Tumor Specific Plasma DNA in Breast Cancer

This study is currently recruiting participants.
Verified September 2013 by Dartmouth-Hitchcock Medical Center
Sponsor:
Information provided by (Responsible Party):
Gary Schwartz, Dartmouth-Hitchcock Medical Center
ClinicalTrials.gov Identifier:
NCT01617915
First received: June 10, 2012
Last updated: September 18, 2013
Last verified: September 2013
  Purpose

In 2011, there was an estimated 233,000 cases of invasive breast cancer, and 39,970 deaths from breast cancer in the United States. The vast majority of patients are diagnosed with Stage I-III resectable and potentially curable disease, and for these patients, the most pressing questions are whether adjuvant endocrine or chemotherapy are indicated, and if so, how to determine whether these treatments are working. Adjuvant systemic therapy reduces relative recurrence rates by 30-50%, depending on the age of the patient and tumor characteristics. However, patients with early stage disease often do not bear measurable markers of disease such as an elevated cancer antigen 27-29 (CA27.29) or circulating tumor cells. Patients with early stage breast cancer are typically treated with adjuvant therapy based on historical evidence showing that such therapy prolongs survival in this population.

The contents of dying tumor cells can be detected in the bloodstream, and this may be enhanced by the leaky vasculature of solid tumors. Protein biomarkers of tumor cell death are difficult to detect due to the complex nature of plasma and the lack of technical sensitivity. In contrast, DNA is easier to detect through polymerase chain reaction (PCR) amplification. Indeed, circulating tumor DNA has been detected in plasma from patients with osteosarcoma, breast cancer, and colorectal cancer. Until recently, it was impractical to develop an assay to routinely quantify circulating tumor DNA due to heterogeneity between patients and tumors. Advances in genomic technology now permit sequencing a tumor genome to identify patient-specific genomic aberrations. Major genomic alterations (i.e., insertions, amplifications, deletions, inversions, translocations) can be readily detected using PCR primers which will recognize tumor DNA but not normal DNA.

While this strategy may be generally applicable to diverse types of solid tumors, two issues are apparent in breast cancer. Firstly, the incidence of chromosomal rearrangements varies widely. Whole-genome sequencing of 15 breast tumors revealed a range of 1-231 major genomic alterations (mean= 68), where 2 tumors had 1 alteration, and 9 tumors had > 20 alterations. Single-base point mutations are more common but difficult to reliably detect using PCR. Therefore, the investigators must consider that a small subset of patients may have a limited number of genomic alterations available for this assay. Secondly, intratumoral heterogeneity may mean that some genomic alterations are not present in every tumor cell. Such heterogeneity has been inferred from FISH and immunohistochemistry (IHC) studies for many years, and is now being verified at the genomic level. The investigators must consider that only a subpopulation of tumor cells may be sensitive to cytotoxic therapy, so changes in the levels of circulating tumor DNA may only be reflected with analysis of genomic alterations specific to the sensitive cells.


Condition
Breast Cancer

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Tumor Specific Plasma DNA in Breast Cancer

Resource links provided by NLM:


Further study details as provided by Dartmouth-Hitchcock Medical Center:

Primary Outcome Measures:
  • Circulating tumor levels correlation to response [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To determine whether acute increases in the levels of circulating tumor DNA correlate with response to neoadjuvant chemotherapy in women with early-stage breast cancer.


Secondary Outcome Measures:
  • Circulating tumor DNA following surgery [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To determine whether the levels of circulating tumor DNA acutely decrease following surgical resection of a primary breast tumor.

  • Half life of circulating tumor DNA [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To determine the half-life and optimal timing for detection of changes in levels of circulating tumor DNA.

  • Circulating tumor DNA detection following surgery [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To determine whether circulating tumor DNA detectable at 1-2 weeks following surgical resection of a primary tumor predicts disease recurrence.

  • Circulating tumor DNA correlation with pathologic complete response [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To determine whether the fall in circulating tumor DNA correlates with pathologic complete response to neoadjuvant chemotherapy.

  • Circulating tumor DNA correlation with clinical evidence of disease recurrence [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    To determine whether circulating tumor DNA levels increase prior to clinical evidence of disease recurrence.


Estimated Enrollment: 6
Study Start Date: October 2012
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Breast cancer patients

Criteria

Inclusion Criteria:

  • Histologic documentation of invasive breast cancer by core needle or incisional biopsy
  • The invasive cancer must be either:

    1. Triple negative with both estrogen and progesterone receptor staining present in fewer than 10% of invasive cancer cells by IHC, and Her-2 negative, defined as IHC 0-1+, or with a FISH ratio of < 1.8 if IHC is 2+ or if IHC has not been done.
    2. Her-2 positive with IHC 3+ or a FISH ratio of 2.2.
  • Clinical Stage II-III invasive breast cancer with the intent to treat with:

    1. pretreatment mammography, ultrasound, and breast MRI for staging.
    2. pretreatment axillary staging
    3. neoadjuvant chemotherapy with either dose dense or conventional cyclophosphamide-doxorubicin given as initial chemotherapy. Treatment with neoadjuvant trastuzumab is allowed, as long as trastuzumab is administered after the first dose if doxorubicin and cyclophosphamide.
    4. post-chemotherapy breast MRI.
    5. surgical resection of the primary with an axillary dissection for one or more positive nodes after neoadjuvant chemotherapy.
  • Patients with multicentric or bilateral disease are eligible if the target lesions meet the other eligibility criteria.
  • The subject must agree to undergo the pre-treatment research biopsy.
  • No prior chemotherapy, endocrine therapy, or radiotherapy with therapeutic intent is allowed.
  • Women or men > age 18.
  • Ability to give informed consent.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01617915

Contacts
Contact: Gary N Schwartz, MD 800-639-6918 Cancer.Research.Nurse@Dartmouth.edu

Locations
United States, New Hampshire
Dartmouth-Hitchcock Medical Center Recruiting
Lebanon, New Hampshire, United States, 03756
Contact: Gary N Schwartz, MD    800-639-6918    Cancer.Research.Nurse@Dartmouth.edu   
Sponsors and Collaborators
Dartmouth-Hitchcock Medical Center
  More Information

No publications provided

Responsible Party: Gary Schwartz, Associate Professor of Medicine, Dartmouth-Hitchcock Medical Center
ClinicalTrials.gov Identifier: NCT01617915     History of Changes
Other Study ID Numbers: D12127
Study First Received: June 10, 2012
Last Updated: September 18, 2013
Health Authority: United States: Data and Safety Monitoring Board

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases

ClinicalTrials.gov processed this record on April 15, 2014