Clinical trial NCT00899548: DNA in Predicting Response After Systemic Therapy in Women With Metastatic Breast Cancer
Official title: DNA Methylation in Serum as a Predictive Marker of Progression and Survival Following Systemic Therapy in Patients With Metastatic Breast Cancer
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Breast Cancer
Keywords: stage IV breast cancer
recurrent breast cancer
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2009-05-12
Enrollment: 182
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Metastatic breast cancer patients and women without a history of breast cancer (ie, healthy women or "normals')

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.

Eligibility 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

Primary outcomes:
measure: Progression-free Survival in Patients With a High vs. Low Cumulative Methylation Index (CMI) Value
timeFrame: from week 4 to up to 87 months
measure: Changes in Methylated Gene Markers as Measured by Cumulative Methylation Index
timeFrame: baseline, week 4
measure: Effects of Common Exposures (i.e., Alcohol, Smoking, Medications, and Dietary Factors) on Patterns of Serum Methylation
timeFrame: 9-12 weeks
measure: Creation of a Predictive Model of DNA Methylation Profiles
timeFrame: 9-12 weeks
Secondary outcomes:
measure: Overall Survival in Patients With a High vs. Low CMI Value
timeFrame: from week 4 to up to 3 years
measure: Correlation of CTCs With Serum Methylation
timeFrame: 3-4 weeks
Other outcomes:
measure: Determination if the Addition of CTCs to Serum Methylation Results in an Improved Predictive Model
timeFrame: 3-4 weeks
Locations:
city: Indianapolis
country: United States
facility: Indiana University Melvin and Bren Simon Cancer Center
state: Indiana
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: Chapel Hill
country: United States
facility: Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
state: North Carolina
Study officials:
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
name: Antonio C. Wolff, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.