Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

This research study is designed to work in cooperation with another study being conducted by the National Cancer Institute. The National Cancer Institute (NCI) is studying the effects of a drug called raloxifene on premenopausal women believed to have a high risk of developing breast cancer (98-C-0123).

In this study, researchers are interested in learning about the effects of raloxifene on the uterus and ovaries of the women participating in the NCI study. To do this researchers plan to conduct ultrasounds on the patients enrolled in the NCI study. In addition researchers plan to take samples of the lining of the uterus in these patients (endometrial biopsy) if found to be necessary.

The purpose of this study is to determine the reproductive effects of raloxifene on women who have normal functioning ovaries by taking ultrasounds of the ovaries and lining of the uterus (endometrium).

Raloxifene is a selective estrogen receptor-modulating agent that has been recently approved by the FDA for the treatment of osteoporosis in postmenopausal patients. A phase II trial evaluating the safety and efficacy of raloxifene in premenopausal patients at high risk for developing breast cancer has been recently approved by the IRB (98-C-0123). In this protocol, for assessment of the effects of raloxifene on the endometrium and ovaries, patients are scheduled to be studied with transvaginal sonography and hysterosonography, once during their menstrual cycle at periodic intervals. They are also scheduled to have endometrial biopsies as indicated. It is known that all SERMs (clomiphene, tamoxifen and in one small study raloxifene) raise the area under the curve of estradiol levels throughout the cycle in premenopausal women. Our study is designed to study the reproductive effects of raloxifene in these young women with competent ovaries using sonography of the ovaries and endometrium, and correlating it with steroid hormone levels which would be obtained under protocol 98-C-0123.

Effects of Raloxifene on the Uterus and Ovaries of Premenopausal Patients

Sonographic Evaluation of the Effects of Raloxifene on the Uterus and Ovaries in Premenopausal Patients at High Risk for Developing Breast Cancer

National Institutes of Health Clinical Center (CC)

Immune System Diseases

Hypersensitivity

Central Nervous System Depressants

All Drugs and Chemicals

Bone Density Conservation Agents

Antineoplastic Agents

Anesthetics

Tamoxifen

Hormones

Estrogens

Anesthetics, Local

Goserelin

Progesterone

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormone Antagonists

Antineoplastic Agents, Hormonal

Estrogen Receptor Modulators

Selective Estrogen Receptor Modulators

Patients should be premenopausal women ,prior to the start of chemotherapy, less than or equal to 45 years of age with oestrogen receptor positive ± progesterone receptor positive who have undergone a primary mass excision, received an neo-/adjuvant chemotherapy ± radiotherapy for their stage I, II or III breast cancer. This arm is ovarian suppression group which have a various starting time of ovarian function suppression after neo-/adjuvant chemotherapy.

Ovarian function suppression will be done by administration of LHRH agonist (ZOLADEXTM) for 2 years. After that, the patients will complete taking tamoxifen 20mg/day for 5 years.

Patients, less than or equal to 45 years of age with hormone receptor positive breast cancer will be enrolled. Included All the patients have already treated by surgery, neo- or adjuvant chemotherapy ±and/or radiotherapy before enrolment. At 0, 6, 12, 18 and 24 months since the baseline asTsessment(0), the ovarian function status will be evaluated by menstruation status or serum FSH level. If the patients are regarded as the premenopausal women, they will be randomized into the additional ovarian function suppression group or tamoxifen only group. The latter will complete taking tamoxifen 20mg/day for 5 years.

Patients, less than or equal to 45 years of age with hormone receptor positive breast cancer will be enrolled. Included All the patients have already treated by surgery, neo- or adjuvant chemotherapy ±and/or radiotherapy before enrolment. Eligible patients except for premenopausal status at the baseline will be followed up until 2 years after the baseline assessment for evaluating the menopausal status. This group still remains to postmenopausal status and will taking tamoxifen 20mg/day for 5 years if they remain in the study.

Patients, less than or equal to 45 years of age with hormone receptor positive breast cancer will be enrolled. Included All the patients have already treated by surgery, neo- or adjuvant chemotherapy ±and/or radiotherapy before enrolment. At 6, 12, 18 and 24 months since the baseline assessment (0), the ovarian function status will be evaluated by menstruation status or serum FSH level. If the patients are regarded as the premenopausal women, they will be randomized into the additional ovarian function suppression group or tamoxifen only group. This group, patients are premenopausal women, they will be randomized into tamoxifen only group, complete taking tamoxifen 20mg/day for 5 years.

Patients, less than or equal to 45 years of age with hormone receptor positive breast cancer will be enrolled. Included All the patients have already treated by surgery, neo- or adjuvant chemotherapy ±and/or radiotherapy before enrolment. At 6, 12, 18 and 24 months since the baseline assessment (0), the ovarian function status will be evaluated by menstruation status or serum FSH level. If the patients are regarded as the premenopausal women, they will be randomized. This group, patients are premenopausal women, they will be randomized into the additional ovarian function suppression group. Ovarian function suppression will be done by administration of LHRH agonist (ZOLADEXTM) for 2 years. Then, Patients will complete taking tamoxifen 20mg/day for 5 years.

1. Zoladex™ administration:

   Zoladex™ depot is available as a sterile disposable syringe. The depot is administered subcutaneously under the abdominal skin under sterile conditions. If necessary the injection site may be pre-treated with a local anaesthetic.
2. Sequence of administration Zoladex depot:

   The substance is administered for 24 months (2 years) at 28-day intervals (a period of 34 days between 2 administrations must not be exceeded).
3. Dosage:

   Each depot contains 3.6mg Zoladex. The substance Zoladex is contained in a while cylindrical rodlet .
4. Storage instructions for Zoladex™ Zoladex™ is kept a room temperature.

goserelin

1. Dose and period of Tamoxifen therapy:

   Tamoxifen is administered in tablet form. Each day 2 X 10 mg or 1 X 20 mg Tamoxifen are taken in the form of the respective tablet.
2. Storage instructions for Tamoxifen Tamoxifen is stored at room temperature away from light.

tamoxifen

Woo-Chul Noh, MD.PhD

The purpose of this study is to compare 5-year disease free survival rate (DFS rate) between the hormone receptor positive breast cancer patients who were added Goserelin to Tamoxifen for ovarian function suppression after neo-/adjuvant cytotoxic chemotherapy and the hormone receptor positive breast cancer patients who were treated with Tamoxifen.

* To compare overall Survival(OS) between the patients added Goserelin(ZOLADEXTM) to Tamoxifen and the patients treated with Tamoxifen alone in premenopausal status
* To compare 5-year disease free survival rate (DFS rate) between the patients who took tamoxifen only in postmenopause and the patients added Goserelin(ZOLADEXTM) to Tamoxifen for inducing ovarian function suppression in premenopause
* To determine the tolerability and safety of Tamoxifen with or without concomitant Zoladex

Evaluating the Role of the Addition of Ovarian Function Suppression (OFS) to Tamoxifen in Young Women

A Randomised Phase III Study for Evaluating the Role of the Addition of Ovarian Function Suppression to Tamoxifen in Young Women With Hormone-Sensitive Breast Cancer Who Remain in Premenopause or Regain Menstruation After Chemotherapy

Korean Breast Cancer Study Group

Woo-Chul, Noh

3,3'-diindolylmethane

75 mg of 3,3´-diindolylmethane (DIM) once a day for 30 days

Two pills of BioResponse DIM® 150 are equal to 75 mg of DIM pure

DIM pills

Placebo pills, proportionate by the same provider, vials and pills were the same size, shape and material containing the DIM pills

Placebo Pill

Breast cancer is a public health problem in Mexico and its incidence rises when the woman is still premenopausal. Estrogen metabolism has been linked to breast cancer. Several studies reported that high concentrations of 2 hydroxyestrone (2OHE1) in urine have a protective effect for this neoplasia, whereas high concentrations of 16 alpha-hydroxyestrone (16αOHE1) in urine have the opposite effect, further has been reported that women with a ratio of estrogen metabolites 2OHE1:16αOHE1 in urine (REMU) less than 0.9, have ten times the risk of developing Breast Cancer than those women with an RMEU equal or more than 0.9. Other studies have showed that the active compounds of cruciferous vegetables, indole-3-carbinol (I3C) and its dimer, 3'3'diindolylmethane (DIM) induce benign pathway of metabolism of estrogens producing 2OHE1. Several studies, evaluate the pharmacokinetics and effect of I3C supplementation, finding that 300 to 600 mg of this compound are well tolerated and able to promote formation of 2OHE1 in women when supplemented for one month. In the case of DIM, only a pilot study has explored its effect in postmenopausal women with personal history of breast cancer in early stages, reporting an increase in the concentrations of 2OHE1. The purpose of this study was to evaluate the effectiveness of supplementation with DIM to increase urinary RMEU in premenopausal women at risk of Breast Cancer (RMEU less than 0.9). A clinical, randomized, double-blind study was performed with women attending on the urogynecology service of Institute National of Perinatology. Subjects were premenopausal women over 34 years who were healthy. The inclusion criteria's was had a RMEU less than 0.9 and were excluded for any medical condition, medication, or dietary or lifestyle habit that might interfere with estrogen metabolism. Patients were randomly assigned to one of two groups: one received orally at a daily dose of 75 mg of DIM for a period of 30 days and other group received orally at a daily placebo for a period of 30 days. All urine samples were collected from the women before DIM or placebo ingestion, after 30 days of DIM or placebo ingestion and finally after another 30 days once suspended supplementation. Analysis of the 2OHE1 and 16αOHE1 were determined using a commercially kit ESTRAMET™. The change in metabolites median concentrations and RMEU was assessed through the Wilcoxon test and these differences between groups through U Mann-Whitney test.

The purpose of this study was to evaluate the effectiveness of supplementation with 3,3´-Diindolylmethane (DIM) to increase the urinary ratio of estrogen metabolites 2OHE1:16alphaOHE1 (RMEU) in women at risk of breast cancer to contribute to generate a tool of early prevention of this disease.

Activities for detect women with REMU less than 0.9:

Check every day in the Institute National of Perinatology urogynecology service, clinical records of the women who attending consultations in order to verify the inclusion and exclusion criteria.

Interviewing these women to corroborate the inclusion and exclusion criteria. Quantify the concentrations of metabolites of estrogens in the urine for detect the presence of REMU less than 0.9.

Provide result and invite women who present REMU less than 0.9 to participate in the project of supplementation with DIM.

When women had a REMU equal or greater than 0.9, provide result and dietary guidance focused on maintaining BMI in normal range (19.0-24.9) or decrease (BMI more than or equal to 25) weight and the increase in the consumption of fruits and vegetables.

Activities for women inclusion in the study of DIM supplementation:

Once explained the study to the patients, women who met the criteria for inclusion were cited to provide an informed consent letter mentioning them that they had the freedom to clarify any doubt that might arise.

Once the woman read out the letter, understood it and agreed to participate, the signing of this was requested.

On the same date that each woman has signed the letter, another appointment was scheduled between day 12 and 15 of the menstrual cycle for the following assessments:

Personal data: Name, date of birth, address, phone, marital status and occupation.

Socioeconomic: With the criteria of the Mexican Association of Agencies of Market and Opinion based 2005

Complete clinical history that included:

Family history of chronic diseases included breast cancer, personal history of diseases and use medication, personal risk factors of breast cancer, type, frequency and duration of physical activity.

Nutrition: Whereas both anthropometric indicators (weight, height and perimeter wrist, waist and hip), body composition (% of body fat and lean mass by the method of displacement of air) and diet (24-hour recall, frequency of consumption of cruciferous vegetables in the last year and use of supplements). The measurements of anthropometric indicators were made using the LOHMAN technique. The information was processed with the NUTRIKCAL system that is standardized for foods commonly consumed in Mexico.

First morning urine. First morning urine with a difference no less than eight hours of previous urine.

Once urine samples were received, added them, for conservation, 0.1 g of ascorbic acid per 10 mL of urine, and stored at -70°C until it´s quantification.

For the analysis of the metabolites 2OHE1 and 16αOHE1, was used a competitive solid phase enzyme immunoassay method, using the commercial kit ESTRAMET™ 2/16 (Immune Care Corporation, Bethlehem, MI. USA), which was validated by the manufacturer by gas chromatography and mass spectrometry. The analysis was performed according to the manufacturer's instructions; briefly: the urine sample was hydrolyzed with an enzyme beta glucuronidase and sulfatase activities. The free urinary metabolites, joined to monoclonal antibodies conjugated with alkaline phosphatase. The quantification of metabolites 2OHE1 and 16αOHE1 were performed in triplicate and the reproducibility of this method has already been reported by our team in a study. For each of the determinations of the RMEU were reference curves, achieving a 97% of accuracy.

Adherence and side effects. In the first assessment is gave women a calendar to daily record consumption or omission of the supplement (active compound or placebo) as well as a series of side effects in order to assess the adherence and safety of supplement. This included side effects that had already been reported in other studies with DIM and I3C. In addition requested participants return the supplements vial to subsequently make the count of pills that were left over.

Sample size.

To estimate the sample size it was considered the following:

Two sets of comparison (Placebo and 75mg DIM). According to literature and hoping to find a difference of .48 in the average of RMEU of the group of supplementation relative to the placebo group.

Other studies have reported a standard deviation of .77 on the RMEU. Calculated with an alpha of 0.05 and a power of 80%. Approximately 31 women are required by group plus 10% to replace losses in the follow-up, which gives an approximate total of 35 women per group.

Statistical Analysis. The statistical analysis of data was carried out in the following way: the differences between baseline characteristics was performed using the student T test for parametric variables with normal distribution, U Mann-Whitney for those who did not have a normal distribution and X2 for the nonparametric. The change of estrogen metabolites and RMEU in each group was evaluated using the Wilcoxon test and the comparison of the effect between groups, the values of concentrations of the metabolites of estrogen and the RMEU as well as their differences, was carried out by means of the test U Mann-Whitney.

Masking. A stranger to the study researcher, received and coded vials containing the DIM supplement and placebo, recording the code in a role that was kept in an envelope that was opened at the end of the study.

Effectiveness of DIM Supplements to Increase 2-OHE1/16 Ratio

Effectiveness of DIM Supplements to Increase 2-OHE1/16 Ratio in Premenopausal Mexican Women With Risk of Breast Cancer

First pregnancy after 35 years or no living children

Have at least one first-degree or second degree family, who has had or have the disease

According to the committee of socioeconomic levels of the Mexican Association of Market Research Agencies and Public Opinion (AMAI)

Number of portions per day (1 cup raw or 1/2 cup cooked) of any cruciferous vegetables

A schedule was provided to the patients to record the daily intake of the supplement DIM/placebo

A schedule was provided to the patients to record daily the presence of side effects that have been reported in other studies such as diarrhea, nausea , vomiting , headache and flatulence.

Instituto Nacional de Perinatologia Isidro Espinosa de los Reyes

Researcher in Medical Sciences B

Menopause

Reproductive Control Agents

Letrozole

Triptorelin Pamoate

Zoledronic Acid

Aromatase Inhibitors

Enzyme Inhibitors

Contraceptive Agents

Contraceptive Agents, Female

Contraceptive Agents, Hormonal

Triptorelin 3.75 mg IM every 4 weeks and Tamoxifen 20 mg daily, for 5 years

Triptorelin 3.75 mg IM every 4 weeks and Letrozole 2.5 mg daily, for 5 years

Triptorelin 3.75 mg IM every 4 weeks and Letrozole 2.5 mg daily for 5 years + zoledronic acid 4 mg every 6 months.

Premenopausal patients will receive triptorelin 3.75 mg IM at the beginning of therapy and every 4 weeks for 5 years or up to age 55

triptorelin

letrozole

zoledronic acid

Andrea De Matteis, M.D.

Ciro Gallo, M.D., Ph.D.

Francesco Perrone, M.D., Ph.D.

The HOBOE study was amended in November 2009, and, after reaching enrollment of the first 500 patients, the study began recruiting premenopausal patients only. The primary objective of the extended study is to compare disease free survival in premenopausal patients with early breast cancer. Patients receive triptorelin and are randomized in a 1:1:1 fashion to receive tamoxifen or letrozole, or letrozole + zoledronic acid.

The purpose of the HOBOE study, Version 1, was to compare the adjuvant hormonal therapy treatments of Tamoxifen, Letrozole and Letrozole + Zoledronate for their effects on bone loss in breast cancer patients. Postmenopausal and premenopausal patients were eligible, the latter also receiving monthly triptorelin. Upon reaching the enrollment of the first 500 patients in March 2010, the study began recruiting premenopausal patients only.

HOBOE: A Phase 3 Study of Adjuvant Triptorelin and Tamoxifen, Letrozole, or Letrozole and Zoledronic Acid in Premenopausal Patients With Breast Cancer.

Phase III Randomized Study of the Effects on Bone Mineral Density of Tamoxifen, Letrozole, and Letrozole + Zoledronic Acid as Adjuvant Treatment of Patients With Early Breast Cancer; VERSION 2 AMENDED Phase 3 Study of Triptorelin and Tamoxifen, Letrozole, or Letrozole + Zoledronic Acid in Adjuvant Treatment of Premenopausal Endocrine Responsive Breast Cancer Patients.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Effects of Raloxifene on the Uterus and Ovaries of Premenopausal Patients	NCT00001837	Breast Cancer Breast Neoplasm		-	National Institutes of Health Clinical Center (CC)
Evaluating the Role of the Addition of Ovarian Function Suppression (OFS) to Tamoxifen in Young Women	NCT00912548	Breast Cancer	goserelin tamoxifen	18 Years - 45 Years	Korean Breast Cancer Study Group
Effectiveness of DIM Supplements to Increase 2-OHE1/16 Ratio	NCT02525159	Breast Cancer	DIM pills Placebo Pill	35 Years - 52 Years	Instituto Nacional de Perinatologia Isidro Espinosa de los Reyes
HOBOE: A Phase 3 Study of Adjuvant Triptorelin and Tamoxifen, Letrozole, or Letrozole and Zoledronic Acid in Premenopausal Patients With Breast Cancer.	NCT00412022	Breast Cancer	tamoxifen triptorelin letrozole zoledronic acid	18 Years -	National Cancer Institute, Naples

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