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ForeCYTE Breast Aspirator used for bilateral collection of Nipple Aspirate Fluid (NAF) for cytologic testing

ForeCYTE Breast Aspirator

Jonathan D. Herman, MD, FACOG

The purpose of this study is to measure the performance characteristics for the collection, fixation and transportation of clinical nipple aspirate fluid (NAF) specimens of the ForeCYTE Breast Aspirator across 3 independent labs and the National Reference Laboratory for Breast Health (NRLBH). The study hypothesis is that each lab will have a specimen acceptability rate of at least 90%. If it is assumed that the true level of acceptability testing is approximately 96%, then the lower bound of a one-sided 95% confidence interval is expected to be at least 90%.

A) NAF Collection at physician's office: The Principle Investigator identified and qualified the study subjects. He and the assigned study coordinator from his clinic completed all entries in the Study Case Report Form related to the collection site. He collected the NAF specimens at the Physician Office Collection Sites in accordance with the Instructions for Use.

B) NAF Processing at physician's office: The Principle Investigator's designate processed the NAF specimens for shipment to the selected laboratories in accordance with the Instructions for Use.

C) NAF Transport from physician's office to laboratory: The patient specimen collection membranes were placed in resealable pouches, packed in shipping boxes (provided) and transported by Federal Express to the participating Independent Clinical Laboratories. The Federal Express packaging was pre-labeled for the PI within each of the four laboratories and the specimens were sent in the order in which they were collected to each of the laboratories. Left and right breast specimen from the same subject were sent to the same lab, but in a subject based sequence. The shipments will be shipped serially to lab ABCD, ABCD, ABCD, ABCD, etc. So specimens from subject 1 went to laboratory A, specimens from subject 2 to lab B, specimens from subject 3 to lab C, specimens from subject 4 to lab D, specimens from subject 5 to lab A, etc. The PI completed the Testing Facility Shipping and Receiving Tracking Form for all specimens.

D) NAF Processing at laboratory: The NAF was processed at the clinical cytology laboratories in accordance with the Instructions for Use that accompanied each patient kit.

E) NAF Cytology Classification: A trained, board-certified pathologist read the slides. The data was reported in the Case Report Form according to the format recommended by the College of American Pathologists. The criteria for reading and interpreting the slides are contained in Table 2 and were adapted from King, et al. The laboratory portion of the Case Report Form was completed for each patient.

ForeCYTE Breast Aspirator for Sample Collection and Cytological Testing of Nipple Aspirate Fluid

A Single-arm, Multi-laboratory Clinical Trial of the ForeCYTE Breast Aspirator for Sample Collection, Processing and Cytological Testing of Nipple Aspirate Fluid

A specimen collected, fixated, shipped and received by the reference lab per specification, and rated by the receiving lab as acceptable for cytological testing and interpretation, is deemed acceptable.

Quest Diagnostics-Nichols Insitute

National Reference Laboratory for Breast Health

Sound Pathology Associates

Puget Sound Institute of Pathology

Atossa Therapeutics, Inc.

All Drugs and Chemicals

Fluorodeoxyglucose F18

Radiopharmaceuticals

2-Fluorodeoxyglucose

Sharon A Savage, M.D.

This study will explore new screening methods for early detection of breast and ovarian cancer in women at high risk for these diseases, because they have an altered breast cancer 1 (BRCA1) or breast cancer 2 (BRCA2) gene. It will also try to determine if breast tissue characteristics in women with a BRCA1 or BRCA2 mutation differ from those in women with a normal gene.

Premenopausal women between 25 and 45 years of age who have participated in National Cancer Institute studies for families or individuals at high genetic risk of cancer (78-C-0039 or 99-C-0081) and who have at least a 50 percent probability of carrying an altered BRCA1 or BRCA2 gene may be eligible for this study.

At the first visit, participants will have from 4 to 24 tablespoons of blood drawn and will be interviewed about breast and ovarian cancer risk factors, family and personal history of cancer, history of pregnancies, use of oral contraceptives and other hormones and drugs, and previous surgery on the breasts and ovaries. In addition, they will undergo the following procedures:

Routine breast and ovarian cancer screening for high-risk women, including a mammogram, breast and pelvic exam, instruction in breast self-examination, CA 125 blood test and transvaginal ultrasound of the ovaries.

Magnetic Resonance Imaging (MRI) of the breast MRI uses a strong magnetic field to show structural and chemical changes in tissues.

Breast Duct Lavage In this procedure samples of fluid and cells from the lining of the breast milk ducts are collected to look for cancerous or pre-cancerous cell changes.

Positron Emission Tomography (PET) scan PET scanning will be done only in participants whose mammogram or MRI findings require additional evaluation. This diagnostic test is based on differences in how cells take up and use glucose (sugar), one of the body s main fuels.

Annual follow-up visits will be scheduled for 3 years and will include routine high-risk screening as described above, blood draw, update of family history and risk factors, breast MRI, breast duct lavage and, if there are changes on the MRI or mammogram that need further evaluation, the PET will be repeated.

Background:

* Women who carry mutations in genes such as BRCA1/2 have a higher lifetime risk of breast cancer (BC) and are at risk of developing BC at earlier ages than women in the general population.
* Prophylactic mastectomy and/or oophorectomy may be used to decrease risk and intensified mammographic and magnetic resonance imaging (MRI) surveillance may allow earlier diagnosis; however, prophylactic mastectomy has not been shown to convey survival advantage over more conservative management.
* Greater breast tissue density and low BC incidence result in a lower positive predictive value of mammography in premenopausal women as compared to postmenopausal women (PPV=0.04 for women aged 40-49).
* This study explores whether high-risk breast imaging phenotypes may be identified by comparing imaging characteristics of mutation carriers/non-carriers using two imaging modalities: mammography and MRI.
* Nipple Aspiration Fluid collection (NAF) and breast duct lavage will be used to obtain cytologic materials which may be used as an adjunct to breast imaging for the early detection of epithelial atypia and pre-invasive cancer.

Objectives:

* Compare four outcomes including two mammographic density measures (qualitative and semiquantitative), fibroglandular volume measure using MRI, and contrast enhancement measure using MRI (both semiquantitative) in mutation carriers/non-carriers to improve lesion detection
* Explore non-ionizing approaches (MRI) to BC screening because the effects of ionizing radiation due to mammography are unknown.
* Use NAF and/or BDL to obtain epithelial cell samples and correlate cytologic and imaging findings.
* Gather prospective data on the transformation from normal/hyperplastic/pre-invasive/invasive disease in BRCA1/2 mutation carriers/non-carriers through molecular/genetic studies of breast tissue (via biopsy of radiographic abnormalities) or breast fluid (via BDL and/or nipple aspiration) and develop molecular markers for early detection of epithelial atypia/pre-invasive cancer.
* Assess the psychosocial impact of participation in a BC screening program.

Eligibility:

* Women 25-56 years of age carrying a known BRCA1/2 deleterious mutation.
* Women between the ages of 25 -56 who are first- or second- degree relatives of individuals with a deleterious BRCA1/2 mutation.
* Women aged 25-56 who are first- or second- degree relatives of individuals with BRCA-associated cancers in families with documented BRCA mutations.

Design:

* Prospective cohort study of 200 women to gather data on the evolution of epithelial cell/molecular changes in BRCA1/2 mutation carriers, by collecting/analyzing NAF, BDL fluid, biopsy tissues (when indicated), and serum/lymphocytes; samples are stored for future studies.
* Women complete questionnaires and undergo breast/pelvis examination, transvaginal ultrasonography, serum pregnancy test, fasting glucose, electrolytes, BUN, creatinine and CA 125. Standard four view mammogram and breast MRI are performed on study entry and annually for three additional years.

Breast Imaging Studies in Women at High Genetic Risk of Breast Cancer: Annual Follow-Up Study

Breast Imaging Screening Studies in Women at High Genetic Risk of Breast Cancer: Annual Follow-up Study

Compare four outcomes including two mammographic density measures (qualitative and semi-quantitative), fibroglandular volume measure using MRI, and contrast enhancement measure using MRI (both semiquantitative) in mutation carriers/non-carriers to improve lesion detection

Use NAF and/or BDL to obtain epithelial cell samples and correlate cytologic and imaging findings.

Gather prospective data on the transformation from normal/hyperplastic/pre-invasive/invasive disease in BRCA1/2 mutation carriers/non-carriers through molecular/genetic studies of breast tissue (via biopsy of radiographic abnormalities) or breast fluid (via BDL and/or nipple aspiration) and develop molecular markers for early detection of epithelial atypia/pre-invasive cancer.

Assess the psychosocial impact of participation in a BC screening program.

National Cancer Institute (NCI)

Jennifer T Loud, C.R.N.P.

Women who carrying a BRCA1 or BRCA2 gene mutation or who are the first- or second-degree relative of an individual with a BRCA-associated cancer in a family documented to have a BRCA1 or BRCA2 mutation will be eligible for enrollment into this pilot study of breast cancer screening modalities. We will recruit up to fifty women (twenty-five women who carry an altered BRCA1 or BRCA2 gene and 25 non-carriers matched by age and family mutation type) with regular menstrual cycling (documented by menstrual history and premenopausal FSH level). A physical exam including exam of the breast and pelvis, a standard four view mammogram, breast MRI and PET scan will be scheduled initially during either the follicular or mid-luteal phase of the menstrual cycle. A unilateral cranio-caudal mammogram, and bilateral MRI and PET scan will be repeated three months after entry during the phase not initially studied. A CA125 and transvaginal color doppler ultrasonography will be done in the follicular phase. Carriers and non-carriers will be compared with respect to menstrual cycle differences in: (1) two measures of mammographic density (qualitative and semiquantitative); (2) a semiquantitative measure of fibroglandular volume (MRI); (3) a semiquantitative measure of contrast enhancement (MRI); and (4) FDG uptake measured over time (PET scan). On the initial and three-month visit, all participants will undergo breast duct lavage to investigate if there are consistent menstrual cycle differences in breast ductal cytologies. Participants will be seen annually thereafter for an additional three years of follow-up. A physical exam, standard four-view mammography, breast MRI, CA 125, transvaginal color doppler ultrasonography and breast duct lavage will be done annually. Consent for a PET study will be requested if an abnormality is detected on mammography or breast MRI requiring additional clinical or radiographic follow-up.

Participants in the Menstrual Cycle Pilot Study, will complete a self-administered questionnaire and telephone interview and will complete periodic follow-up questionnaires to assess various behavioral and psychosocial endpoints.

As part of the Menstrual Cycle Pilot Study, we will recruit 25 volunteers to assist in training study investigators in performing breast duct lavage. Cytologies obtained from volunteers will be used to develop oncogene probe panels to be used in the study.

Asymptomatic, premenopausal women are (1) known carriers of an altered BRCA1 or BRCA2 gene, or (2) first- or second-degree relatives of individuals with a BRCA-associated cancer in a family documented to have a BRCA1 or BRCA2 gene mutation will be eligible for inclusion in this pilot study to assess new approaches to early detection of breast and ovarian cancer in high-risk women. We will recruit up to fifty women (twenty-five women who carry an altered BRCA1 or BRCA2 gene and 25 non-carriers matched by age and family mutation type) with regular menstrual cycling (documented by menstrual history and premenopausal FSH level). A physical exam including exam of the breast and pelvis, a standard four view mammogram and breast MRI will be scheduled initially during either the follicular or mid-luteal phase of the menstrual cycle. A unilateral cranio-caudal mammogram and bilateral MRI will be repeated three months after entry during the phase not initially studied. A CA125 and transvaginal color doppler ultrasonography will be done in the follicular phase. Carriers and non-carriers will be compared with respect to menstrual cycle differences in: (1) two measures of mammographic density (qualitative and semiquantitative); (2) a semiquantitative measure of fibroglandular volume (MRI); and (3) a semiquantitative measure of contrast enhancement (MRI). On the initial and three-month visit, all participants will undergo breast duct lavage to investigate if there are consistent menstrual cycle differences in breast ductal cytologies. Participants will be seen annually thereafter for an additional three years of follow-up. A physical exam, standard four-view mammography, breast MRI, CA 125, transvaginal color doppler ultrasonography and breast duct lavage will be done annually.

Participants in the Menstrual Cycle Pilot Study, will complete a self-administered questionnaire and telephone interview and will complete periodic follow-up questionnaires to assess various behavioral and psychosocial endpoints.

As part of the Menstrual Cycle Pilot Study, we will recruit 25 volunteers to assist in training study investigators in performing breast duct lavage. Cytologies obtained from volunteers will be used to develop oncogene probe panels to be used in the study.

Breast Imaging Studies in Women at High Genetic Risk of Breast Cancer: Menstrual Cycle Study

Breast Imaging Studies in Women at High Genetic Risk of Breast Cancer: Menstrual Cycle Pilot Study

These are: 2 measures of mammographic density (qualitative and semiquantitative), a semiquantitative measure of fibroglandular volume and of dynamic contrast enhancement (MRI), and FDG uptake over time (PET scan). We will determine if these measures vary between the carriers \&amp; non carriers of BRCA1/2 mutations.Due to the difficulty in tracking and timing menstrual cycles in women who resided great distances from the NIH, we abandoned further recruitment after the pilot study of ductal lavage.

Symptoms and General Pathology

Hyperplasia

Menopause

Hormones

Carol J Fabian, MD

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
ForeCYTE Breast Aspirator for Sample Collection and Cytological Testing of Nipple Aspirate Fluid	NCT02218385	Breast Neoplasm...	ForeCYTE Breast...	20 Years - 75 Years	Atossa Therapeutics, Inc.
Breast Imaging Studies in Women at High Genetic Risk of Breast Cancer: Annual Follow-Up Study	NCT00006421	Breast Cancer	2-Fluorodeoxygl...	18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Breast Imaging Studies in Women at High Genetic Risk of Breast Cancer: Menstrual Cycle Study	NCT00006425	Breast Cancer		18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Breast Imaging Studies in Women at High Genetic Risk of Breast Cancer: Menstrual Cycle Study	NCT00006425	Breast Cancer		18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Protocol for Postmenopausal Women at Increased Risk of Developing Breast Cancer	NCT00291083	Breast Cancer		18 Years -	University of Kansas Medical Center

Spots Global Cancer Trial Database for nipple aspirate fluid