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Omega 3 Fatty Acid

Participants receive tamoxifen PO QD for 180 days in the absence of unacceptable toxicity. Participants may continue to receive tamoxifen PO QD for up to 60 additional days in the case of scheduling delays. Participants also undergo mammography at screening and undergo RPFNA and collection of blood samples at screening and on study.

Participants receive tamoxifen PO QD and omega-3 fatty acids PO BID for 180 days in the absence of unacceptable toxicity. Participants may continue to receive tamoxifen PO QD and omega-3 fatty acids PO BID for up to 60 additional days in the case of scheduling delays. Participants also undergo mammography at screening and undergo RPFNA and collection of blood samples at screening and on study.

Biospecimen Collection

Mammography

Omega-3-Acid Ethyl Esters

Questionnaire Administration

Random Periareolar Fine-Needle Aspiration

Lauren Nye

Sagar D. Sardesai

This phase II trial evaluates tamoxifen, with or without omega-3 fatty acids, for reducing risk of breast cancer among postmenopausal and overweight or obese women who are at increased risk of developing breast cancer. Tamoxifen is a selective estrogen receptor modulator. It works by blocking the effects of the hormone estrogen in the breast. Tamoxifen is approved by the Food and Drug Administration for prevention of breast cancer in women at increased risk. Omega-3 fatty acids have been shown to decrease the amount of fats made in the liver. Omega-3 fatty acids may work to prevent cancer in overweight or obese individuals. Tamoxifen with or without omega-3 fatty acids may be effective at reducing risk of breast cancer among women who are postmenopausal, overweight or obese, and at increased risk.

PRIMARY OBJECTIVES:

I. To investigate average change in serum adiponectin within the low dose tamoxifen (LDTAM) + high dose omega-3-acid ethyl esters (omega-3 fatty acids) arm.

II. To study the beneficial effects of addition of high dose omega-3 fatty acids to LDTAM by comparing the relative difference in change in serum adiponectin in overweight and obese high-risk postmenopausal women randomized to 6 months of LDTAM or LDTAM + high dose omega-3 fatty acids.

SECONDARY OBJECTIVES:

I. To determine effect of LDTAM +/- high dose omega-3 fatty acids on insulin resistance, insulin sensitivity, and insulin secretory function (homeostatic model assessment for insulin resistance \[HOMA-IR\], homeostatic model assessment of insulin sensitivity \[HOMA%S\] homeostatic model assessment of beta cell function, \[HOMA%B\]), respectively.

II. To determine effect of LDTAM +/- high dose omega-3 fatty acids on benign breast tissue estrogen response gene index (ERGI).

EXPLANATORY OBJECTIVES:

I. Effect of change in red blood cell (RBC) omega-3: omega-6 fatty acid ratio on within arm change in blood adiponectin.

II. Effect of change in RBC omega-3: omega-6 fatty acid ratio on within arm change in tissue ERGI.

III. Effect of baseline bioavailable estradiol on within arm change in blood adiponectin.

IV. Effect of baseline and 6-month bioavailable estradiol on within arm change in tissue ERGI.

V. Effect of 6- month tamoxifen active metabolites (endoxifen and 4-hydroxy \[4OH\] tamoxifen) on change in ERGI.

VI. Effect of eicosapentaenoic acid/docosahexaenoic acid (EPA/DHA) dietary intake as measured by DHA Food Frequency Questionnaire on RBC omega 3:6 fatty acid ratio change.

EXPLORATORY OBJECTIVES:

I. Assess within arm effects of LDTAM +/- high dose omega-3 fatty acids on serum triglycerides.

II. Assess within arm effects of LDTAM+/- high dose omega-3 fatty acids on adiponectin:leptin ratio.

III. Assess within arm effects of LDTAM +/- high dose omega-3 fatty acids on anterior gradient protein 2 homolog (AGR2) messenger ribonucleic acid (mRNA).

IV. Assess within effects of LDTAM +/- high dose omega-3 fatty acids on forkhead box A1 (FOXA1) protein (immunohistochemistry \[IHC\]).

V. Assess within arm effects of LDTAM +/- high dose omega-3 fatty acids on AGR2 protein (IHC).

VI. Assess effects of LDTAM +/- high dose omega-3 fatty acids on Ki-67 (IHC) in individuals with \> 500 cells in baseline ThinPrep and measurable baseline Ki-67.

OUTLINE: Participants are randomized to 1 of 2 groups.

GROUP 1: Participants receive tamoxifen by mouth (PO) once daily (QD) for 180 days in the absence of unacceptable toxicity. Participants may continue to receive tamoxifen PO QD for up to 60 additional days in the case of scheduling delays. Participants also undergo mammography at screening and undergo random periareolar fine needle aspiration (RPFNA) and collection of blood samples at screening and on study.

GROUP 2: Participants receive tamoxifen PO QD and omega-3 fatty acids PO twice daily (BID) for 180 days in the absence of unacceptable toxicity. Participants may continue to receive tamoxifen PO QD and omega-3 fatty acids PO BID for up to 60 additional days in the case of scheduling delays. Participants also undergo mammography at screening and undergo RPFNA and collection of blood samples at screening and on study.

After completion of study intervention, participants are followed up at 21-35 days.

Low Dose Tamoxifen With or Without Omega-3 Fatty Acids for Breast Cancer Risk Reduction

Phase 2 Study of Low Dose Tamoxifen +/- High Dose Omega-3 Fatty Acids in Overweight Postmenopausal Women at Increased Risk for Breast Cancer

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Will evaluate within arm effects of low dose tamoxifen +/- high dose omega-3 fatty acids on this exploratory outcome.

An analysis for difference between the two arms will be conducted to document a beneficial effect of addition of high dose omega-3 fatty acids to low dose tamoxifen. Paired and unpaired t-tests will be used.

Evaluated using Homeostatic Model Assessment of Insulin Resistance, as calculated using fasting glucose and fasting insulin. Paired and unpaired t-tests will be used. Spearman correlation between change in biomarkers will be estimated and compared across the study arms using Fisher's Z-transformed values.

Evaluated using Homeostatic Model Assessment of Insulin Sensitivity. Paired and unpaired t-tests will be used. Spearman correlation between change in biomarkers will be estimated and compared across the study arms using Fisher's Z-transformed values.

Evaluated using Homeostatic Model Assessment of Beta Cell Function. Paired and unpaired t-tests will be used. Spearman correlation between change in biomarkers will be estimated and compared across the study arms using Fisher's Z-transformed values.

The estrogen response gene index reflects change in gene expression over time. The genes assayed for this index are: ESR1 (codes for estrogen receptor alpha), ESR2 (codes for estrogen receptor beta), GREB1 (codes for growth regulation by estrogen in breast cancer 1), PGR (codes for progesterone receptor) and TFF1 (also known as pS2, which codes for trefoil factor 1). The log2-transformed values of the ratio of relative abundance (6-month value: baseline value) for GREB1, PGR, TFF1, and the ratio of ESR1:ESR2 are averaged to produce the ERGI. Paired and unpaired t-tests will be used. Spearman correlation between change in biomarkers will be estimated and compared across the study arms using Fisher's Z-transformed values.

National Cancer Institute (NCI)

Afimoxifene

Topical 4-OHT (4-hydroxytamoxifen) gel 4 mg/each breast/day

+oral placebo

Topical 4-OHT (4-hydroxytamoxifen) gel 4 mg/each breast/day

Topical 4-OHT( 4-hydroxytamoxifen)gel 4 mg/each breast/day

Placebo

Denice Gehling, RN

Lisa R Seymour

Zachary Feldman

Seema Khan, M.D.

Denice Gehling, R.N.

Lisa Seymour, B.S

Amy Degnim, M.D.

The investigators plan to prospectively study breast tissue changes after a short course of Tamoxifen (Tam).

Women with atypical hyperplasia (AH) and lobular carcinoma in situ (LCIS) are at increased risk of breast cancer (BC) (\~1-2 % per year). Over two decades ago, placebo-controlled randomized trials established that oral tamoxifen (20 mg/day) reduces breast cancer risk by 50% in generally defined high risk women, with \~70% reduction in women at high risk specifically due to atypical hyperplasia.\[1\] Years later, the side effects and toxicity of oral tamoxifen at 20 mg/day remain a significant barrier to its uptake and longterm compliance.\[2, 3\] To address the issue of toxicity, two main strategies have been pursued: 1) using a lower dose of oral tamoxifen, and 2) using a topical formulation of tamoxifen to avoid systemic side effects. The investigators will perform a prospective study of women with AH or LCIS who will take a short course of prevention therapy; breast tissue samples will be evaluated pre- and post-therapy to identify and evaluate very early biomarkers of response. The overall goal of the study is to evaluate short-term changes in background breast tissue induced by either low-dose oral tamoxifen or topical 4-OHT gel in women with AH or LCIS.

Subjects will be randomized 2:2:1 with either Oral Tamoxifen 10 mg/day

* gel placebo, Topical 4-OHT gel 4 mg/each breast/day
* oral placebo, or Control Oral and gel placebo for 4 weeks of treatment.

Subjects with be randomized by MedidataRave and Pharmacy.

Oral Tamoxifen vs. TamGel vs. Control in Women With Atypical Hyperplasia or Lobular Carcinoma In Situ

A Phase IIB Randomized Trial of Oral Tamoxifen vs. Topical 4-hydroxytamoxifen Gel vs. Control in Women With Atypical Hyperplasia or Lobular Carcinoma In Situ

Treatment Evaluation/Measurement of Effect

Amy C. Degnim

Principal Investigator

Menopause

Patients receive acolbifene PO QD for 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo 3D mammography and collection of blood samples during screening and at the end of acolbifene treatment. In addition, patients undergo RPFNA during screening and during day 1-10 of their menstrual cycle, or if not menstruating, at the convenience of the patient and study staff.

Patients receive tamoxifen PO QD for 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo 3D mammography and collection of blood samples during screening and at the end of tamoxifen treatment. In addition, patients undergo RPFNA during screening and day 1-10 of their menstrual cycle, or if not menstruating, at the convenience of the patient and study staff.

Acolbifene Hydrochloride

Lisa D. Yee

Seema A. Khan

Carol J. Fabian

Carol J Fabian

This phase IIA trial compares the effect of acolbifene versus low dose tamoxifen in preventing breast cancer in premenopausal women at high risk for developing breast cancer. The usual approach for patients at increased risk for breast cancer is to undergo yearly breast magnetic resonance imaging (MRI) or ultrasound in addition to yearly mammogram. Premenopausal women at very high lifetime risk for breast cancer (greater than 50%) can consider preventive removal (mastectomy) of both breasts. Premenopausal women age 35 or older with a prior diagnosis of atypical hyperplasia, lobular carcinoma in situ, or an estimated 10-year risk of greater than or equal to 3% or estimated 10-year risk of greater than or equal to 2-5 times that of the average woman (depending on age) may be advised to consider five years of standard dose tamoxifen. Standard dose tamoxifen is four times the dose used in this study. Estrogen can cause the development and growth of breast cancer cells. Acolbifene and tamoxifen blocks the use of estrogen by breast cells. This study may help researchers measure the effects of acolbifene and low dose tamoxifen on markers of breast cancer risk in mammogram imaging, breast tissue, and in blood samples.

PRIMARY OBJECTIVE:

I. To determine if there is a difference in change in expression of the endocrine resistance gene anterior gradient 2 (AGR2) in benign breast tissue of premenopausal women at increased risk for breast cancer randomized to acolbifene 20 mg vs tamoxifen 5 mg orally daily for 6 months.

SECONDARY OBJECTIVES:

I. To determine if there is significant within-arm effect of 6 months of acolbifene 20 mg or tamoxifen 5 mg as assessed on the Estrogen Response Gene Index (ERGI) in benign breast tissue.

II. To determine if there is significant within-arm effect of 6 months of acolbifene 20 mg or tamoxifen 5 mg on mammographic density as measured by relative change in % dense area (LIBRA \[Trademark\]).

III. Assess the feasibility of assessment of change in absolute fibroglandular volume (FGV) and % dense volume (Volpara \[Trademark\]) in a multisite trial.

IV. To determine if there is a significant within-arm effect of 6 months of acolbifene 20 mg or tamoxifen 5 mg on Menopause-Specific Quality of Life Questionnaire (MENQOL) or Hot Flash Score.

EXPLORATORY OBJECTIVES:

I. Assess within arm change in breast epithelial cell protein expression of Ki-67 in specimens with \>= 2% baseline Ki-67.

II. Assess within arm change in bioavailable serum estradiol, testosterone, progesterone.

III. Association of baseline AMH (\>= 1 ng/ml associated with normal ovarian reserve) with 6-month serum estradiol and change in tissue estrogen responsive gene expression (ERGI and AGR2).

IV. Association of tamoxifen and acolbifene parent drug and active metabolite levels with change in tissue estrogen response genes and mammographic density.

V. Assess within arm change of AGR2, FOXA1, estrogen receptor (ER), progesterone receptor (PR) by immunohistochemistry (IHC) on residual fixed random periareolar fine needle aspiration (RPFNA) specimens processed to blocks.

VI. Assess within arm change in metabolic measures including triglycerides, measures of insulin sensitivity and thyroid binding globulin (University of Kansas Medical Center \[KUMC\] participants only).

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I: Patients receive acolbifene orally (PO) once daily (QD) for 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo three-dimensional (3D) mammography and collection of blood samples during screening and at the end of acolbifene treatment. In addition, patients undergo RPFNA during screening and on day 1-10 of their menstrual cycle, or if not menstruating, at the convenience of the patient and study staff.

GROUP II: Patients receive tamoxifen PO QD for 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo 3D mammography and collection of blood samples during screening and at the end of tamoxifen treatment. In addition, patients undergo RPFNA during screening and day 1-10 of their menstrual cycle, or if not menstruating, at the convenience of the patient and study staff.

After completion of study treatment, patients are followed up between 21-35 days.

Acolbifene Versus Low Dose Tamoxifen for the Prevention of Breast Cancer in Premenopausal Women at High Risk for Development of Breast Cancer

Phase IIA Trial of Acolbifene (20 mg) vs Low Dose Tamoxifen (5 mg) in Pre-Menopausal Women at High Risk for Development of Breast Cancer

Will be assessed in benign breast tissue acquired by random periareolar fine-needle aspiration (RPFNA). Change over the intervention period is expressed as the ratio of the relative abundance values (6-month value: baseline value) and then this fold change (FC) value is log transformed (base 2) for analysis. For this variable, values of zero indicate no change in the relative abundance of AGR2; positive values indicate an increase in the relative abundance; and negative values a decrease in the relative abundance.

The genes assayed for this index are: ESR1, ESR2, GREB1, progesterone receptor (PGR), and TFF1. The log2-transformed values of the ratio of relative abundance (6-month value: baseline value) for GREB1, PGR, TFF1, and the ratio of ESR1:ESR2 are averaged to produce the ERGI. In cases where a specific gene or ratio cannot be evaluated for change over time, it is omitted from the average.

Will be assessed via the completely automated LIBRA (Trademark) software program. This will be performed from Digital Imaging and Communications in Medicine processed image files. Will also assess the feasibility of obtaining the Volpara (Trademark) scorecard for volumetric assessments as the volume of density (absolute or % breast volume). The volumetric measures may be less susceptible to technical variance (such as compression) than area of density. We will assess relative change between baseline and 6-month fibroglandular volume determinations.

The responses to the 32 questions (will ask about symptoms over prior week) are clustered into four domains (vasomotor, psychosocial, physical, sexual). Worsening of problems (higher scores) over the course of the intervention will assessed by average scores for each of the four individual domains as well as the total MENQOL score.

The Hot Flash Score uses the product of the average number of hot flash/night sweat episodes per day and the average intensity (0= N/A, not experienced; 1= Mild; 2= Moderate; 3= Severe; 4= Very Severe).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Low Dose Tamoxifen With or Without Omega-3 Fatty Acids for Breast Cancer Risk Reduction	NCT06195306	Breast Atypical... Breast Carcinom... Breast Ductal C... Breast Lobular ...	Biospecimen Col... Mammography Omega-3-Acid Et... Questionnaire A... Random Periareo... Tamoxifen	45 Years - 65 Years	National Cancer Institute (NCI)
Oral Tamoxifen vs. TamGel vs. Control in Women With Atypical Hyperplasia or Lobular Carcinoma In Situ	NCT04570956	Breast Atypical... Breast Lobular ... Breast Atypical...	Tamoxifen Topical 4-OHT( ... Placebo	18 Years - 80 Years	Mayo Clinic
Acolbifene Versus Low Dose Tamoxifen for the Prevention of Breast Cancer in Premenopausal Women at High Risk for Development of Breast Cancer	NCT05941520	Breast Atypical... Breast Carcinom... Breast Ductal C... Breast Lobular ...	Acolbifene Hydr... Biospecimen Col... Mammography Random Periareo... Tamoxifen	35 Years -	National Cancer Institute (NCI)
Low Dose Tamoxifen With or Without Omega-3 Fatty Acids for Breast Cancer Risk Reduction	NCT06195306	Breast Atypical... Breast Carcinom... Breast Ductal C... Breast Lobular ...	Biospecimen Col... Mammography Omega-3-Acid Et... Questionnaire A... Random Periareo... Tamoxifen	45 Years - 65 Years	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for breast atypical hyperplasia