Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Breast Neoplasms

Hyperplasia

Breast Diseases

Skin Diseases

Bruce Kimler, Ph.D.

Carol J Fabian, MD

Bruce Kimler, PhD

The overall goal of this project is to develop an integrative system of breast cancer risk assessment based on epidemiologic and biologic risk variables, as well as to develop or refine risk biomarkers which may be useful in predicting and monitoring response to prevention interventions.

1. To correlate established risk biomarkers such as cytomorphology obtained from random periareolar fine needle aspiration ( RPFNA), mammographic breast density, serum bioavailable estradiol and IGF-1/IGFBP-3 with each other and with 5-10 year Gail risk estimates. Where available, and with appropriate safe guards to maintain status for breast cancer susceptibility genes may be included.
2. To determine the relative predictive value of established risk biomarkers for the development of DCIS and/or invasive cancer.
3. To evaluate potential new breast tissue-based biomarkers including Ki-67, PCNA, ER, COX-2, aromatase, methylation of key tumor suppressor genes (i.e., RAR, p16, etc), proteomic patterns in RPFNA and nipple aspirate fluid (NAF), as well as NAF hormone levels, and correlate them with other risk biomarkers listed in 1.
4. To determine the prevalence of polymorphisms of a panel of genes important in hormone and xenobiotic metabolism as well as DNA repair and correlate these polymorphisms with established risk biomarkers listed in 1, as well as with development of DCIS and invasive cancer.
5. To maintain contact with this initially identified cohort of high risk women, acquire demographic data, biologic specimens and data and follow them prospectively for the development.

Protocol for Women at Increased Risk of Developing Breast Cancer

High Risk Breast Clinic: Protocol for Women at Increased Risk for Developing Breast Cancer

development of algorithm for predicting risk for developing breast cancer based on random sampling of benign breast tissue.

Carol Fabian, MD

Professor, Director Breast Cancer Prevention Unit

Anti-Inflammatory Agents

Antirheumatic Agents

Analgesics

All Drugs and Chemicals

Anti-Infective Agents

Celecoxib

Formaldehyde

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

Cyclooxygenase 2 Inhibitors

Cyclooxygenase Inhibitors

Enzyme Inhibitors

celecoxib 400 mg BID

To assess the quantitative real time PCR results results of oligonucleotide probes for a number of gene transcription products that may be useful as predictors of indicators of response to celecoxib.

To assess the quantitative real time PCR results of oligonucleotide probes for a number of gene transcription products that may be useful as predictors or indicators of response to celecoxib, the feasibility of performing six different molecular assays by qRTPCR on formalin fixed paraffin embedded tissue obtained from breast cancer core biopsies and breast cancer reexcision patients, to assess change in Ki-67, PCNA, and several other markers by qRTPCR, correlate change in expression of Ki-67, PCNA, CAX-2, and bcl-2, measured by immunohistochemistry to change measured by qRTPCR, and to determine the reliability of the qRTPCR and immunohistochemical assays by performed selected assays on the same tissue in two different institutions

An Examination of Predictors of Indicators of Response to Celecoxib in Women Who Have a Diagnosis of Early Breast Cancer

Quantitative Real Time PCR in Formalin Fixed Breast Tissue From Biopsy and Re-Excision Specimens: An Ancillary Protocol to a Chemoprevention Trial of Celecoxib

University of Kansas

Antineoplastic Agents

Letrozole

Aromatase Inhibitors

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

letrozole 2.5 mg

To assess the quantitative real time PCR results of oligonucleotide probes for a number of gene transcription products that may be useful as predictors or indicators of response to letrozole

To assess the quantitative real time PCR results of oligonucleotide probes for a number of gene transcription products (PCNA, cyclin-D1, ER alpha, PR, pS2, 450 aromatase, bcl-2, bax, caspase-3, and VEGFR) that may be useful as predictors or indicators of response to letrozole

An Examination of Predictors of Indicators of Response to Letrozole 2.5 mg

Quantitative Real Time PCR in Cytolytic Formalin Fixed Breast Cells Obtained by Periareolar Fine Needle Aspiration. An Ancillary Protocol to a Chemoprevention Trial of Letrozole

Oral Celecoxib 400 mg twice daily for 12 months

Matched blinded placebo twice daily for 12 months

celecoxib

placebo

To assess the effects of twelve months of celecoxib administration by evaluating breast tissue needle aspirations, to determine if cell growth can be slowed.

A blind randomized study of celecoxib in women at high risk of developing breast cancer. Subjects are to take twelve months of drug/placebo. At baseline and after twelve months subjects will have a random periareolar fine needle breast aspiration that will be assessed for epithelial cell growth and other markers of risk. Baseline and twelve month serum samples will also be assessed for hormones and growth factors which may be associated with breast cancer risk. Mammograms at baseline and twelve months will also be assessed for breast density changes.

A Double-blinded Phase II Study of the Expression of Ki-67/MIB-1 in Women With Hyperplasia of the Breast Randomized to Receive Daily Celecoxib 400 mg BID or Placebo

Immunocytochemical staining of breast epithelial cells. Positive cells reflect proliferative activity.

The percent of mammographic breast area that is considered to be at increased density. Evaluated using the semi-automated computer program Cumulus.

Susan G. Komen Breast Cancer Foundation

Randomized to receive celecoxib daily for 12 months

Randomized to receive palcebo daily for 12 months

Placebo

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Dr. Carol Fabian

Randomized to receive placebo daily for 12 months

Change in Percent of Breast Epithelial Cells Staining Positive for Ki-67

Difference between groups, two-sided. Endpoint not specifically powered for effect.

Oral Celecoxib 400 mg twice daily for 12 months

celecoxib: Celecoxib 400 mg BID

Matched blinded placebo twice daily for 12 months

placebo: placebo

Subjects completing 12 months, with baseline and 12 month mammograms suitable for density analysis, such that a change in density over time can be computed

Mammographic Breast Density

Serum Estradiol Concentration

Serum Sex Hormone Binding Globulin (SHBG) Concentration

Molecular Ratio of Serum Concentration of IGF-1 to IGFBP3

Overall Study

Oral Letrozole 2.5 mg daily for six months

letrozole

A pilot study to assess the effects of six months of letrozole on breast tissue risk markers in postmenopausal women on hormone replacement therapy at high risk of developing breast cancer.

A pilot study of letrozole in postmenopausal women on hormone replacement therapy at high risk of developing breast cancer. Subjects will have hyperplasia with atypia (or borderline Epithelial Hyperplasia/Atypical Hyperplasia) and evidence of Estrogen Receptor expression by random periareolar fine needle aspiration and baseline serum estradiol levels less than or equal to 150 pg/ml. The feasibility of performing RT-qPCR on breast specimens for aromatase expression will also be done at baseline.

Study of the Effect of Letrozole on Breast Biomarkers of High Risk Postmenopausal Women Receiving Hormone Replacement Therapy

Proliferation assessment by immunocytochemistry using Ki-67. Expressed as percent of cells staining positive for Ki-67.

Novartis

Carol J. Fabian, M.D.

All subjects completed study and were used for analysis

Change in Proliferation of Breast Epithelial Cells Obtained by Random Periareolar Fine Needle Aspiration.

Menopause

To examine nipple aspirate fluid for secretions that may be identified as a high risk indicator for development of breast cancer, and compare those to serum analysis.

To examine nipple aspirate fluid analysis in lactating women for local concentration of estrogen, prolactin, glucocorticoids, insulin, parity, prior lactation and age. NAF secretors have been reported to have modest increase in breast cancer risk compared to non-secretors . Estrogen levels have been found to be markedly higher in NAF samples than in the serum collected from the same women. Estradiol and estrone concentrations in premenopausal women are 10x and 20x greater in NAF samples than in serum and 50x and 35x greater in post-menopausal women not on HRT. It has been suggested that the disparity between serum and NAF levels may be due to local estrogen production via aromatase and sulfatase.

Protocol for Postmenopausal Women at Increased Risk of Developing Breast Cancer

Study of Manual Nipple Fluid Aspiration IN Post-Menopausal Women

Bone Density Conservation Agents

Micronutrients

Vitamins

Vitamin D

Cholecalciferol

Trace Elements

Calcium

Calcium, Dietary

Vitamin D3

Calciferol

oral capsules, 10,000 IU per week for 6 months

vitamin D3

The overall goal of this project is to determine if high dose vitamin D3 given to premenopausal women at high risk for development of breast cancer, who initially have insufficient levels of 25-hydroxy vitamin D (\<30 ng/ml), will raise 25(OH)D levels above 50 ng/ml. If so, will certain risk biomarkers for development of breast cancer be reliably and favorably modulated?

Protocol Objectives:

To determine if high dose vitamin D3 given to premenopausal women who initially have insufficient levels of 25-hydroxy vitamin D (\<30 ng/ml) will raise 25(OH)D levels above the 50 ng/ml level considered to be required for breast health. If so, will certain risk biomarkers for development of breast cancer be reliably and favorably modulated? The primary endpoint will be a decrease in mammographic breast density (percent area considered at increased density). Change in proliferation (a decrease as assessed by Ki-67) will also be examined. Modulate of expression of genes important in breast cancer risk or reflective of vitamin D's mechanism of action will be studied using quantitative real time polymerase chain reaction (qRT-PCR).

Study Design:

The study is a single-arm open label clinical trial. Women who are high risk for development of breast cancer on the basis of family or personal history will undergo random periareolar fine needle aspiration (RPFNA) to acquire breast cells for assessment of gene expression by qRT-PCR. Women with mammographic density \>10% will be eligible for enrollment. All subjects will receive high dose vitamin D3 (3 capsules of 10,000 IU of vitamin D3 every week for 6-8 months). At that time, a repeat RPFNA and mammogram will be performed. Measurement of serum levels of 25(OH)D will be performed at baseline, 3 months, and 6 months.

Modulation of Breast Cancer Risk Biomarkers by High Dose Vitamin D

Change in the percent of the breast area that is considered to be at higher density on mammogram.

Change in percent of cells expressing staining for Ki-67 antibody in breast epithelial cell specimens acquird by Random Periareolar Fine Needle Aspiration.

Assessment of 25(OH)D levels as a measure of circulating vitamin D.

BTR Group

Group/Cohort Label vitamin D3

vitamin D3: oral capsules, 10,000 IU per week for 6 months

High Dose Vitamin D3 (10,000 IU Weekly)

Female

Sex/Gender, Customized

Race (NIH/OMB)

Ethnicity (NIH/OMB)

Gail model is an algorithm to calculate a predicted probability of developing breast cancer within the next 5 years.

Gail Risk 5-year Probability of Cancer Development

Single arm pilot trial so all comparisons are within subject for change over the course of the study.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Protocol for Women at Increased Risk of Developing Breast Cancer	NCT00291096	Breast Cancer		30 Years - 65 Years	University of Kansas Medical Center
Protocol for Women at Increased Risk of Developing Breast Cancer	NCT00291096	Breast Cancer		30 Years - 65 Years	University of Kansas Medical Center
An Examination of Predictors of Indicators of Response to Celecoxib in Women Who Have a Diagnosis of Early Breast Cancer	NCT00291122	Breast Cancer	celecoxib 400 m...	18 Years -	University of Kansas Medical Center
An Examination of Predictors of Indicators of Response to Celecoxib in Women Who Have a Diagnosis of Early Breast Cancer	NCT00291122	Breast Cancer	celecoxib 400 m...	18 Years -	University of Kansas Medical Center
An Examination of Predictors of Indicators of Response to Letrozole 2.5 mg	NCT00291109	Breast Cancer	letrozole 2.5 m...	18 Years -	University of Kansas Medical Center
Protocol for Women at Increased Risk of Developing Breast Cancer	NCT00291694	Breast Cancer	celecoxib placebo	18 Years -	University of Kansas Medical Center
Protocol for Women at Increased Risk of Developing Breast Cancer	NCT00291135	Breast Cancer	letrozole	18 Years -	University of Kansas Medical Center
Protocol for Postmenopausal Women at Increased Risk of Developing Breast Cancer	NCT00291083	Breast Cancer		18 Years -	University of Kansas Medical Center
Modulation of Breast Cancer Risk Biomarkers by High Dose Vitamin D	NCT01166763	Breast Cancer	vitamin D3	- 55 Years	University of Kansas Medical Center
Protocol for Women at Increased Risk of Developing Breast Cancer	NCT00291135	Breast Cancer	letrozole	18 Years -	University of Kansas Medical Center

Spots Global Cancer Trial Database for breast epithelial hyperplasia