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Paget Disease of the Breast

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Citrate

Tamoxifen Plus Medroxyprogesterone Acetate (MPA) x 5 years

medroxyprogesterone

tamoxifen citrate

adjuvant therapy

Ronald K. Potkul, MD

Barbara L. Smith, MD, PhD

RATIONALE: It is not yet known whether medroxyprogesterone is effective in preventing endometrial disorder in patients with breast cancer who are taking tamoxifen.

PURPOSE: Randomized phase III trial to study the effectiveness of medroxyprogesterone in preventing endometrial disorder in postmenopausal women who have ductal carcinoma in situ, lobular carcinoma in situ, Paget's disease of the nipple, stage I breast cancer, or stage II breast cancer and who are taking tamoxifen.

OBJECTIVES:

* Compare endometrial pathologic diagnoses (proliferative changes, simple or cystic hyperplasia, complex adenomatous hyperplasia, hyperplasia with atypia, and carcinoma) in postmenopausal women with breast carcinoma treated with adjuvant tamoxifen who are randomly assigned to medroxyprogesterone acetate (MA) vs observation.
* Compare endometrial pathologic diagnoses (persistent endometrial hyperplasia, atypia, or carcinoma) resulting in tamoxifen discontinuation and intermittent bleeding in patients treated with these regimens.
* Characterize the incidence of spontaneous regression and progression of simple or cystic hyperplasia in these patients.
* Characterize endometrial biopsy results using different endometrial stripe width cut-off points, for cases in which the width is at least 5 mm by endovaginal ultrasound in patients receiving tamoxifen.
* Compare changes over time in endometrial oncogene expression (e.g., c-fos, c-jun, p53, IGF1) and receptor status in patients receiving tamoxifen with or without prior chemotherapy who are randomly assigned to MA vs observation.
* Describe the associations among change in gene expression, receptor status, endometrial abnormality, length of tamoxifen exposure, and prior chemotherapy in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to adjuvant chemotherapy (yes vs no), number of positive nodes (0-3 vs at least 4), and endovaginal sonogram endometrial stripe (less than 5 mm vs at least 5 mm). Patients are randomized to 1 of 2 arms.

All patients receive adjuvant oral tamoxifen daily for five years.

* Arm I: Patients undergo observation.
* Arm II: Patients receive oral medroxyprogesterone acetate on days 1-14. Treatment repeats every 3 months for 5 years.

Patients are followed every 6 months for 2 years and then annually thereafter.

PROJECTED ACCRUAL: A total of 330 patients (165 per arm) will be accrued for this study.

S9630, Medroxyprogesterone in Treating Women With Breast Cancer

A Randomized Comparison Of Medroxyprogesterone Acetate (MA) And Observation For Prevention Of Endometrial Pathology In Postmenopausal Breast Cancer Patients Treated With Tamoxifen, Phase III

Endometrial pathologic diagnosis at 2 years after registration

Endometrial pathologic diagnosis at 5 years after registration

National Cancer Institute (NCI)

Cancer and Leukemia Group B

SWOG Cancer Research Network

Triple Negative Breast Neoplasms

Precancerous Conditions

Fibrocystic Breast Disease

Carcinoma, Ductal

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Omega 3 Fatty Acid

Docosahexaenoic Acid orally twice a day (PO BID) for 12 weeks.

Placebo orally twice a day (PO BID) for 12 weeks.

Docosahexaenoic Acid

Placebo

Ayca Gucalp

Powel H. Brown, MD

This randomized phase II trial studies how well docosahexaenoic acid works in preventing recurrence in breast cancer survivors. Docosahexaenoic acid supplement may prevent recurrence in breast cancer survivors.

PRIMARY OBJECTIVES:

I. To determine whether treatment with docosahexaenoic acid (DHA) for 12 weeks at 1000 mg twice daily as compared to placebo reduces normal breast tissue levels of tumor necrosis factor-alpha (TNF-alpha) in overweight and obese patients with a history of stage I-III invasive breast cancer, ductal carcinoma in situ (DCIS), Paget's disease, lobular carcinoma in situ (LCIS), or proliferative benign breast disease.

SECONDARY OBJECTIVES:

I. To investigate the effect of DHA at 1000 mg twice daily on tissue biomarkers

* Change from the baseline in cyclooxygenase-2 (COX-2)/interleukin-1-beta (IL-1beta)/aromatase measured by quantitative real-time polymerase chain reaction (PCR).
* Change from the baseline in crown-like structures of the breast (CLS-B) measured by immunohistochemical techniques for cluster of differentiation (CD)68.
* Change from baseline in CLS-B index determined as follows: (\[number of slides with evidence of at least one CLS-B\]/\[total number of slides examined\]).
* Change from baseline in CLS-B/cm\^2 defined as the number of CLS-B/cm\^2. II. Evaluate age as a predictor of CLS-B and inflammatory biomarkers (TNF-alpha/COX-2/IL-1beta) at baseline and over the time of treatment.

III. Evaluate red blood cell (RBC) fatty acid level as a surrogate of compliance.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive docosahexaenoic acid orally (PO) twice daily (BID) for 12 weeks.

ARM II: Patients receive placebo PO BID for 12 weeks.

Study of Docosahexaenoic Acid (DHA) in Triple Negative Breast Cancer Survivors

A Multicenter Phase II Study of Docosahexaenoic Acid (DHA) in Patients With a History of Breast Cancer, Premalignant Lesions, or Benign Breast Disease

Differences in normal breast tissue levels of TNF-α 12 weeks post-treatment relative to pre-treatment for active treatment and placebo arm, compared using analysis of covariance where the post-treatment measurements were used as a dependent variable and the pretreatment measurements were included as a covariate in the analysis. For the primary study end-point TNF-α levels will be measured by quantitative real-time PCR (mRNA essays) on extracted RNA from breast core biopsies. Relative expression determined using the Computed Tomography (ΔΔCT) analysis protocol.

An indicator of whether a subject is detected with CLS-B or not.

To assess the severity of CLS-B using the following formula: number of CLS-B/cm\^2. The absolute change in the CLS-B/cm\^2 calculated according to the formula; Change in CLS-B/cm\^2 = (post-treatment CLS-B/cm\^2) - (pre-treatment CLS-B/cm\^2).

Biomarkers COX-2 are measured by quantitative real-time PCR. Differences between active treatment and placebo arm for each biomarker will be compared using analysis of covariance where the post treatment measurements will be used as a dependent variable and the pretreatment measurements will be included as a covariate in the analysis.

Biomarkers IL-1Beta are measured by quantitative real-time PCR. Differences between active treatment and placebo arm for each biomarker will be compared using analysis of covariance where the post treatment measurements will be used as a dependent variable and the pretreatment measurements will be included as a covariate in the analysis.

Biomarkers Aromatase are measured by quantitative real-time PCR. Differences between active treatment and placebo arm for each biomarker will be compared using analysis of covariance where the post treatment measurements will be used as a dependent variable and the pretreatment measurements will be included as a covariate in the analysis.

Whole blood samples collected for red blood cell fatty acid analyses at baseline and week 12 (+ 2 weeks). RBC fatty acid composition analyzed by gas chromatography (GC) with flame ionization detection.

Docosahexaenoic Acid 1000 mg orally twice a day for 12 weeks.

DHA 1000 mg orally twice a day for 12 weeks.

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Powel H. Brown, MD/Chair, Clinical Cancer Prevention

Baseline

Post-Treatment

Post-treatment vs. Baseline Change

Docosahexaenoic Acid (DHA) 1000 mg orally twice a day for 12 weeks.

6 participants in the Placebo group and 1 participant in the DHA group were not evaluable due to tissue was not available quantitative RT-PCR.

Normal Breast Tissue Expression of Tumor Necrosis Factor Alpha (TNF-alpha) Levels

Post-treatment

Positive both Baseline and Post-treatment

4 participants on the placebo arm and 1 participant on the DHA arm did not have a post treatment biopsy.

Number of Participants With Crown-like Structures of the Breast (CLS-B) at Baseline and Post-treatment

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
S9630, Medroxyprogesterone in Treating Women With Breast Cancer	NCT00002920	Breast Cancer Endometrial Can...	medroxyprogeste... tamoxifen citra... adjuvant therap...	18 Years -	SWOG Cancer Research Network
Study of Docosahexaenoic Acid (DHA) in Triple Negative Breast Cancer Survivors	NCT01849250	Benign Breast N... Ductal Breast C... Invasive Breast... Lobular Breast ... Paget Disease o... Stage IA Breast... Stage IB Breast... Stage IIA Breas... Stage IIB Breas... Stage IIIA Brea... Stage IIIB Brea... Stage IIIC Brea...	Docosahexaenoic... Placebo	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for paget disease of the breast