Novel Molecular Targets for Ductal Carcinoma In Situ (DCIS)
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Breast Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 2/17/2019 |
| Start Date: | October 1, 2016 |
| End Date: | December 31, 2019 |
This project is an immunohistochemical study of archived patient breast tissue, specifically
pre-invasive lesion specimens. The purpose is the discovery of novel molecular markers of
pre-invasive breast lesions. These novel markers, once validated in this study, can serve as
targets for individualized prevention therapy, neoadjuvant therapy for ductal carcinoma in
situ (DCIS), or predictors of lesion aggressiveness. We have discovered two novel classes of
DCIS molecular pathways required for the survival of DCIS neoplastic cells that will serve as
the basis for the candidate molecules to be evaluated in this proposed study. The first class
of DCIS molecular markers is autophagy, a cell survival mechanism that we discovered to be
highly augmented in the hypoxic and nutrient deprived intraductal neoplastic cells of human
DCIS (1-4). The second class of biomarker is calcium efflux that is mediated in breast cells
by the calcium export pump Plasma Membrane Calcium ATPase (PMCA2) (5, 6). During normal
lactation, breast epithelium pumps large concentrations of calcium into milk. In neoplastic
lesions, calcium is exported by PMCA2 as a cell survival mechanism, since cells under
metabolic stress accumulate calcium to a toxic level. Calcium export in DCIS may also
contribute to intraductal calcifications, a hallmark of high grade DCIS and the most common
marker of DCIS on mammography (7).
Sentara cares for hundreds of patients per year who are diagnosed with breast pre-invasive
lesions, including atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), and
lobular carcinoma in situ (LCIS). Sentara treats 25% of the women with breast cancer in
Virginia. Coupled with information from the Sentara Cancer Registry, Dr. Hoefer or a research
team member will identify eligible patients with ADH, DCIS, and/or LCIS at the time of the
core biopsy diagnosis, surgical therapy, and/or upon lesion recurrence. After receiving
written informed consent from the eligible patients, Sentara Pathology will retrieve the
corresponding tissue blocks. The recut tissue sections will be processed at George Mason
University, Center for Applied Proteomics and Molecular Medicine for markers relevant to
calcium signaling, Vitamin D response, proliferation, autophagy and inflammation. Combined
with the translational research expertise/technology in the Center for Applied Proteomics and
Molecular Medicine at George Mason University, Sentara's diverse patient cohort provides an
opportunity to address the most fundamental unanswered questions surrounding the etiology,
progression, and therapy of pre-invasive breast lesions.
pre-invasive lesion specimens. The purpose is the discovery of novel molecular markers of
pre-invasive breast lesions. These novel markers, once validated in this study, can serve as
targets for individualized prevention therapy, neoadjuvant therapy for ductal carcinoma in
situ (DCIS), or predictors of lesion aggressiveness. We have discovered two novel classes of
DCIS molecular pathways required for the survival of DCIS neoplastic cells that will serve as
the basis for the candidate molecules to be evaluated in this proposed study. The first class
of DCIS molecular markers is autophagy, a cell survival mechanism that we discovered to be
highly augmented in the hypoxic and nutrient deprived intraductal neoplastic cells of human
DCIS (1-4). The second class of biomarker is calcium efflux that is mediated in breast cells
by the calcium export pump Plasma Membrane Calcium ATPase (PMCA2) (5, 6). During normal
lactation, breast epithelium pumps large concentrations of calcium into milk. In neoplastic
lesions, calcium is exported by PMCA2 as a cell survival mechanism, since cells under
metabolic stress accumulate calcium to a toxic level. Calcium export in DCIS may also
contribute to intraductal calcifications, a hallmark of high grade DCIS and the most common
marker of DCIS on mammography (7).
Sentara cares for hundreds of patients per year who are diagnosed with breast pre-invasive
lesions, including atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), and
lobular carcinoma in situ (LCIS). Sentara treats 25% of the women with breast cancer in
Virginia. Coupled with information from the Sentara Cancer Registry, Dr. Hoefer or a research
team member will identify eligible patients with ADH, DCIS, and/or LCIS at the time of the
core biopsy diagnosis, surgical therapy, and/or upon lesion recurrence. After receiving
written informed consent from the eligible patients, Sentara Pathology will retrieve the
corresponding tissue blocks. The recut tissue sections will be processed at George Mason
University, Center for Applied Proteomics and Molecular Medicine for markers relevant to
calcium signaling, Vitamin D response, proliferation, autophagy and inflammation. Combined
with the translational research expertise/technology in the Center for Applied Proteomics and
Molecular Medicine at George Mason University, Sentara's diverse patient cohort provides an
opportunity to address the most fundamental unanswered questions surrounding the etiology,
progression, and therapy of pre-invasive breast lesions.
Sentara Healthcare is a progressive and integrated healthcare organization that cares for
hundreds of patients per year who are diagnosed with breast cancer and pre-invasive lesions,
including atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), and lobular
carcinoma in situ (LCIS). Sentara Healthcare maintains a Cancer Registry which includes
complete clinical information and disposition information of tissue blocks collected at the
time of the core biopsy diagnosis, the surgical therapy, and upon lesion recurrence. Combined
with the translational research expertise/technology in the Center for Applied Proteomics and
Molecular Medicine (CAPMM) at George Mason University (GMU), the Sentara Healthcare extensive
patient cohort provides an opportunity to address the most fundamental unanswered questions
surrounding over-treatment and under-treatment of pre-invasive breast lesions:
1. Does the histopathologic/molecular character of the carcinoma in situ, the immune
infiltrate, and/or the stroma, correlate with the type of lesion (ADH, DCIS or LCIS),
the grade of the lesion, or the presence of later recurrence?
2. Does the level of autophagy within the lesion duct, or the level of PMCA2, of the
pre-invasive lesion, correlate with lesion grade, the level of apoptosis, or the
presence of later recurrence?
3. Does the level of Vitamin D receptor correlate with the level of PMCA2?
hundreds of patients per year who are diagnosed with breast cancer and pre-invasive lesions,
including atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS), and lobular
carcinoma in situ (LCIS). Sentara Healthcare maintains a Cancer Registry which includes
complete clinical information and disposition information of tissue blocks collected at the
time of the core biopsy diagnosis, the surgical therapy, and upon lesion recurrence. Combined
with the translational research expertise/technology in the Center for Applied Proteomics and
Molecular Medicine (CAPMM) at George Mason University (GMU), the Sentara Healthcare extensive
patient cohort provides an opportunity to address the most fundamental unanswered questions
surrounding over-treatment and under-treatment of pre-invasive breast lesions:
1. Does the histopathologic/molecular character of the carcinoma in situ, the immune
infiltrate, and/or the stroma, correlate with the type of lesion (ADH, DCIS or LCIS),
the grade of the lesion, or the presence of later recurrence?
2. Does the level of autophagy within the lesion duct, or the level of PMCA2, of the
pre-invasive lesion, correlate with lesion grade, the level of apoptosis, or the
presence of later recurrence?
3. Does the level of Vitamin D receptor correlate with the level of PMCA2?
Inclusion Criteria:
- Patients must be female, at least 18 years of age.
- Patients or their legally authorized representative must have signed and dated an
informed consent form
- Patients must have at minimum, adequate samples of breast tissue available for use in
this study.
- Patients with a tissue diagnosis of low, intermediate or high grade ductal carcinoma
in situ or ductal carcinoma in situ with microinvasion.
- Patients with a diagnosis of atypical ductal hyperplasia, lobular cancer in situ or
any preinvasive breast lesion.
- Patients with ductal carcinoma in situ undergoing either lumpectomy and radiation or
mastectomy.
- Patients with a diagnosis of invasive ductal cancer.
Exclusion Criteria:
- Male.
- Patients under the age of 18 or over the age of 89.
- Patient desires not to participate in the study.
- Inability to consent.
We found this trial at
1
site
Newport News, Virginia 23606
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