthy pre-menopausal women using the CHC pill, compared to the control group of 9 age-matched healthy women that have not used hormonal contraceptives in the six months prior the start of the study. By analyzing the gut microbiota composition in both groups during one menstrual cycle, we found that CHC usage is associated with a minor decrease in gut microbiota diversity and differences in the abundance of several bacterial taxa. These results call for further investigation of the mechanisms underlying hormonal and hormonal contraceptive-related changes of the gut microbiota and the potential implications of these changes for women's health. This article is protected by copyright. All rights reserved.

  • Research Article
  • Cite Count Icon 9
  • 10.1007/s11596-013-1083-1
Analysis of clinicopathological factors associated with bone metastasis in breast cancer
  • Feb 1, 2013
  • Journal of Huazhong University of Science and Technology [Medical Sciences]
  • Jing Chen + 9 more

Breast cancer is the second leading cause of cancer death in women today. Once breast cancer metastasizes to bone, mortality increases. Thus, there is an urgent need to identify patients with high risk of bone metastasis, and to find predictive factors for the occurrence of bone metastasis at an earlier stage of breast cancer. Three hundred and sixty patients with pathologically proved breast cancer visiting the Department of Nuclear Medicine for whole body bone scan from January 2006 and January 2009 were investigated in this study. Clinicopathological information was obtained, which consisted of age, menopausal status, clinical staging, lymph node stage, histological grade, the expression of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2). Correlation between bone metastasis and the associated factors was tested by using the Chi-square test. A Cox multivariate analysis was used to assess the factors which independently contributed to survival after bone metastasis in breast cancer patients. Survival curves were drawn for metastasis-free interval and the independent factors which contributed to survival, using the Kaplan-Meier method. Twenty-four patients were excluded from subsequent analysis. Three hundred and thirty-six enrolled patients ranged in age from 22 to 77 years (mean, 47.8 years). ER/PR status [ER(+) vs. ER(-), χ (2)=4.328, P=0.037; ER(+)PR(+) vs. ER(+)PR(-), χ (2)=4.425, P=0.035] and histological grade (χ (2)=7.131, P=0.028) were significantly associated with bone metastasis. ER status (x (2)=8.315, P=0.004) and metastasis-free interval (χ (2)=6.863, P=0.009) were independent prognostic factors for survival in breast cancer patients with bone metastasis. Our study suggested that ER/PR status and histological grade are risk factors for the development of bone metastasis in breast cancer patients. However, ER status and metastasis-free interval are independent prognostic factors for survival in breast cancer patients with bone metastasis. Breast cancer bone metastasis has its unique characteristics, which is helpful to choose the appropriate treatment for breast cancer patients with bone metastasis.

  • Research Article
  • Cite Count Icon 5
  • 10.1016/j.amsu.2021.102532
Correlation between ER, PR, HER-2, and Ki-67 with the risk of bone metastases detected by bone scintigraphy in breast cancer patients: A cross sectional study
  • Jun 29, 2021
  • Annals of Medicine &amp; Surgery
  • Hanif Afkari + 4 more

Correlation between ER, PR, HER-2, and Ki-67 with the risk of bone metastases detected by bone scintigraphy in breast cancer patients: A cross sectional study

  • Research Article
  • Cite Count Icon 20
  • 10.1002/jbmr.4041
Circulating Osteocalcin-Positive Cells as a Novel Diagnostic Biomarker for Bone Metastasis in Breast Cancer Patients.
  • May 7, 2020
  • Journal of Bone and Mineral Research
  • Kyung-Hun Lee + 8 more

Current diagnosis of bone metastasis (BM) in breast cancer relies on structural changes of bone that occur only in the advanced stage. A sensitive biomarker for detecting early progression of bone metastasis is urgently required. We performed clinical and preclinical studies to investigate diagnostic value of circulating osteocalcin-positive cells (cOC) in breast cancer bone metastasis. Metastatic breast cancer patients (n = 92) with or without bone metastasis (ie, BM+ or BM- ) were enrolled, and cOC were measured at enrollment. Patients were followed up for bone metastasis progression for 18 months. BM+ patients (n = 59) were divided into progressive (PD) or stable disease (SD) groups, based on imaging studies at the end of the 18-month study. The PD group had higher baseline cOC compared with the SD group. Furthermore, higher cOC resulted in reduced BM progression-free survival. Three patients in the BM- group (n = 33) developed new BM during the 18-month study, and these patients had a higher level of baseline cOC compared with the remaining BM- patients. In murine preclinical studies, cOC increased at early time points when micro-metastases were evident only by histology but undetectable by bioluminescence imaging. Also, cOC levels predicted the progression of BM and correlated significantly with BM tumor burden. cOC increased in the early phase of breast cancer BM and can predict BM progression, supporting cOC as a potential novel biomarker. © 2020 American Society for Bone and Mineral Research.

  • Research Article
  • 10.1007/s10552-025-02057-5
Molecular mechanisms of bone metastasis in breast cancer based on transcriptomic and microbiomic analysis.
  • Dec 1, 2025
  • Cancer causes & control : CCC
  • Dihui Zhang + 6 more

Bone metastasis (BM) in breast cancer affects patient prognosis, but its molecular mechanisms and relationship with the gut microbiome are not well understood. This study aims to explore gene expression and gut microbiome differences between BM and non-bone metastasis (BNM) patients, which could shed light on cancer progression and metastasis. We utilized a multi-omics approach, integrating transcriptomic and microbiomic data. Bioinformatics techniques including differential expression analysis, functional enrichment, protein-protein interaction network analysis, and LDA effect size analysis were applied. We also constructed miRNA regulatory networks and gene-gene interaction networks to identify key genes and microbial functions involved in BM. The analysis identified significant upregulation of genes such as IBSP, PROM1, and IDO1 in BM patients. miRNA analysis suggested that let-7 family members might regulate these genes and influence cancer progression. Gene-gene network analysis revealed a synergistic role for genes like THBS1 and ITGB3 in tumor progression. Regarding the gut microbiome, BM patients exhibited enriched pathways related to arachidonic acid metabolism, steroid hormone synthesis, and thyroid hormone synthesis, potentially impacting immunity and metabolism. Additionally, Human papillomavirus (HPV) infection pathways were significantly enriched, indicating a possible role in BM. The study highlights distinct gene expression and gut microbiome differences between BM and BNM patients. HPV infection may play a crucial role in BM development, offering new potential biomarkers and therapeutic targets for early diagnosis and treatment of BM in breast cancer.

  • Research Article
  • 10.1158/1557-3265.sabcs24-p3-08-14
Abstract P3-08-14: Analysis of the Occurrence Time of Bone Metastasis and Disease Treatment Patterns in 737 Patients with Breast Cancer Bone Metastasis: A Retrospective Study from China
  • Jun 13, 2025
  • Clinical Cancer Research
  • Xiaojia Wang + 8 more

Background:Bone is the most frequent site of metastasis in breast cancer, with a significant proportion of patients experiencing bone involvement at the initial metastasis. Identifying the critical time periods for its occurrence is crucial for guiding bone metastasis screening, enabling early detection, and facilitating prompt treatment. Since bone targeted agents(BTAs) are vital component of systemic therapy for advanced breast cancer, elucidating real-world treatment patterns holds significant importance for guiding clinical practice advancements. Methods:This single-center retrospective study analyzed patients with advanced breast cancer and bone metastasis admitted to Zhejiang Cancer Hospital between January 1, 2021, and February 28, 2023. Subgroup analyses were performed to analyze correlations between the time from diagnosis to bone metastasis and clinical factors. The skeletal-related events (SREs) were collected during the follow-up. For quantitative indicators that conformed to normal distribution, independent sample t-tests or analysis of variance (ANOVA) were employed; otherwise, non-parametric Mann-Whitney U tests or Kruskal-Wallis tests were used. Bone CT values were quantitatively assessed to evaluate the therapeutic efficacy of bone metastases. Results:Among 737 breast cancer patients with bone metastasis, 416 (71.1%) had bone metastases at the initial metastasis, and within this group, 180 patients (43.8%) had bone as the only site of metastasis; the other 169 patients (28.9%) did not exhibit bone metastasis initially but developed it during subsequent treatment and follow-up. The time from breast cancer diagnosis to the first occurrence of bone metastasis (median, months[mos]) was significantly associated with factors such as receipt of neoadjuvant therapy (73.7mos for no neoadjuvant therapy received, 50.6mos for neoadjuvant therapy received; p&amp;lt;0.001), surgical approach (radical surgery 71.2mos, palliative surgery 24.8mos; p=0.001), number of postoperative pathological lymph node metastases (N0 72.5mos, N1 72.8mos, N2 60.9mos, N3 51.5mos; p=0.001); vascular tumor thrombus invasion (positive 48.2mos, negative 65.1mos; p=0.001); postoperative stage (Stage I 54.6mos, Stage II 64.1mos, Stage III 53.5mos; p&amp;lt;0.001); molecular subtype (HER2+ 48.6mos, Luminal A 77.6mos, Luminal B HER2+ 65.2mos, Luminal B HER2- 63.9mos, TNBC 43.5mos; p&amp;lt;0.001); and Ki 67 expression (73.3ms for Ki 67&amp;lt;15%, 55.4ms for Ki 67≥15%; p=0.005). Of which, the shorter time to bone metastasis were observed with higher Ki 67 values. However, no significant correlation was found between the time from breast cancer diagnosis to bone metastasis and tumor size, histological grade, or pathological type. Among these patients, 90.4% received BTA treatment, and 95.8% of them adhered to the treatment schedule. Furthermore, 35.6% of the patients changed the type of BTA during treatment. Quantitative assessment of bone lesion efficacy using CT values revealed a median pre-treatment CT value of 306.0, which increased to 445.6 post-treatment (p&amp;lt;0.001). During follow-up, 176 patients (23.9%) experienced SREs, primarily bone radiation therapy (47.4%), pathological fractures (35.8%), and bone surgery (27.8%). Conclusion:The timing of bone metastasis after breast cancer diagnosis is significantly correlated with factors such as whether or not neoadjuvant therapy was administered, the surgical approach used, the number of metastatic lymph nodes, the postoperative staging, the molecular subtype, the expression of Ki 67, and the presence of vascular invasion by tumor thrombus. Real-world data from this center suggests that bone targeted agents for breast cancer patients with bone metastasis contribute to improving bone lesion CT values. Citation Format: Xiaojia Wang, Mengyu Ding, Hai Hu, Zhanhong Chen, Yabing Zhen, Wenming Cao, Xiying Shao, Junqing Chen, Huanhuan Zhou. Analysis of the Occurrence Time of Bone Metastasis and Disease Treatment Patterns in 737 Patients with Breast Cancer Bone Metastasis: A Retrospective Study from China [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-08-14.

  • Discussion
  • Cite Count Icon 7
  • 10.2353/ajpath.2007.070582
BMP7: A New Bone Metastases Prevention?
  • Sep 1, 2007
  • The American Journal of Pathology
  • Pierrick G.J Fournier + 1 more

BMP7: A New Bone Metastases Prevention?

  • Research Article
  • Cite Count Icon 101
  • 10.2147/cmar.s155524
Bone metastasis pattern in initial metastatic breast cancer: a population-based study
  • Feb 9, 2018
  • Cancer Management and Research
  • Zhenchong Xiong + 7 more

PurposeBone is one of the most common sites of breast cancer metastasis, and population-based studies of patients with bone metastasis in initial metastatic breast cancer (MBC) are lacking.Materials and methodsFrom 2010 to 2013, 245,707 breast cancer patients and 8901 patients diagnosed with initial bone metastasis were identified by Surveillance, Epidemiology, and End Results database of the National Cancer Institute. Multivariate logistic and Cox regression were used to identify predictive factors for the presence of bone metastasis and prognosis factors. Kaplan–Meier method and log-rank test were used for survival analysis.ResultsEight thousand nine hundred one patients with initial MBC had bone involvement, accounting for 3.6% of the entire cohort and 62.5% of the patients with initial MBC. Also, 70.5% of patients with bone metastasis were hormone receptor (HR) positive (HR+/human epidermal growth factor receptor 2 [HER2]−: 57.6%; HR+/HER2+: 12.9%). Patients with initial bone metastasis had a better 5-year survival rate compared to those with initial brain, liver, or lung metastasis. HR+/HER2− and HR+/HER2+ breast cancer had a propensity of bone metastasis in the entire cohort and were correlated with better prognosis in patients with initial bone metastasis. Local surgery had significantly improved overall survival in initial MBC patients with bone metastasis.ConclusionOur study has provided population-based estimates of epidemiologic characteristics and prognosis in patients with bone metastasis at the time of breast cancer diagnosis. These findings would lend support to optimal surveillance and treatment of bone metastasis in breast cancer.

  • Research Article
  • 10.1158/1535-7163.targ-23-a007
Abstract A007: Preclinical bone metastasis technology platform – Predictive evaluation of experimental therapies on bone metastasis
  • Dec 1, 2023
  • Molecular Cancer Therapeutics
  • Tiina E Kähkönen + 2 more

Most cancer deaths are due to metastases, and bone metastases are a considerable problem especially in breast and prostate cancer, being developed in 70-90% of advanced-stage patients. Despite major investments in oncology drug development, bone metastases are currently incurable and a high unmet medical need with only 5% of patients being alive 5 years after the diagnosis. Development of therapies for bone metastasis has been challenging due to lack of appropriate preclinical models available to support decision making in next phases of drug development. In the absence of clinically relevant preclinical bone metastasis models, the current strategy is to rely on preclinical efficacy data obtained with subcutaneous models that lack the clinically relevant local tissue microenvironment, which has a major impact on tumor growth. The use of clinically non-relevant models in preclinical-stage development may be one important reason for the current &amp;gt;95% failure rate of oncology drugs in clinical trials. To support predictive evaluation of therapies for bone metastatic cancers, we describe a preclinical bone metastasis technology platform for evaluating efficacy of novel therapies on bone metastases. The platform utilizes tumors growing in bone microenvironment, mimicking growth of bone metastases in patients. Syngeneic or humanized mouse models with tumor and immune cells of same species are needed for supporting development of immunotherapies, allowing interactions of tumor and immune cells in the bone metastatic microenvironment, according to the novel osteoimmuno-oncology concept. The platform provides a predictive tool for studying unique biological features associated with different types of bone metastases in cancer-type specific manner. Here we summarize case examples where results from preclinical bone metastasis studies align with clinical findings of different therapies approved or evaluated for bone metastasis. Zoledronic acid, an anti-resorptive bisphosphonate that is currently used in breast cancer patients with bone metastases to prevent cancer-induced bone loss, showed improved bone health but no effects on tumor growth. Radium-223 dichloride, an approved treatment for bone metastatic castration-resistant prostate cancer in patients, showed reduced prostate cancer growth and decreased tumor-induced bone changes. As for immunotherapies, an IDO1 inhibitor had no effects on breast cancer bone metastases and the anti-PD-1 antibody pembrolizumab had no effects on breast and prostate cancer bone metastases, predicting recent clinical findings that demonstrate lack of efficacy of anti-PD-1 in clinical prostate cancer trials. We conclude that the bone metastasis technology platform is a biologically relevant tool for preclinical evaluation of the efficacy of experimental therapies on bone metastasis, and it has been validated with positive and negative case examples, demonstrating its clinically predictive power. Citation Format: Tiina E Kähkönen, Jussi M Halleen, Jenni Bernoulli. Preclinical bone metastasis technology platform – Predictive evaluation of experimental therapies on bone metastasis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A007.

  • Research Article
  • Cite Count Icon 3
  • 10.7754/clin.lab.2019.190438
The Diagnostic Value of Serum miR-129 in Breast Cancer Patients with Bone Metastasis
  • Jan 1, 2020
  • Clinical Laboratory
  • Chongqiang Wang + 4 more

The current study aims to investigate the expression of serum miR-129 in breast cancer patients with bone metastasis and to further study its diagnostic role. Serum samples of 60 patients with bone metastasis of breast cancer and 60 patients with non-bone metastasis of breast cancer were collected. The expression of serum miR-129 in breast cancer patients was detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). The relationship between miR-129 and bone metastasis or bone pain in breast cancer patients with bone metastasis was analyzed. Receiver operating characteristic (ROC) curve was performed to analyze the diagnostic role of serum miR-129 expression in breast cancer patients with bone metastasis. The expression of miR-129 in serum of breast cancer patients with bone metastasis was significantly lower than that of non-bone metastasis patients. Furthermore, the lower the expression level of serum miR-129 was, the higher the degree of bone metastasis and bone pain was found in breast cancer patients. The ROC curve showed that the area under the curve (AUC) of miR-129 expression in serum for diagnosis of bone metastasis of breast cancer was 0.941 (95% CI: 0.891 - 0.991) with the sensitivity and specificity of 87.5% and 91.7%, respectively. In summary, decreased serum miR-129 in breast cancer patients can be used as a potential diagnostic marker of bone metastasis in breast cancer patients.

  • Research Article
  • 10.1158/1538-7445.sabcs23-po5-05-13
Abstract PO5-05-13: Clinical utility of whole body low dose computed tomography for detecting bone metastasis in breast cancer patients: A cross sectional study
  • May 2, 2024
  • Cancer Research
  • Lipton Mitra + 8 more

Clinical utility of Whole Body Low Dose CT scan for detecting bone metastasis in Breast cancer patients: A cross sectional study Background: Skeletal scintigraphy (Bone scan) is the imaging of choice to detect bone metastasis in locally advanced and metastatic breast cancer patients. Nuclear medicine facilities are however limited in their availability. As an alternative diagnostic modality to bone scan, we studied the diagnostic capability of Whole-Body Low Dose CT (WBLDCT) scan for detection of bone metastasis in these patients. Materials and Method: This cross-sectional study was conducted from November 2021 to May 2023 at a tertiary healthcare center in India with an aim to study the clinical applicability of whole-body low dose computed tomography scan for detecting bone metastasis in patients with breast cancer. Breast cancer patients with primary tumor measuring 5cm or more, pathologically proven axillary lymph node metastasis, Stage III/IV disease, symptoms attributable to metastasis and suspected disease recurrence were included. All patients underwent WBLDCT and Bone scan within a period of about 2 weeks. WBLDCT was done during the same time as conventional dose CT scan was being done as part of metastatic workup. WBLDCT acquisition protocol was set in CT scan machine by modulating the technical parameters like Care dose 4D-automated, Care kV semi, rotation time &amp; noise index. The image analysis was performed by Radiologist and Nuclear medicine experts in a blinded fashion. Data was recorded in MS Excel sheet. Sensitivity, specificity, positive and negative predicative value, and concordance rates were calculated using SPSS software ver 25.0. Agreement amongst WBLDCT and Bone scan was calculated using Inter-rater agreement. p value &amp;lt; 0.05 was taken as significant. Results: 110 patients were enrolled in this study. The mean age of participants was 48.5 years and three fourth had stage III disease at presentation. Estrogen receptor positive disease was seen in 43.64% participants while 30% were triple negative. Her2neu positive disease was seen in 27.27% patients. Bone scan couldn’t be done in 03 patients who deferred treatment (these had no bone metastasis on WBLDCT). Both bone scan and WBLDCT detected bone metastasis in 19 patients. Bone scan picked up additional metastasis in three patients which were missed on WBLDCT. WBLDCT detected bone metastasis additionally in three patients which were not detected on Bone scan. Multiple lesions were most seen in vertebrae in 38.5% and 28.6% on bone scan and WBLDCT respectively. The sensitivity and specificity of WBLDCT for detection of bone metastasis was 86.36% and 96.47% respectively. The concordance rate between Bone scan and WBLDCT scan was 94.39% with an Inter-rater Kappa(k) quotient for agreement of 0.828 (p&amp;lt; 0.0001). Conclusion: WBLDCT scan has comparable diagnostic capability to skeletal scintigraphy in detecting bone metastasis in breast cancer and may be a useful alternative specially in resource limited settings. Table 1: Sensitivity, specificity, positive predictive value and negative predictive value of WBLDCT for detection of metastasis Variables Values Sensitivity (95% CI) 86.36% Specificity (95% CI) 96.47% AUC (95% CI) 0.91 Positive Predictive Value (95% CI) 86.36% Negative Predictive Value (95% CI) 96.47% Diagnostic accuracy 94.39% Inter-rater agreement (kappa) 0.828 Citation Format: Lipton Mitra, Suhani Suhani, Ankur Goyal, Rakesh Kumar, Mohit Joshi, Hemanga Bhattacharjee, Haresh KP, Raju Sharma, Rajinder Parshad. Clinical utility of whole body low dose computed tomography for detecting bone metastasis in breast cancer patients: A cross sectional study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-05-13.

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