Breast Cancer
Conditions
Keywords
stage IV breast cancer, recurrent breast cancer
Brief 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. 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. 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.
Interventions
GENETICDNA methylation analysis
laboratory analysis
GENETICmicroarray analysis
laboratory analysis
GENETICpolymerase chain reaction
laboratory analysis
OTHERlaboratory biomarker analysis
laboratory analysis
Sponsors
National Cancer Institute (NCI)
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival in Patients With a High vs. Low Cumulative Methylation Index (CMI) Value | from week 4 to up to 87 months | — |
| Changes in Methylated Gene Markers as Measured by Cumulative Methylation Index | 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 | 9-12 weeks | — |
| Creation of a Predictive Model of DNA Methylation Profiles | 9-12 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Correlation of CTCs With Serum Methylation | 3-4 weeks |
| Overall Survival in Patients With a High vs. Low CMI Value | from week 4 to up to 3 years |
Other
| Measure | Time frame |
|---|---|
| Determination if the Addition of CTCs to Serum Methylation Results in an Improved Predictive Model | 3-4 weeks |
Countries
United States
Participant flow
Recruitment details
Participants were recruited at each of the participating institutions at Johns Hopkins and within the Translational Breast Cancer Research Consortium.
Participants by arm
| Arm | Count |
|---|---|
| Metastatic Breast Cancer Patients Adult women with metastatic breast cancer. | 182 |
| Total | 182 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 3 |
Baseline characteristics
| Characteristic | Metastatic Breast Cancer Patients |
|---|---|
| Age, Continuous | 56 years |
| Region of Enrollment United States | 182 Participants |
| Sex: Female, Male Female | 182 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 182 |
| other Total, other adverse events | 0 / 182 |
| serious Total, serious adverse events | 3 / 182 |
Outcome results
Primary
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.
Time frame: baseline, week 4
Population: Data to assess this outcome measure was only collected from 129/182 participants with metastatic breast cancer.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Metastatic Breast Cancer Patients -- CMI High | Changes in Methylated Gene Markers as Measured by Cumulative Methylation Index | -1.20 log CMI change | Standard Deviation 1.84 |
Comparison: Hazard ratiop-value: 0.00195% CI: [1.07, 1.32]Regression, Cox
Primary
Creation of a Predictive Model of DNA Methylation Profiles
Time frame: 9-12 weeks
Population: Data was not collected to assess this outcome measure
Primary
Effects of Common Exposures (i.e., Alcohol, Smoking, Medications, and Dietary Factors) on Patterns of Serum Methylation
Time frame: 9-12 weeks
Population: Data was not collected to assess this outcome measure
Primary
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
Population: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Metastatic Breast Cancer Patients -- CMI High | Progression-free Survival in Patients With a High vs. Low Cumulative Methylation Index (CMI) Value | 2.1 months |
| Metastatic Breast Cancer Patients -- CMI Low | Progression-free Survival in Patients With a High vs. Low Cumulative Methylation Index (CMI) Value | 5.8 months |
p-value: 0.000295% CI: [1.23, 2.52]Gehan
Secondary
Correlation of CTCs With Serum Methylation
Time frame: 3-4 weeks
Population: Data was not collected for this outcome measure
Secondary
Overall Survival in Patients With a High vs. Low CMI Value
Time frame: from week 4 to up to 3 years
Population: 141/179 participants who completed the study were evaluable for this outcome measure. Of these, 7 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Metastatic Breast Cancer Patients -- CMI High | Overall Survival in Patients With a High vs. Low CMI Value | 12.3 months |
| Metastatic Breast Cancer Patients -- CMI Low | Overall Survival in Patients With a High vs. Low CMI Value | 21.7 months |
p-value: 0.00195% CI: [1.18, 2.45]Gehan
Other Pre-specified
Determination if the Addition of CTCs to Serum Methylation Results in an Improved Predictive Model
Time frame: 3-4 weeks
Post Hoc
Overall Survival in Participants With High CTC vs. Low CTC
overall survival in participants with high or low cumulative tumor cells (CTC). high CTC refers to \>5 cells/7.5mL and low CTC refers to \<5 cells/7.5mL.
Time frame: 4 weeks
Population: Data for this outcome measure was collected from only 96 participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Metastatic Breast Cancer Patients -- CMI High | Overall Survival in Participants With High CTC vs. Low CTC | High CTC (>5 cells/7.5 mL) | 8.1 months |
| Metastatic Breast Cancer Patients -- CMI High | Overall Survival in Participants With High CTC vs. Low CTC | Low CTC (<5 cells/7.5 mL) | 20.8 months |