Circulating Osteocalcin-positive Cells in Breast Cancer Bone Metastasis (COP-BREAST)

• ClinicalTrials.gov Identifier: NCT03814811
• Recruitment Status: Unknown
• First Posted: January 24, 2019
• Last Update Posted: January 24, 2019
• Sponsor: Seoul National University Hospital
• Collaborator: National Cancer Center, Korea
• Information provided by (Responsible Party): Seoul National University Hospital

Study Description

Brief Summary:

Bone metastasis (i.e. cancer cell spreading to bone) is the major clinical problem of advanced breast cancer patients. Bone metastasis is not curable nor preventable. Currently available therapeutic approaches are only palliative. The major hurdle for improving bone metastasis treatment is lack of sensitive diagnostic tools. Diagnosis of bone metastasis is heavily dependent on radiographic imaging of bone destruction that are detectable only when the lesion is significantly large. Accordingly, if bone metastasis can be detected at an earlier time point when bone destruction is minimal or incipient, treatments can be given earlier and the patients can expect better outcomes. We and others previously have found that a subset of bone-forming cells (i.e. circulating osteocalcin-positive cells) exists in the blood stream of the patients with bone diseases (e.g. bone metastasis and inflammation) or active bone formation (e.g. adolescence) in mouse models anf human samples. Extended from this laboratory observation, this clinical study proposes to test the hypothesis that circulating osteocalcin-positive cells are the early biomarker of breast cancer bone metastasis. For this aim, this study will measure circulating osteocalcin-positive cells in the blood samples of breast cancer patient, and examine whether the measure sensitively detects bone metastasis.

Condition or disease	Intervention/treatment
Breast Neoplasms; Bone Metastases	Diagnostic Test: Circulating Osteocalcin-positive (cOC) cells

Detailed Description:

Bone is the most common site of breast cancer metastasis, and the skeletal-related events (SRE) of bone metastasis such as pathologic fractures, cord compression, hypercalcemia and severe pain, accounting for poor quality of life in the terminal stage of the afflicted patients. Since previous SREs are the major risk factors for subsequent SREs related to serious morbidity and mortality, the early detection of bone metastasis prior to clinical symptoms is essential to the better management of breast cancer patients. Currently, diagnosis of bone metastasis is dependent on imaging modalities such as whole-body bone scintigraphy (WBBS). However, detectability of radionuclide activity in the WBBS depends on gross structural bone destruction resulting from considerable progression of macro-metastasis.

Circulating osteoprogenitor cells that is defined a small monocytic cells expressing osteocalcin, a late osteoblast differentiation marker, had been identified in human peripheral blood mononuclear cells (PBMCs). Flow cytometric analyses of the PBMCs using anti-osteocalcin antibody demonstrated that adolescents who are in the period of rapid bone growth showed higher fractions of osteocalcin-positive cells than adults. Moreover, these cells also positively correlated with pathologic changes of bone turnover in such conditions as fracture, hypoparathyroidism, or diabetes. Collectively, circulating osteoprogenitor cells reflects changes of bone turnover in either physiologic or pathologic status.

The scientific hypothesis of this study is that circulating osteoprogenitor cells increases in the early phase of bone micro-metastasis, and the aim of this clinical study is to investigate the difference of circulating osteoprogenitor cells in metastatic breast cancer with or without bone metastasis. This study will also examine whether the patients who have higher number of osteocalcin-positive cells develop bone metastasis at an earlier time point, to validate the value of circulating osteoprogenitor cells in monitoring and/or predictinng the progression of bone metastasis.

Study Design

• Study Type: Observational
• Estimated Enrollment: 200 participants
• Observational Model: Case-Control
• Time Perspective: Cross-Sectional
• Official Title: Circulating Osteocalcin-positive Cells as a Cell-Based Biomarker of Breast Cancer Bone Metastasis Progression
• Actual Study Start Date: July 1, 2017
• Actual Primary Completion Date: September 30, 2017
• Estimated Study Completion Date: December 31, 2021

Groups and Cohorts

Group/Cohort	Intervention/treatment
Bone metastasis(+) with low cOC; Patients who have bone metastasis with low number of circulating osteocalcin-positive (cOC) cells	Diagnostic Test: Circulating Osteocalcin-positive (cOC) cells; Quantitative measurement of osteocalcin-positive cells in the peripheral blood mononuclear cells by flow cytometry
Bone metastasis(+) with high cOC; Patients who have bone metastasis with high number of circulating osteocalcin-positive (cOC) cells	Diagnostic Test: Circulating Osteocalcin-positive (cOC) cells; Quantitative measurement of osteocalcin-positive cells in the peripheral blood mononuclear cells by flow cytometry
Bone metastasis(-) with low cOC; Patients who have metastasis only in extraskeletal sites with low number of circulating osteocalcin-positive (cOC) cells	Diagnostic Test: Circulating Osteocalcin-positive (cOC) cells; Quantitative measurement of osteocalcin-positive cells in the peripheral blood mononuclear cells by flow cytometry
Bone metastasis(-) with high cOC; Patients who have metastasis only in extraskeletal sites with high number of circulating osteocalcin-positive (cOC) cells	Diagnostic Test: Circulating Osteocalcin-positive (cOC) cells; Quantitative measurement of osteocalcin-positive cells in the peripheral blood mononuclear cells by flow cytometry

Outcome Measures

Primary Outcome Measures :

1. Progression of bone metastasis [ Time Frame: 18 months after enrollment ]
   Metastatic bone lesions will be re-evaluated at 18 months using imaging studies such as bone scan, CT, MRI, or PET or incidence of active skeletal-related events (SREs) such as pathologic fracture or progressive neurologic signs
2. Diagnosis of new bone metastasis [ Time Frame: 18 months after enrollment ]
   De novo bone metastasis will be diagnosed using imaging studies

Biospecimen Retention:   Samples Without DNA

Blood

Eligibility Criteria

• Ages Eligible for Study: 20 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Only females are eligible.
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

• Patients in Seoul National University Hospital or Korea University Anam Hospital, Seoul, Korea
• Residents of the Republic of Korea

Criteria

Inclusion Criteria:

• Stages 2A-4 breast cancer patients who are subject to adjuvant chemotherapy or radiotherapy
• 20 years of age or greater
• Female
• Ability to understand the study objectives and willingness to sign written consent
• ECOG status 0, 1 or 2

Exclusion Criteria:

• History of primary cancer diagnosis in other sites than breast within 5 years
• Diseases of bone metabolism including primary hyperparathyroidism, Paget's disease, osteomalacia, osteogenesis imperfecta
• ECOG status 3 or 4
• Retraction of written consent

Contacts and Locations

Contacts

Contact: Sun Wook Cho, M.D., Ph.D.; +82-2-2072-4761; swchomd@snu.ac.kr

Contact: Young Shin Song, M.D., Ph.D.; +82-2-2072-4761; yssongmd@gmail.com

Locations

Korea, Republic of

Korea University Anam Hospital; Recruiting

Seoul, Korea, Republic of, 02841

Contact: Kyung Hwa Park, M.D., Ph.D. +82-2-920-6841 katyoncopark@gmail.com

Seoul National University Hospital; Recruiting

Seoul, Korea, Republic of, 03080

Contact: Sun Wook Cho, M.D., Ph.D. +82-2-2072-4761 swchomd@snu.ac.kr

Sponsors and Collaborators

Seoul National University Hospital

National Cancer Center, Korea

Investigators

• Principal Investigator: Sun Wook Cho, M.D., Ph.D.; Seoul National University Hospital

More Information

Publications:

Jeong HM, Cho SW, Park SI. Osteoblasts Are the Centerpiece of the Metastatic Bone Microenvironment. Endocrinol Metab (Seoul). 2016 Dec;31(4):485-492. doi: 10.3803/EnM.2016.31.4.485. Review.

Eghbali-Fatourechi GZ, Lamsam J, Fraser D, Nagel D, Riggs BL, Khosla S. Circulating osteoblast-lineage cells in humans. N Engl J Med. 2005 May 12;352(19):1959-66.

Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009 Mar;9(3):162-74. doi: 10.1038/nri2506. Review.

Manavalan JS, Cremers S, Dempster DW, Zhou H, Dworakowski E, Kode A, Kousteni S, Rubin MR. Circulating osteogenic precursor cells in type 2 diabetes mellitus. J Clin Endocrinol Metab. 2012 Sep;97(9):3240-50. doi: 10.1210/jc.2012-1546. Epub 2012 Jun 27.

• Responsible Party: Seoul National University Hospital
• ClinicalTrials.gov Identifier: NCT03814811
• Other Study ID Numbers: SNUH-IRB-1706069859
• First Posted: January 24, 2019
• Last Update Posted: January 24, 2019
• Last Verified: January 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Seoul National University Hospital:

Breast Cancer; Bone; Metastasis; Osteoblast

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasm Metastasis; Neoplasms, Second Primary; Bone Neoplasms; Bone Marrow Diseases; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Neoplastic Processes; Pathologic Processes; Bone Diseases; Musculoskeletal Diseases; Hematologic Diseases