Breast CancerNCT00899548

DNA in Predicting Response After Systemic Therapy in Women With Metastatic Breast Cancer

An observational study of Breast Cancer, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 4 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

RATIONALE: Studying samples of blood from patients with cancer and from healthy participants in the laboratory may help doctors learn more about changes that may occur in DNA and identify biomarkers related to cancer. It may also help doctors predict how well patients will respond to systemic therapy. Read more about this study

Who is it for?: Ages 18 years and older, women onlyHealthy volunteers can take part
Conditions the study is for: Breast Cancer
What is being tested?: DNA methylation analysis, microarray analysis and polymerase chain reaction
How many people: 182 participants
Where: 4 sitesUnited States
Study dates: Jan 2007to Oct 2016
Phase: Observational
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
Women only
Healthy volunteers accepted
Adult, Older adult

Study population: Metastatic breast cancer patients and women without a history of breast cancer (ie, healthy women or "normals')

DISEASE CHARACTERISTICS:

Meets 1 of the following criteria:
Histologically and/or cytologically confirmed stage IV adenocarcinoma of the breast (patient)
No diagnosis of an abnormal breast biopsy (including atypical ductal or lobular hyperplasia), or new diagnosis of breast cancer or breast cancer recurrence within the past five years (healthy participant)
Evidence of disease progression AND initiating a new systemic treatment regimen with trastuzumab (Herceptin®), chemotherapy, endocrine therapy, or investigational agent(s) (patient)
Treatment may be given as a single agent or in combination
Measurable or evaluable disease (patient)
Measurable disease is defined as ≥ 1 measurable lesion identified by RECIST criteria
Patients with evaluable disease only must have ≥ 1 tumor marker (e.g., carcinoembryonic antigen, CA 27-29, or CA 15-3) above normal level
Treated brain metastases (surgery or radiation therapy) allowed provided patient has evidence of disease stability or presence of other site(s) of measurable or evaluable disease (patient)
No leptomeningeal disease
Hormone receptor status not specified

PATIENT CHARACTERISTICS:

Female
Menopausal status not specified
ECOG performance status 0-2
No known cancer within the past 5 years other than basal cell or squamous cell carcinoma of the skin and/or adequately treated cervical cancer (healthy participant)
Not pregnant or nursing

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
Prior therapy in the preoperative, adjuvant, and/or metastatic setting allowed
Any number of prior regimens in any setting allowed
No prior radiation therapy to the only site of disease unless there is evidence of post-radiation disease progression
No selective estrogen receptor modulator or aromatase inhibitor for breast cancer prevention or therapy within the past 12 months (healthy participant)
Prior or concurrent use of raloxifene for osteopenia or osteoporosis therapy allowed (healthy participant)
Concurrent participation in another clinical trial, including one involving an investigational agent(s), allowed

Trial locations and contacts

4 sites in 1 country.

United States4 sites

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, 21231-2410
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
Chapel Hill, North Carolina, 27599-7295
Indiana University Melvin and Bren Simon Cancer Center
Indianapolis, Indiana, 46202-5289
Mayo Clinic Cancer Center
Rochester, Minnesota, 55905

Other trials in United States

About this study

Official title: DNA Methylation in Serum as a Predictive Marker of Progression and Survival Following Systemic Therapy in Patients With Metastatic Breast Cancer

PURPOSE: This laboratory study is looking at DNA in predicting response after systemic therapy in women with metastatic breast cancer.

Read the detailed description

OBJECTIVES:

Primary

Identify a panel of methylated gene markers in serum from women with metastatic breast cancer that is significantly different from that observed in healthy participants.
Assess changes in a panel of methylated gene markers from baseline, after 3-4 weeks, and after 9-12 weeks of systemic therapy in patients with metastatic breast cancer.
Determine the potential effects of common exposures (i.e., alcohol, smoking, medications, and dietary factors) on patterns of serum methylation in patients with metastatic breast cancer and in healthy participants.
Develop a predictive model using DNA methylation profiles in serum that predicts clinical outcome for an individual patient with metastatic disease.

Secondary

Correlate circulating tumor cells (CTCs) with clinical outcome in patients with metastatic breast cancer.
Correlate CTCs with serum methylation in these patients.
Determine if the addition of CTCs to serum methylation results in an improved predictive model.

OUTLINE: This is a prospective, multicenter study.

Patients and healthy participants fill out health assessment questionnaires at baseline, week 3-4, and week 9-12.

Patients undergo blood collection for methylated marker analysis at baseline, weeks 3-4, and weeks 9-12 and circulating tumor cell levels at baseline and weeks 3-4. Healthy participants undergo blood collection for methylated marker analysis at baseline. An additional cohort of healthy participants undergo follow-up blood collection ≥ 1 week after baseline.

DNA methylation is measured by quantitative multiplex methylation-specific polymerase chain reaction (QM-MSP) assay.

After completion of study procedures, patients are followed every 3-4 months.

PROJECTED ACCRUAL: A total of 150 patients and 150 healthy participants will be accrued for this study.

Conditions: Breast Cancer
Being tested: DNA methylation analysis, microarray analysis, polymerase chain reaction, laboratory biomarker analysis
Keywords: stage IV breast cancer, recurrent breast cancer
Medical subject headings: Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

DNA methylation analysisGenetic
laboratory analysis
microarray analysisGenetic
laboratory analysis
polymerase chain reactionGenetic
laboratory analysis
laboratory biomarker analysisOther
laboratory analysis

Study groups in NCT00899548
Study group	Role	What they receive
Metastatic breast cancer patients		DNA methylation analysis, microarray analysis, polymerase chain reaction, laboratory biomarker analysis Receives: Genetic: DNA methylation analysis; Genetic: microarray analysis; Genetic: polymerase chain reaction; Other: laboratory biomarker analysis

What is being measured

The primary outcome is the main question the study is designed to answer.

Progression-free Survival in Patients With a High vs. Low Cumulative Methylation Index (CMI) Value
Measured: from week 4 to up to 87 months
Changes in Methylated Gene Markers as Measured by Cumulative Methylation Index
log change in cumulative methylation index (CMI) from baseline to week 4. Individual gene methylation (M) is calculated as a methylation index (MI) where MI = (methylated copies)/(number of methylated genes + gene standard copies) * 100. The MI of each sample was averaged across duplicates. The cumulative methylation index (CMI) is the sum of the MI for all genes. The log change from based line to week 4 could increase or decrease. CMI was evaluated as a continuous marker for change from baseline.
Measured: baseline, week 4
Effects of Common Exposures (i.e., Alcohol, Smoking, Medications, and Dietary Factors) on Patterns of Serum Methylation
Measured: 9-12 weeks
Creation of a Predictive Model of DNA Methylation Profiles
Measured: 9-12 weeks

Secondary outcomes (2)

Overall Survival in Patients With a High vs. Low CMI Value
Measured: from week 4 to up to 3 years
Correlation of CTCs With Serum Methylation
Measured: 3-4 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Jan 2007Oct 2016

First posted12 May 2009 (estimated)
Study startJan 2007
Primary completionJun 2010
Study completionOct 2016

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Breast CancerStudies of the same condition, open and under way.
More trials run by Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Observational
Observational model: Cohort
Time perspective: Prospective
Enrolment: 182 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00899548
Sponsor's protocol ID: J0524
Other IDs: P30CA006973, JHOC-J0524, JHOC-SKCCC-J0524, CDR0000509417, NA_00000717
Status last verified: Jul 2019
First submitted: 9 May 2009
Last updated: 26 Jul 2019
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
Individual data sharing: Yes: Data set will be available upon review and approval by the Correlative Science Review Committee of the Translational Breast Cancer Research Consortium (TBCRC). Inquiries should be addressed to the study chair, Dr. Antonio Wolff

Publications

Visvanathan K, Fackler MS, Zhang Z, Lopez-Bujanda ZA, Jeter SC, Sokoll LJ, Garrett-Mayer E, Cope LM, Umbricht CB, Euhus DM, Forero A, Storniolo AM, Nanda R, Lin NU, Carey LA, Ingle JN, Sukumar S, Wolff AC. Monitoring of Serum DNA Methylation as an Early Independent Marker of Response and Survival in Metastatic Breast Cancer: TBCRC 005 Prospective Biomarker Study. J Clin Oncol. 2017 Mar;35(7):751-758. doi: 10.1200/JCO.2015.66.2080. Epub 2016 Nov 21.
PubMed 27870562

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Study at a glance

From the registry record, last updated by the sponsor on 26 Jul 2019. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: DNA Methylation in Serum as a Predictive Marker of Progression and Survival Following Systemic Therapy in Patients With Metastatic Breast Cancer
ClinicalTrials.gov ID: NCT00899548
Acronym / sponsor ID: J0524
Conditions: Breast Cancer
Keywords: stage IV breast cancer, recurrent breast cancer
Study type: Observational
Recruitment status: Completed
Enrolment: 182 participants (actual)
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsUniversity, hospital or other
Collaborators: National Cancer Institute (NCI)
Study start: Jan 2007 (actual)
Primary completion: Jun 2010 (actual)
Study completion: Oct 2016 (actual)
First posted: 12 May 2009 (estimated)
Results: Posted 26 Jul 2019

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

PURPOSE: This laboratory study is looking at DNA in predicting response after systemic therapy in women with metastatic breast cancer.

Detailed description

OBJECTIVES:

Primary

Identify a panel of methylated gene markers in serum from women with metastatic breast cancer that is significantly different from that observed in healthy participants.
Assess changes in a panel of methylated gene markers from baseline, after 3-4 weeks, and after 9-12 weeks of systemic therapy in patients with metastatic breast cancer.
Determine the potential effects of common exposures (i.e., alcohol, smoking, medications, and dietary factors) on patterns of serum methylation in patients with metastatic breast cancer and in healthy participants.
Develop a predictive model using DNA methylation profiles in serum that predicts clinical outcome for an individual patient with metastatic disease.

Secondary

Correlate circulating tumor cells (CTCs) with clinical outcome in patients with metastatic breast cancer.
Correlate CTCs with serum methylation in these patients.
Determine if the addition of CTCs to serum methylation results in an improved predictive model.

OUTLINE: This is a prospective, multicenter study.

Patients and healthy participants fill out health assessment questionnaires at baseline, week 3-4, and week 9-12.

DNA methylation is measured by quantitative multiplex methylation-specific polymerase chain reaction (QM-MSP) assay.

After completion of study procedures, patients are followed every 3-4 months.

PROJECTED ACCRUAL: A total of 150 patients and 150 healthy participants will be accrued for this study.

Study design

Observational model: Cohort
Time perspective: Prospective
Number of arms: 1

Arm	Type	Receives
Metastatic breast cancer patients	–	Genetic: DNA methylation analysis, Genetic: microarray analysis, Genetic: polymerase chain reaction, Other: laboratory biomarker analysisDNA methylation analysis, microarray analysis, polymerase chain reaction, laboratory biomarker analysis

Who may qualify

Ages: 18 years and older
Sex: Female only
Healthy volunteers: Accepted
Age groups: Adult, Older adult
Study population: Metastatic breast cancer patients and women without a history of breast cancer (ie, healthy women or "normals')

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
DNA methylation analysislaboratory analysis	Genetic	Metastatic breast cancer patients
microarray analysislaboratory analysis	Genetic	Metastatic breast cancer patients
polymerase chain reactionlaboratory analysis	Genetic	Metastatic breast cancer patients
laboratory biomarker analysislaboratory analysis	Other	Metastatic breast cancer patients

Primary outcome

Progression-free Survival in Patients With a High vs. Low Cumulative Methylation Index (CMI) Value
Time frame: from week 4 to up to 87 months
Changes in Methylated Gene Markers as Measured by Cumulative Methylation Index
Time frame: baseline, week 4
log change in cumulative methylation index (CMI) from baseline to week 4. Individual gene methylation (M) is calculated as a methylation index (MI) where MI = (methylated copies)/(number of methylated genes + gene standard copies) * 100. The MI of each sample was averaged across duplicates. The cumulative methylation index (CMI) is the sum of the MI for all genes. The log change from based line to week 4 could increase or decrease. CMI was evaluated as a continuous marker for change from baseline.
Effects of Common Exposures (i.e., Alcohol, Smoking, Medications, and Dietary Factors) on Patterns of Serum Methylation
Time frame: 9-12 weeks
Creation of a Predictive Model of DNA Methylation Profiles
Time frame: 9-12 weeks

2 secondary outcomes

Overall Survival in Patients With a High vs. Low CMI Value
Time frame: from week 4 to up to 3 years
Correlation of CTCs With Serum Methylation
Time frame: 3-4 weeks

Results and safety

Results posted to the registry on 26 Jul 2019, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Metastatic Breast Cancer Patients	182	179

Primary outcome: Progression-free Survival in Patients With a High vs. Low Cumulative Methylation Index (CMI) Value

Time frame: from week 4 to up to 87 months. Median (95% Confidence Interval). Unit: months

Measure	Metastatic Breast Cancer Patients -- CMI High n = 71	Metastatic Breast Cancer Patients -- CMI Low n = 57
Value	2.1 (1.7 to 3.2)	5.8 (4.7 to 7.4)

Metastatic Breast Cancer Patients -- CMI High vs Metastatic Breast Cancer Patients -- CMI Low: Hazard Ratio (HR): 1.76 (95% CI 1.23 to 2.52), p = .0002, Gehan

Population analysed: 141/179 participants who completed the study were evaluable for this outcome measure. Of these, 8 participants were excluded from analysis for events experienced before week 4, 2 participants had inadequate samples for analysis and data was not collected from 3 participants.

Primary outcome: Changes in Methylated Gene Markers as Measured by Cumulative Methylation Index

Time frame: baseline, week 4. Mean (Standard Deviation). Unit: log CMI change

Measure	Metastatic Breast Cancer Patients n = 129
Value	-1.20 (1.84)

Metastatic Breast Cancer Patients: Cox Proportional Hazard: 1.19 (95% CI 1.07 to 1.32), p = 0.001, Regression, Cox

Population analysed: Data to assess this outcome measure was only collected from 129/182 participants with metastatic breast cancer.

Primary outcome: Effects of Common Exposures (i.e., Alcohol, Smoking, Medications, and Dietary Factors) on Patterns of Serum Methylation

Time frame: 9-12 weeks

Population analysed: Data was not collected to assess this outcome measure

Primary outcome: Creation of a Predictive Model of DNA Methylation Profiles

Time frame: 9-12 weeks

Population analysed: Data was not collected to assess this outcome measure

2 secondary outcomes are reported in the full results.

Adverse events

Time frame: up to 12 weeks from time of consenting to study. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Metastatic Breast Cancer Patients	3 of 182 (1.6%)	0 of 182 (0%)	3 of 182

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 26 Jul 2019.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Results publication: PubMed 27870562Visvanathan K, Fackler MS, Zhang Z, Lopez-Bujanda ZA, Jeter SC, Sokoll LJ, Garrett-Mayer E, Cope LM, Umbricht CB, Euhus DM, Forero A, Storniolo AM, Nanda R, Lin NU, Carey LA, Ingle JN, Sukumar S, Wolff AC. Monitoring of Serum DNA Methylation as an Early Independent Marker of Response and Survival in Metastatic Breast Cancer: TBCRC 005 Prospective Biomarker Study. J Clin Oncol. 2017 Mar;35(7):751-758. doi: 10.1200/JCO.2015.66.2080. Epub 2016 Nov 21.
Individual participant dataSharing planned: Yes. Data set will be available upon review and approval by the Correlative Science Review Committee of the Translational Breast Cancer Research Consortium (TBCRC). Inquiries should be addressed to the study chair, Dr. Antonio Wolff

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Antonio C. Wolff, MD principal investigator

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

4 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

An observational study of Breast Cancer, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 4 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Jul 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Yes. Results are posted in the registry (first posted 26 Jul 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression-free Survival in Patients With a High vs. Low Cumulative Methylation Index (CMI) Value (time frame: from week 4 to up to 87 months). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00899548, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Jul 2019.